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I'm Not As Slim As That Mouse

The Agony of Genetically Disrupted Melanocortin Receptors (MC4R).

A new study suggests that blocking MC4R function in the central nervous system of rodents produces obesity by altering lipid metabolism and promoting fat deposition (Nogueiras et al., 2007). This effect was independent of food intake, suggesting a possible genetic propensity for obesity in humans (at least in a small percentage of the population). Wikipedia notes that

Defects in MC4R are a cause of autosomal dominant obesity, accounting for 6% of all cases of early-onset obesity (Farooqi et al., 2003).

Conversely, stimulation of MC4R increases lipid mobilization (Nogueires et al., 2007) and reduces food intake (Adan et al., 2006). Thus,

Brain clue could provide anti-obesity drugs

... Experiments on rats have shown that a part of the brain called the hypothalamus helps determine how much food energy is stored, raising the possibility of a new kind of anti-obesity drug.

Matthias Tschöp of the University of Cincinnati in Ohio used drugs that either stimulated or blocked receptors for the hormone melanocortin on hypothalamus cells in the brains of rats. Those given stimulatory drugs burned more of the carbohydrates in food, while those given inhibitory drugs converted them to fat and made extra fat in their liver (The Journal of Clinical Investigation).

Tschöp thinks the receptors communicate with fat and liver cells through the sympathetic nervous system, which also controls heartbeat and digestion. The same system may exist in humans, he believes, because people with faulty melanocortin receptors are often morbidly obese.

The paper by Nogueiras et al. (PDF freely available) contains this wonderful diagram of how blocking melanocortin receptors affects fat storage and metabolism.


Figure 8 (Nogueiras et al., 2007). Schematic overview summarizing the physiological effects of CNS-Mcr blockade on peripheral tissues. Blockade of CNSMcr decreases thermogenesis and glucose utilization in BAT [brown adipose tissue]; decreases glucose utilization in muscle; increases TAG [triglyceride] content, lipoprotein assembly, and secretion in liver; and increases TAG synthesis and uptake as well as glucose uptake and insulin sensitivity in fat tissue. Combined, these parallel metabolic changes in multiple tissues represent a synergistic shift in substrate choice and nutrient partitioning, resulting in increased energy storage.

References

Adan RA, Tiesjema B, Hillebrand JJ, la Fleur SE, Kas MJ, de Krom M. (2006). The MC4 receptor and control of appetite. Br J Pharmacol. 149:815-27.

Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S (2003). Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348:1085-95.

Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM, Howles PN, Morgan DA, Benoit SC, Szanto I, Schrott B, Schurmann A, Joost HG, Hammond C, Hui DY, Woods SC, Rahmouni K, Butler AA, Farooqi IS, O'rahilly S, Rohner-Jeanrenaud F, Tschop MH. (2007). The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest. 2007 Sep 20; [Epub ahead of print].

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.


Obscurely Self-Referential

Obscure reference #1: I'm Not As Slim As That Girl

Obscure reference #2: The Joy Of Melanocortin Receptors

On Your NeuroMark, Get Set...

...it's not set to GO yet!

Oops, it seems that someone [The Lane Communications Group??] jumped the gun in submitting this press release for publication, because the company's website isn't ready yet:

NeuroMark

We are very sorry to inconvenience you. However, the informational site we are preparing for the Mark-C test for predicting risk for suicidal ideation when taking Citalopram is scheduled to be available on October 1st.

The availability of our test was to be announced October 1st to the national media. However, through an inadvertent technical error, the American Journal of Psychiatry publication was published online October 27th [sic], ahead of the October 1st embargoed date.

We are working diligently to make our site available to you as quickly as we can....

Their product? It's REALLY a big deal, if it turns out to be true:

Genetic test announced for suicidal ideation in patients using antidepressant drugs
Safer prescribing anticipated

Boulder, CO, October 1, 2007 – NeuroMark, a Boulder, Colorado company, announced today the immediate availability of a genetic test to identify people at risk of suicidal ideation—thoughts of committing suicide—when prescribed an antidepressant drug. The test, called the Mark-C™ test, is expected to help restore public confidence in antidepressant medication and help to reduce a recently announced spike in suicide rates among U.S. youth. “This is an exciting example of the power of genetics to address a critical need and make important drugs safer for patients worldwide,” stated Kim Bechthold, NeuroMark’s CEO.

In September 2007, the Centers for Disease Control (CDC), announced that in 2004 there was a 8% rise in suicide rates among 10-19 year olds, the year that the FDA issued public health warnings linking antidepressant drugs with suicidal ideation and behavior. "The largest percentage increase in rates from 2003 to 2004 was among females aged 10—14 (75.9%), followed by females aged 15—19 years (32.3%) and males aged 15—19 years (9%)," according to the CDC.

In a statement, the company said, “We feel a sense of responsibility, given the current climate, to provide the test to physicians immediately so that they may identify patients who would benefit from closer monitoring or even a change in therapy. It is our hope that this early test will encourage more people to consider antidepressant drug treatment who would benefit from it."

"Before the NeuroMark test, we couldn’t differentiate between the subset of patients who were at risk of suicidal ideation and those who could more safely take an antidepressant drug," stated NeuroMark president Dr. Peter Tolias. “The Mark-C test is highly predictive and identifies citalopram-treated patients who are at high risk for suicidal ideation. The test also identifies people at low risk, giving the physician more confidence in prescribing citalopram," he added.

Here's the relevant citation in the American Journal of Psychiatry:

Gonzalo Laje, Silvia Paddock, Husseini Manji, A. John Rush, Alexander F. Wilson, Dennis Charney, and Francis J. McMahon (2007). Genetic Markers of Suicidal Ideation Emerging During Citalopram Treatment of Major Depression. Am J Psychiatry 164:1530-1538.

Yesterday, World of Psychology had a post about this paper:

Suicidal Genes Discovered
By John M. Grohol, Psy.D.
September 26th, 2007

The Oct. 1 issue of The American Journal of Psychiatry will release both a study and editorial suggesting that a set of suicidal gene markers have been discovered. That is, people with these markers have a higher incidence of suicidal thinking (which is often the precursor to suicidal action). This is a significant finding, since there has been little previous evidence that suicidal thoughts or behaviors might be coded all the way down into our genes.

. . .

Rumor has it that a company will also be marketing a genetic test kit for this set of “suicide markers.”

Why yes, that rumor appears to be true.

The Insulta and Anorexia

graphic adapted from the New York Times

Neurophilosophy points to a silly typo in a serious press release about a neuroimaging study in women who have recovered from anorexia nervosa:

Sense of taste different in women with anorexia nervosa

Imaging study finds brain changes associated with the regulation of appetite

Although anorexia nervosa is categorized as an eating disorder, it is not known whether there are alterations of the portions of the brain that regulate appetite. Now, a new study finds that women with anorexia have distinct differences in the insulta – the specific part of the brain that is important for recognizing taste – according to a new study by University of Pittsburgh and University of California, San Diego researchers currently on line in advance of publication in the journal Neuropsychopharmacology.

Oops!!

graphic adapted from the New York Times

The ORIGINAL press release from University of California, San Diego Medical Center spells "insula" correctly and goes on to state:

The study also implies that there may be differences in the processing of information related to self-awareness in recovering anorexics compared to those without the illness – findings that may lead to a better understanding of the cause of this serious and sometimes fatal mental disorder.

. . .

In response to both the sucrose and water, imaging results showed that women who had recovered from anorexia had significantly reduced response in the insula and related brain regions when compared to the control group. These areas of the brain recognize taste and judge how rewarding that taste is to the person. In addition, while the controls showed a strong relationship between how they judged the pleasantness of the taste and the activity of the insula, this relationship was not seen in those who had recovered from anorexia.

On the other hand, one could have expected the recovered anorexic women to show greater activity in the insula (Ellison et al., 1998), because this region is known to be activated in response to disgust.

References

Ellison Z, Foong J, Howard R, Bullmore E, Williams S, Treasure J. (1998). Functional anatomy of calorie fear in anorexia nervosa. Lancet 352:1192.

Wagner A, Aizenstein H, Mazurkewicz L, Fudge J, Frank GK, Putnam K, Bailer UF, Fischer L, Kaye WH. (2007). Altered Insula Response to Taste Stimuli in Individuals Recovered from Restricting-Type Anorexia Nervosa. Neuropsychopharmacology May 9; [Epub ahead of print].

Anorexia nervosa (AN) is an illness characterized by aversion to ingestion of normally palatable foods. We examined whether there is a primary disturbance of taste processing and experience of pleasure using a sucrose/water task in conjunction with functional magnetic resonance imaging (fMRI). To avoid confounding effects of illness, 16 women recovered from restricting-type AN were compared to 16 control women (CW). We used a region of interest-based fMRI approach to test the idea that individuals with AN have differential neural activation in primary and secondary taste cortical regions after sucrose and water administration. Compared to CW, individuals recovered from AN showed a significantly lower neural activation of the insula, including the primary cortical taste region, and ventral and dorsal striatum to both sucrose and water. In addition, insular neural activity correlated with pleasantness ratings for sucrose in CW, but not in AN subjects. Altered taste processing may occur in AN, based on differences in activity in insular–striatal circuits. These data provide the first evidence that individuals with AN process taste stimuli differently than controls, based on differences in neural activation patterns.

Encephalon 32

Encephalon 32, A Neuroscience Carnival is now available for your reading pleasure at Living the Scientific Life (Scientist, Interrupted).

In other news, The Traumatically Brain Injured One post seems to be getting a large number of hits from this article in Slate about O.J. Simpson:

Squeezing O.J.'s Brain
Could brain injuries suffered on the football field explain O.J. Simpson's erratic behavior?
By Chadwick Matlin

. . . As a pro, Simpson carried the ball more than 2,400 times. As the evidence mounts that football can cause massive head trauma, it's worth wondering: Could O.J.'s erratic behavior have something to do with taking too many gridiron collisions?
. . .

It appears that Simpson never had a documented head injury. A search of online newspaper archives didn't find any reports of concussions. Jim Peters, a sportswriter who covered Simpson's career in Buffalo, told me he couldn't remember Simpson missing any action because of a blow to the head.

A lack of published reports doesn't mean Simpson never sustained brain trauma. In the 1960s and 1970s, when the dangers of head injuries weren't well-known, players and trainers rarely reported concussions. Even today, players often don't say when they've suffered a head injury.

This is all speculative, of course, but the article does mention other professional athletes who have sustained serious traumatic brain injuries.

An occupational hazard? Try deployment to Iraq:

Scientists: Brain injuries from war worse than thought

By Gregg Zoroya, USA TODAY

Scientists trying to understand traumatic brain injury from bomb blasts are finding the wound more insidious than they once thought.

They find that even when there are no outward signs of injury from the blast, cells deep within the brain can be altered, their metabolism changed, causing them to die, says Geoff Ling, an advance-research scientist with the Pentagon.

. . . The findings could mean that the number of brain-injured soldiers and Marines — many of whom appear unhurt after exposure to a blast — may be far greater than reported, says Ibolja Cernak, a scientist with the Johns Hopkins University Applied Physics Laboratory.

This cellular death leads to symptoms that may not surface for months or years, Cernak says. The symptoms can include memory deficit, headaches, vertigo, anxiety and apathy or lethargy. "These soldiers could have hidden injuries with long-term consequences," he says.

Physicians and scientists are calling TBI the "signature wound" of the Iraq war because of its increasing prevalence among troops.

No "signature quips" here, nothing about that sad fact is amusing.

I'm a Thinking C-List Blogger!

Thanks to John Grohol from World of Psychology, who has kindly nominated me for a Thinking Blogger Award. The Neurocritic was previously tagged by Retrospectacle and Neurofuture, fine blogs all.

But the real prestige, of course, lies in being a C-list blogger as I've bragged (blogged) previously.

Your Results:

With 96 links in the last 180 days, Technorati places http://neurocritic.blogspot.com/ in the middle authority group.

That makes you a C-List Blogger!

The Traumatically Brain Injured One

The Brave One (2007) - Jodie Foster

In The Brave One, Jodie Foster plays a public radio talk show host who becomes the victim of a shocking, violent, and brutal crime that leaves her in a coma for three weeks. From a clinical standpoint, she clearly sustained traumatic brain injury from the severe beating, but in typical Hollywood fashion she shows absolutely no post-traumatic amnesia and no cognitive or behavioral deficits.

Well, she does buy an illegal, unregistered handgun, and then becomes a vigilante. The movie doesn't suggest that her change in personality is a direct consequence of TBI, but rather an extreme reaction to intense feelings of fear and loss. People keep asking her, "how do you put the pieces of your life back together?" and she answers, "you don't, you become a different person."

David Amodio Responds

Dr. David Amodio has graciously taken the time to respond to many of the criticisms of his paper, Neurocognitive correlates of liberalism and conservatism, made by The Neurocritic and others. [EDIT: His comments first appeared here, and I have taken the liberty to repost them as a new entry.]

Hi Neurocritic,

I like your blog – it’s important to a have a critical voice out there. However, given how this study has been misconstrued and sensationalized in the media, as well as among science bloggers, it’s important to address the criticisms directly. Though I’ve generally not worried about the “lay” coverage (how can you argue science with pundits?), it might be worthwhile to respond to a blog that is read by neuroscientists (including myself from time to time):

1) There were no gender differences on any variable. Moreover, 63% women is actually fairly balanced for a psychology study, so I’m surprised this has even come up. We didn’t report gender effects for the sake of brevity, though in hindsight, I wish we had slipped it in.

2) People have complained that there were more liberals the conservatives in the sample. True, in an absolute sense. But this is typical in political psychology: Americans are more conservative on average, and so more extreme conservatives usually rate themselves as moderate conservatives, whereas moderate liberals tend to rate themselves more extremely (see Linda Skitka’s work and comments on the paper). It’s a scaling issue that psychologists deal with all the time.

Nevertheless, we’re talking about a correlation. The clear linear effect suggests the stronger liberalism is associated with greater conflict-related ACC activity. Not sure how anyone can argue with that.

3) The sample was actually rather large for a neuro study. Also, please note our use of *inferential statistics* – I’ve been surprised by the criticism of the size given the strength of the effect!

4) Outliers? There weren’t any. (Not sure what Broussard was referring to in the highly-critical comment you posted. Maybe someone should lend him a stats book…)

5) On reporting group differences in RTs and error rates – to be clear, we did not conduct group analyses (though one graph displays the median split of ERN waves). We looked at correlations along a continuum. Group analyses would have been psychometrically problematic, and furthermore, we didn’t want to suggest that political orientation is categorical. Though of course this didn’t stop the media and bloggers to speak in terms of categories…

In the end, the study reports a correlation. You can’t “disprove” it – you can only interpret it. Our interpretation was face valid – this measure of political orientation was strongly correlated with the ERN and No-Go N2 from the Go/No-Go task. Simple as that. Might there be 3rd variables at play? Probably. But that doesn’t contradict our interpretation or cast doubt on the quality of the study.

Good science is an art. But so is good science critique. Without a plausible alternative interpretation, you don’t have a critique. I suppose people are just cranky because this bullet-point of a study has been so over-sensationalized. Or maybe some folks just aren’t familiar with how you do this kind of research. So I hope this post clarifies some things.

DA

And here is my reply.

Hi DA,

Thank you for taking the time to respond and for being so gracious despite some...well...highly critical remarks. Some of which are not my own, so perhaps I should not have been such a "sounding board." I just have a couple of replies to your comments.

1) I (personally) didn't have an issue with possible gender differences, but it's good to have that clarified.

2) I'm rather ignorant of standard rating systems in political psychology, but is self-rating always used? Aren't there more "objective" questionnaires used to classify American participants along the liberal-conservative continuum?

I'm not familiar with Linda Skitka's work. I wouldn't know where to start [even if I had time to read her papers], perhaps with Skitka & Tetlock (1993)? ¹ [Hmm, Mullen et al. (2003) looks quite interesting, if not entirely relevant here.]

3) Your correlations are strong, yes. It seems people had more of a problem with the restricted range of the conservative sample.

4) You're right, he's wrong, not sure which points would be considered outliers. I went back to the original post and put the offending passages in strikeout font. However, it does seem the 7 conservatives' ERNs were quite variable (values from -2 to -23).

5) I was basing my comments about group analyses on the fact that you had to do them to show the EEG data in Figure 1b. And the fact that mean accurate rates were reported in (ahem) newspaper articles. My criticism about the lack of RT data in the paper still stands:

There was absolutely no information about RTs at all, so we don't know whether there was a speed-accuracy trade-off in the conservatives (a reckless and disinhibited response style) or whether they were "conscientious" (RT comparable to [or slower than] liberals), but just couldn't stop themselves from pressing the key on No-Go trials.

That could comprise part of an alternate explanation, along with "3rd variables at play" as I've sarcastically suggested with my Liberals Are Neurotic and Conservatives Are Antisocial quip.

At any rate, I would beg to differ that good science critique must provide an alternate interpretation. Some science critique can be based on methods, analysis, reporting of results, etc. Standard peer-review stuff.

My closing remarks are based on the assumption that the error-related negativity (ERN) brain wave is a direct measure of conflict monitoring in the anterior cingulate cortex (ACC). [I've focused on the ERN rather than the N2 because the former is illustrated in the paper and the latter is not.] A quick review of the literature indicates that's not necessarily the case. First, not everyone agrees that the ERN measures response conflict rather than error processing more specifically (Carbonnell & Falkenstein, 2006), or that ACC hemodynamic activity during error commission is a reflection of response conflict (Critchley et al., 2005; Garavan et al., 2003). Second, when people make mistakes, it seems that more of the brain is active than just the ACC (Klein et al., 2007; Ullsperger & von Cramon, 2006).

At least, these are my impressions...

TN


Footnote

¹ Measures

Liberalism–conservatism

To measure the cognitive conservatism and liberal-humanism factors identified in earlier research (high scores on dogmatism, authoritarianism, and identification with the political right; Skitka & Tetlock, 1992) we adopted Altemeyer's (1981, 1988) 30-item balanced Right-Wing Authoritarianism (RWA) scale. The RWA scale is an updated measure with sound psychometric properties (see review by Winter, 1990) that we judged to be superior to the scales we used in earlier studies of ideo-affective resonances. The scale ranges from liberal-democrat to authoritarian (see Altemeyer, 1988, p. 263). Altemeyer (1981) reported Cronbach's alpha of .88 for a sample of 965 University of Manitoba students. We observed an alpha of .86 with the present sample, indicating adequate internal consistency in measuring the construct.

References

Carbonnell L, Falkenstein M. (2006). Does the error negativity reflect the degree of response conflict? Brain Res. 1095:124-30.

Critchley HD, Tang J, Glaser D, Butterworth B, Dolan RJ. (2005). Anterior cingulate activity during error and autonomic response. Neuroimage 27:885-95.

Garavan H, Ross TJ, Kaufman J, Stein EA. (2003). A midline dissociation between error-processing and response-conflict monitoring. Neuroimage 20:1132-9.

Klein TA, Endrass T, Kathmann N, Neumann J, von Cramon DY, Ullsperger M. (2007). Neural correlates of error awareness. Neuroimage 34:1774-81.

Mullen, E., Bauman, C. W., & Skitka, L. J. (2003). Avoiding the pitfalls of politicized psychology. Analyses of Social Issues and Public Policy, 3, 171-176.

This article provides two arguments for using caution when interpreting the results of a Global Change Game simulation indicating that people high in right-wing authoritarianism are particularly likely to bring the world to ruin. First, we review research that demonstrates that extremists on both the political left and right share characteristics likely to be associated with poor performance in the Global Change Game (e.g., lower levels of integrative complexity) and that there are reasons to be cautious about letting political extremists on either the left or right inherit the earth. Second, we caution that political psychologists need to be aware of how their own values shape the types of research they conduct and the inferences they draw from that research and that the same results can be construed very differently depending on the lens through which they are viewed.

Skitka, L. J. & Tetlock, P. E. (1993). Providing public assistance: Cognitive and motivational processes underlying liberal and conservative policy preferences. Journal of Personality and Social Psychology, 65, 1205 - 1223.

Previous research in a wide variety of policy domains (e.g., azidothymidine for AIDS patients, low-income housing) has indicated that under no scarcity, liberals tend to help all claimants for assistance, whereas conservatives withhold assistance from people who are personally responsible for their predicament (Skitka & Tetlock, 1992). Three studies explore 6 explanations for this robust finding: deterrence, self-interest, punitiveness, mindlessness, value orientation, and avoidance of trade-off reasoning. The findings shed light on both the cognitive strategies and motivational priorities of liberals and conservatives. It was discovered that liberals are not mindlessly egalitarian, but try to avoid socially awkward value trade-offs that require placing monetary values on lives. By contrast, conservatives are motivated to punish violators of social norms (e.g., deviations from traditional norms of sexuality or responsible behavior) and to deter free riders.

Ullsperger M, von Cramon DY. (2006). The role of intact frontostriatal circuits in error processing. J Cog Neurosci. 18:651-64.

Blue Sky Sailboat with Superimposed Human Brain

Steven Pinker's Photos of Cape Cod I / blue sky sailboat with superimposed human brain

The Corporate Brain

Remember Corporate Cognitive Neuroscience? Now it's called The Social Cognitive Neuroscience of Corporate Thinking, a forthcoming volume from the Annals of the New York Academy of Sciences.

Edited by: Carl Senior; Michael J. Butler

Social cognitive neuroscience is an emerging branch of cognitive neuroscience that bridges together social psychology and neuroscience. At its core is an understanding of the relationship between the brain and social interaction.

The social cognitive neuroscientist places empirical endeavor within a three-stage framework, and questions falling under the SCN rubric undergo interrogation at each of these three levels. Firstly, we seek to understand a neuroscience of social interactions at the social level. Here we need to understand the motivational and other social factors that drive our behavior and experience in the real world.

It goes without saying that any study of the cognitive neuroscience of socially interactive behavior must first be informed by social psychological theory to maintain ecological validity. Second, the social cognitive neuroscientist must be an adroit cognitive psychologist and be able to examine interactive behavior from the cognitive level. It is here that information-processing models and theories are applied to the understanding of our social behavior. Finally, studies at the neural level seek to inform us about the cortical structures, as well as the way they interact with other, in the mediation of the previous cognitive level.

This volume brings together contributions from leading thinkers in both the social cognitive neurosciences and business to provide a comprehensive introduction and overview of a social cognitive neuroscience of the business brain.

Image from My AD Agency, Inc.

used with permission

Liberals Are Neurotic and Conservatives Are Antisocial

An awful lot of cyberink has been spilled over the liberal-conservative EEG study published online in Nature Neuroscience a few days ago. The Neurocritic is not an expert in social psychology or personality, so to be fair in the sequel to The Error of Prognosticating Political View by Brain Wave, I decided to read [skim] the 2003 paper by Jost and colleagues, Political Conservatism as Motivated Social Cognition (PDF here). An obvious question for the uninitiated is whether there is any truth to the title of this post, other than the inference I made based on the error-related negativity literature: ¹

Liberals showed larger ERN waves than conservatives when mistakenly responding on No-Go trials. However, so do individuals with clinical diagnoses such as obsessive-compulsive disorder (Gehring et al., 2000) or major depressive disorder (Chiu & Deldin, 2007).

On the other hand, individuals with schizophrenia (Mathalon et al., 2002) or psychopathy (Munro et al., 2007) show smaller ERN waves than control participants. These findings extend to the normal population, i.e., people who do not fit the criteria for a clinical diagnosis, but who score higher or lower on certain traits. For example, people who score high on negative affect have bigger ERNs (Hajcak et al., 2004), while individuals with "externalizing psychopathology" have smaller ERNs (Hall et al., 2007). Does this mean that liberals are neurotic and conservatives are antisocial? Since these were not assessed along with political orientation, we can only hazard a guess...

Actually, we may not need to hazard a guess, because such measures may have been already obtained from these subjects, as stated in the Supplementary Methods:

A measure of political attitudes was embedded in a larger set of personality and attitudes surveys completed at the every [sic] beginning of the experimental session.

So a paper about neurotic liberals with large ERNs and antisocial conservatives with small ERNs may yet appear in a journal near you. This begs the question,

Perhaps there were any other correlations? I wonder what the odds were of a stastically [sic] significant finding given the number of personality and attitude surveys.

But back to the 2003 paper. I do remember that it raised a big stink in the media at the time, not surprising given a press release like this:

Disparate conservatives share a resistance to change and acceptance of inequality, the authors said. Hitler, Mussolini, and former President Ronald Reagan were individuals, but all were right-wing conservatives because they preached a return to an idealized past and condoned inequality in some form. Talk host Rush Limbaugh can be described the same way, the authors commented in a published reply to the article.

Here's the abstract of the paper (Jost et al., 2003), which really is all about conservatism: ²

Analyzing political conservatism as motivated social cognition integrates theories of personality (authoritarianism, dogmatism–intolerance of ambiguity), epistemic and existential needs (for closure, regulatory focus, terror management), and ideological rationalization (social dominance, system justification). A meta-analysis (88 samples, 12 countries, 22,818 cases) confirms that several psychological variables predict political conservatism: death anxiety (weighted mean r=
.50); system instability (.47); dogmatism–intolerance of ambiguity (.34); openness to experience (–.32); uncertainty tolerance (–.27); needs for order, structure, and closure (.26); integrative complexity (–.20); fear of threat and loss (.18); and self-esteem (–.09). The core ideology of conservatism stresses resistance to change and justification of inequality and is motivated by needs that vary situationally and dispositionally to manage uncertainty and threat.

OK then, "resistance to change" appears to extend to a lowered ability to inhibit habitual responding and a diminished brain response to such mistakes (Amodio et al., 2007). It's still not clear to me, however, how brain systems responsible for personality constructs like intolerance of ambiguity and needs for order, structure, and closure overlap with brain systems responsible for not pressing a key to a letter presented 20% of the time.

Now back to the 2007 NN article again. I hate to belabor the point, but it's only fair to examine the paper on its merits, not on the ideologies of the authors, no matter how much I might agree with them. But really, this blog comment sums it up:

It is useless to try to infer anything from this study. The experimenter has 26 liberals and 7 conservatives. Not exactly equal sample sizes, and not a big enough sample of conservatives to gain any inference about the range of responses here, even if you buy into the non-sequiter introduction set out by the authors. [NOTE: the following objections were addressed by the first author.] A thought experiment: would the correlation hold up if the two biggest outliers were excluded. Doesn't look like it. No mention of possible sex differences etc. usually discussed in these papers. The authors fail to address these confounds even in the supplementary info. A sad commentary on the state of science when a journal with this level of impact publishes a study of this low quality.

Posted by: John Broussard | September 11, 2007 6:48 PM

Huh. So this would imply that the brain wave data shown in Fig 1b of Amodio et al. (2007) were averages from 7 conservatives and ~26 liberals!

And a very important bit of data -- mean accuracy rates for conservatives and liberals -- didn't appear anywhere in the paper [someone correct me if I'm wrong], but was published in this newspaper article:

In the 400 easy trials, just about everyone got it right.

But in the 100 tough trials, when students saw the letter that meant they shouldn't press a button, self-described conservatives pressed the button anyway nearly half the time - an error rate of 44 out of 100.

Liberals fumbled about a third of the time, with an error rate of 34 out of 100.

Neurophilosophy reported slightly different figures [not sure where he got them]:

It was found that those who considered themselves to be conservatives made more response errors when upon presentatin of the infrequent letters than those who considered themselves as liberals (respectively, 47% and 37% of the time).

Have any of you ever published papers in less prestigious journals without including mean accuracy and reaction time values for your comparison populations?? There was absolutely no information about RTs at all, so we don't know whether there was a speed-accuracy trade-off in the conservatives (a "reckless" and disinhibited response style) or whether they were "conscientious" (RT comparable to [or slower than] liberals), but just couldn't stop themselves from pressing the key on No-Go trials.

Enough already with the ranting.

Peace. Shana Tova.


Footnotes

¹ See previous post for a list of those references.

² This paper doesn't discuss the psychological variables that predict liberalism, so in the end we don't know if liberals are neurotic; the incidence of antisocial traits in conservatives was not reported.

References

Amodio DM, Jost JT, Master SL, Yee CM. (2007). Neurocognitive correlates of liberalism and conservatism. Nature Neurosci. Published online 9 September 2007.

Jost JT, Glaser J, Kruglanski AW, Sulloway FJ. (2003). Political conservatism as motivated social cognition. Psychol Bull. 129:339-75.

The Error of Prognosticating Political View by Brain Wave

Figure 1. Liberals and conservatives in the study of Amodio et al. (2007) voted primarily for Kerry and Bush, respectively, in 2004. Brain wave recordings adapted from Mathalon et al. (2002).

You've seen the headlines:

Brains of liberals, conservatives may work differently, study finds

. . .

In a study likely to raise the hackles of some conservatives, psychologist David Amodio and others found that a specific region of the brain’s cortex is more sensitive in people who consider themselves liberals than in self-declared conservatives.

The brain region in question helps people shift gears when their usual response would be inappropriate, supporting the notion that liberals are more flexible in their thinking.

And the overblown quotes:

Are We Predisposed to Political Beliefs?

...

"In the past, people thought that…[political leanings were]…all environmentally influenced, a combination of biological dispositions as well as cultural shaping," says David Amodio, an assistant professor of psychology at New York University. However, a new study, led by Amodio, indicates that political bent "is not just a choice people have, but it seems to be linked to fundamental differences in the way people process information."

And the baseless assertion of innate differences between the brains of liberals and conservatives:

brain neurons of liberals and conservatives fire differently [sic] when confronted with tough choices, suggesting that some political divides may be hard-wired, according a study released Sunday.

But perhaps you've read a critical analysis of the leaps of logic made in the study (and if you haven't read it, you should):

Liberal and Conservative Anterior Cingulate Cortices

. . .

Let's face it, the intro to this paper, which is necessarily short because it's only a "brief communication," is terrible. I have no idea why they hypothesized a relationship between, say, tolerance for uncertainty and conflict monitoring. That hypothesis feels about as non sequitur as this:

Given that these associations between political orientation and cognitive styles have been shown to be heritable, evident in early childhood, and relatively stable across the lifespan, we hypothesized that political orientation may be associated with individual differences in a basic neurocognitive mechanism involved broadly in self-regulation. (p. 1)

Well alrighty, then. Eye color is heritable, evident in early childhood, and relatively stable across the lifespan, but I've never seen someone associate it with self-regulation.

The Neurocritic has another ax to grind, a problem with attributing the observed results to political viewpoint and not to other factors. First, let's start out with the measures of brain activity reported in the paper. The study used EEG recordings, specifically event-related potentials. The ERP brain waves reflect electrophysiological activity recorded remotely from the scalp. While it's great for determining the temporal parameters of neural activity, it's not so great at determining where the activity is located in the brain.

One brain wave of interest here is

the No-Go N2 component, which is believed to reflect conflict-monitoring activity associated with the successful inhibition of the prepotent Go response on No-Go trials.

Another brain wave of interest is the error-related negativity (ERN), recorded at the time that people make mistakes in a task:

The response-locked error-related negativity (ERN), which peaks at approximately 50 ms following an incorrect behavioral response, reflects conflict between a habitual tendency (for example, the Go response) and an alternative response (for example, to inhibit behavior in response to a No-Go stimulus).

However, it's not at all clear that ERN reflects conflict-monitoring (Carbonnell & Falkenstein, 2006). Thus, based on a smaller-sized ERN in conservatives, one cannot conclude that they are "less responsive to conflict." In fact, if one wants to apply the logic of conflict monitoring to political viewpoint, one could say that conservatives might be more freaked out by ambiguity and conflict, since it violates their simplistic world view.

Anyway, back to the experiment. The participants in the study performed a Go/No-Go task that involved rapid responses to the letter "M" on 80% of the trials, and withholding a response to the letter "W" on 20% of the trials. The ERN was recorded when people incorrectly responded to W, and N2 was recorded when people correctly refrained from responding to W.

What were the results? Liberals showed larger ERN waves than conservatives when mistakenly responding on No-Go trials. However, so do individuals with clinical diagnoses such as obsessive-compulsive disorder (Gehring et al., 2000) or major depressive disorder (Chiu & Deldin, 2007).

Figure 2. ERN waves for liberals versus conservatives (left; adapted from Fig. 1b of Amodio et al.) and for OCD versus control participants (right; adapted from Fig. 1 of Gehring et al.).

On the other hand, individuals with schizophrenia (Mathalon et al., 2002) or psychopathy (Munro et al., 2007) show smaller ERN waves than control participants. These findings extend to the normal population, i.e., people who do not fit the criteria for a clinical diagnosis, but who score higher or lower on certain traits. For example, people who score high on negative affect have bigger ERNs (Hajcak et al., 2004), while individuals with "externalizing psychopathology"¹ have smaller ERNs (Hall et al., 2007). Does this mean that liberals are neurotic and conservatives are antisocial? Since these were not assessed along with political orientation, we can only hazard a guess...


Footnote

¹ According to Hall et al. (2007):

Recent research examining patterns of diagnostic co-morbidity in community-epidemiological samples indicates that conduct disorder in children, antisocial behavior in adults, and substance-use disorders—along with personality traits related to behavioral disinhibition—are indicators of a common underlying vulnerability factor, labeled externalizing.

References

Amodio DM, Jost JT, Master SL, Yee CM. (2007). Neurocognitive correlates of liberalism and conservatism. Nature Neurosci. Published online 9 September 2007.

Political scientists and psychologists have noted that, on average, conservatives show more structured and persistent cognitive styles, whereas liberals are more responsive to informational complexity, ambiguity and novelty. We tested the hypothesis that these profiles relate to differences in general neurocognitive functioning using event-related potentials, and found that greater liberalism was associated with stronger conflict-related anterior cingulate activity, suggesting greater neurocognitive sensitivity to cues for altering a habitual response pattern.

Carbonnell L, Falkenstein M. (2006). Does the error negativity reflect the degree of response conflict? Brain Res. 1095:124-30.

Chiu PH, Deldin PJ. (2007). Neural evidence for enhanced error detection in major depressive disorder. Am J Psychiatry 164:608-16.

Gehring WJ, Himle J, Nisenson LG. (2000). Action-monitoring dysfunction in obsessive-compulsive disorder. Psychol Sci. 11:1-6.

Hajcak G, McDonald N, Simons RF. (2004). Error-related psychophysiology and negative affect. Brain Cogn. 56:189-97.

Hall JR, Bernat EM, Patrick CJ. (2007). Externalizing psychopathology and the error-related negativity. Psychol Sci. 18:326-33.

Mathalon DH, Fedor M, Faustman WO, Gray M, Askari N, Ford JM. (2002). Response-monitoring dysfunction in schizophrenia: an event-related brain potential study. J Abnorm Psychol. 111:22-41.

Munro GE, Dywan J, Harris GT, McKee S, Unsal A, Segalowitz SJ. (2007). ERN varies with degree of psychopathy in an emotion discrimination task. Biol Psychol. 76:31-42.

ADDENDUM: Cognitive Daily has just posted another critique of this paper, The claim: Politically liberal brains are better at handling change

To Do or Not To Do...

...that is the question asked by Brass and Haggard (2007) in their recently published paper, which speaks of "free will" in the abstract [of their article]:

The mental control of action has an enduring scientific interest, linked to the philosophical concept of "free will."

The concept of free will has been debated for centuries: is our behavior totally determined, partially determined, or not determined (i.e., free and of our own choosing)? What does "determined" mean? What are the implications for ethics? Some neurobiologists even ask, Do Fruit Flies Have Free Will? I'm not going to address those questions today, but see Volume 25, Issue 2 of Behavioral Sciences & the Law for a Special Issue on Free Will.

In the fMRI experiment of Brass and Haggard (2007),

participants were instructed to freely decide when to execute a simple key press while observing a rotating clock hand (Libet et al., 1983). Furthermore, they were told to cancel the intended response at the last possible moment in some trials that they freely selected. After each trial, they had to determine the clock position when they formed the intention to act. Our interest focused on the comparison between trials in which subjects intentionally inhibited the action and trials in which they intentionally executed it.

The task was based on the famous studies of the late great Benjamin Libet, who was asking empirical questions about free will, consciousness, and the brain before many of us were born. In the present experiment, neural activity during action trials was compared to neural activity during inhibition trials, and the results are illustrated below.


Fig 2 [from Brass & Haggard, 2007]. A: Activation in the dorsal fronto-median cortex (dFMC) for the contrast of inhibition vs. action trials. B: Activation in the left anterior ventral insula for the contrast of inhibition vs. action trials.

Three major regions were more active during inhibition than during action: A: the medial portion of Brodmann area 9, or "dorsal fronto-median cortex" [usually called dorsomedial prefrontal cortex and not the former], B: the left ventral anterior insula, and the superior temporal sulcus (not illustrated here, but see this figure). Furthermore, activity in dFMC showed a negative correlation with activity in the motor cortex.

On the other hand, what regions were recruited more for action than for inhibition? As you might expect,

The reverse contrast between action trials and inhibition trials yielded activation in a number of motor-related areas such as the primary sensorimotor cortex and the cerebellum...

...but also, there was

...no activation in medial or lateral prefrontal cortex. The absence of any significant difference in areas known to be involved in preparation of voluntary action, such as pre-SMA and SMA [supplementary motor area], suggests that subjects prepared intentional actions equally both in the action trials and in the inhibition trials.

Does this study have anything at all to do with what is normally referred to as "self-control"? The authors believe it does...

Our results provide the first clear neuroscientific basis for the widely held view that people can refrain from doing something even if they genuinely wish to do it. We speculate that the dFMC may be involved in those aspects of behavior and personality that reflect "self-control".

...even though pressing a button in a psychology experiment is devoid of the emotion and desire one might feel while screaming at a motorist who cut you off or snorting cocaine or gambling away the last of your life's savings. Or (in the extreme) drowning your five children while suffering from severe postpartum depression and psychosis.

References

Brass M, Haggard P. (2007). To do or not to do: the neural signature of self-control. J Neurosci. 27:9141-5.

Voluntary action is fundamental to human existence. Recent research suggests that volition involves a specific network of brain activity, centered on the fronto-median cortex. An important but neglected aspect of intentional action involves the decision whether to act or not. This decision process is crucial in daily life because it allows us to form intentions without necessarily implementing them. In the present study, we investigate the neural correlates of intentionally inhibiting actions using functional magnetic resonance imaging. Our data show that a specific area of the fronto-median cortex is more strongly activated when people prepare manual actions but then intentionally cancel them, compared with when they prepare and then complete the same actions. Our results suggest that the human brain network for intentional action includes a control structure for self-initiated inhibition or withholding of intended actions. The mental control of action has an enduring scientific interest, linked to the philosophical concept of "free will." Our results identify a candidate brain area that reflects the crucial decision to do or not to do.

Libet B, Gleason CA, Wright EW, Pearl DK (1983). Time of conscious intention to act in relation to onset of cerebral activity (readiness-potential). The unconscious initiation of a freely voluntary act. Brain 106:623–642.

Scientists Spot Brain's 'Free Willy' Center

No...wait...

Scientists Spot Brain's 'Free Will' Center
It helps people refrain from actions good and bad, experts say.

By Amanda Gardner
HealthDay Reporter

THURSDAY, Aug. 23 (HealthDay News) -- If you've ever been of "two minds" about doing something, a new study may explain why.

Scientists say one part of the brain is responsible for initiating action, while a totally separate area is in charge of not taking that action.

This newly identified region, involved in an aspect of self-control, may change conceptions of human free will, the researchers said. It could also explain the basis of impulsive as well as reluctant behavior, they added.

...doesn't this suggest the existence of two 'free will' centers [to do or not to do]¹? And how was this demonstrated?

Using functional magnetic resonance imaging (fMRI), the researchers studied the brain activity of participants in two situations -- when they acted out as they had planned, or when they decided not to follow their original intention.

Fifteen right-handed individuals ... participated in a "go-no-go" exercise. They were asked to press a button on a keyboard but first to indicate what time they were going to perform this action. They were also asked to choose instances in which they stopped before actually pressing the button.

When participants decided not to press the button, a specific area of the frontal lobe region of the brain lit up. When participants followed through, however, the area did not light up.

In a surprising show of moderation and restraint in interpreting the results², the HealthDay article concludes:

For now, the implications of the research are esoteric but, down the line, who knows?

Footnotes

¹That's actually the title of the original article by Brass and Haggard (2007). More about it in the next post.

²Unlike the headline (as usual), which is probably not the reporter's fault.

Glutamate Agonist LY2140023: A New Treatment for Schizophrenia?

High hopes for new schizophrenia drugs
Drug trial hailed as first major breakthrough for 50 years.

By Alison Abbott

. . .

The side effects of LY2140023, including insomnia and emotional instability, are slightly different to those of olanzapine although they are of roughly the same overall severity — but unlike any existing antipsychotic, the new drug did not cause weight gain.

The idea that the glutamate system might be involved in schizophrenia first emerged when doctors noticed that the 1980s party drug phencyclidine (PCP) induced a temporary psychosis similar to the disease. But the new drug is the first to demonstrate that this system can be deliberately manipulated to help schizophrenics.

As noted by Bita Moghaddam, the "glutamate hypothesis of schizophrenia" dates back to 1980:

The idea of a glutamatergic abnormality in schizophrenia was first proposed by Kim, Kornhauber, and colleagues in 1980 (Kim et al., 1980) based on their findings of low cerebrospinal fluid (CSF) glutamate levels in patients with schizophrenia. This theory was not received well because, first, these findings could not be replicated in subsequent studies and, second, our limited knowledge of the glutamate system at the time suggested that disruptions in glutamate neurotransmission would result in overt toxicity and gross developmental abnormalities, something not seen in schizophrenia. In the last two decades, however, basic and clinical evidence has been accumulating to support the idea that aberrant NMDA receptor function subserves many aspects of molecular, cellular, and behavioral abnormalities associated with schizophrenia.

She goes on to list six lines of evidence in favor of this idea. It's definitely worth reading her review, which is freely available at the Schizophrenia Research Forum.

Reference

Patil ST, et al. (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Medicine. Published online: 2 September 2007.

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

Would I Lie To You Yet Again?

The Deception Blog alerts our attention to yet another breathless and swooning report on reading the fMRI tea leaves of lie detection in their post, More fMRI stuff and nonsense. The ABC report says virtually nothing specific about what purportedly happens in the brain of someone lying compared to telling the truth, only:

The FMRI results visibly showed more blood rushing to the specific parts of the brain when I was lying.

"We're looking beyond just the anxiety, what you're doing cognitively when telling a lie. When you're telling a lie, you're overriding a normal response of telling the truth, " said George. "So your brain is putting on a brake and overlearning a response. It's harder to tell a lie then tell the truth, [to] remember what you're lying about. You've created a false way the world is. So we're looking at overworking, inhibiting, multitasking. Those areas are pretty predictive in catching someone when you're lying."

That, and the lovely figure below. Notice the only activity in the truth-telling brain on the left seems to located mostly outside the cerebral cortex. Great.

Who needs Pinocchio's nose to find a lie? The FMRI scan on the right detects a brain processing a false statement; the less colorful brain on the left corresponds to someone in the middle of a truthful statement. (ABC)