Sunday, November 04, 2007

Breaking into the brain   posted by p-ter @ 11/04/2007 11:25:00 AM

Nature has a news piece on vastly improved models for psychology-related phenotypes in model organisms. It's worth a read, keeping in mind James Watson's claim from last year that "the past century was the coming together of chemistry and biology, and this century will be the coming together of psychology and biology".

The story highlights the progress being made in studying the brain the way other organs have been studied for years. And right after I read it, I saw a couple papers that hammer the story home.

First, Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions, which shows that genetically identical mice can be divided into two groups based on how they respond to social defeat (from the paper: "An episode of social defeat is accomplished by forcing a mouse to intrude into the space territorialized by a larger mouse of a more aggressive genetic strain, leading to an agonistic encounter that ultimately results in intruder subordination.") and identifies particular molecules whose expression levels differentiate the two, mostly involved in a specific signaling pathway that goes through a protein encoded by BNDF (brain-derived neurotrophic factor).

How could genetically identical mouse strains react so differently to stress? The authors don't really know, offering only this:
Such examples of phenotypic variability in inbred mice have always been attributed to environmental influences that are difficult to control and measure, such as variations in prenatal and postnatal development and early dominance hierarchies ([Peaston and Whitelaw, 2006] and [Wong et al., 2005]). However, experiments performed on inbred mice raised in strictly defined environments have shown that up to 80% of random variability in quantitative traits (e.g., body weight) are unrelated to genetic and environmental influences (Gartner, 1990). This third component to natural variation is thought to maintain Gaussian distributions of biological variables independent of environmental influences and sequence constraints and is now attributed to chromatin remodeling events such as histone acetylation or methylation.
So perhaps it's just random chance?

In humans, however, there is genetic variation in the genes these authors identify, including a non-synonymous (Met->Val) polymorphism in Bndf that affects the expression level of the gene. The authors are able to test this polymorphism in their framework:
We show here that while Val/Val and Met/Met mice showed comparable behavior on baseline measures of emotionality, Met/Met mice displayed a striking Unsusceptible [to depression following social defeat] phenotype in the social defeat paradigm, which was associated with a ~50% reduction in levels of BDNF protein
It's quite possible, then, that this polymorphism plays an important role in how humans respond to certain social situations, though this remains to be seen.

The other paper that caught my eye was on the results of performing brain MRIs on people from the general population. I never would have thought to check if individuals had had random small strokes, but that's what they find:
Asymptomatic brain infarcts were present in 145 persons (7.2%). Among findings other than infarcts, cerebral aneurysms (1.8%) and benign primary tumors (1.6%), mainly meningiomas, were the most frequent. The prevalence of asymptomatic brain infarcts and meningiomas increased with age, as did the volume of white-matter lesions, whereas aneurysms showed no age-related increase in prevalence.
So around 10% of individuals over 50 are walking around with some sort of brain damage. I suppose there are a couple ways to respond to that information-- either you adapt your view of what a normal brain is, or you become suspicious of anyone above a certain age.

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Monday, May 28, 2007

Building a Better Mouse   posted by Fly @ 5/28/2007 11:04:00 AM

'Smart' mice teach scientists about learning process, brain disorders

Mice genetically engineered to lack a single enzyme in their brains are more adept at learning than their normal cousins, and are quicker to figure out that their environment has changed, a team led by researchers at UT Southwestern Medical Center has found.
The group is also beginning a search for drugs that might create the same effects without genetic manipulation and monitoring the animals' health and behavior over time.
The key in this study was being able to "knock out" the gene for Cdk5 only in the brain, and only when the mice were adults. This technique, only recently developed and called conditional knockout, allows much more sophisticated experiments than traditional knockout, which entirely eliminates the gene.
Normally, Cdk5 works with another enzyme to break up a molecule called NR2B, which is found in nerve-cell membranes and stimulates the cell to fire when a nerve cell signaling molecule, or neurotransmitter, binds to it. NR2B previously has been implicated in the early stages of learning.

The new research showed that when Cdk5 is removed from the brain, the levels of NR2B significantly increase, and the mice are primed to learn, Dr. Bibb said.

Evolved biological systems aren't optimal...just good enough. Knowing how the system works should lead to interventions that improve function. In the coming decades there should be nutritional, drug, training, genetic, and cybernetic enhancement of brain function.


Tuesday, February 20, 2007

Left-handedness and pedophilia: Brain damage   posted by agnostic @ 2/20/2007 05:58:00 PM

It seems that "pathological" left-handedness and pedophilia might share a common origin in some early developmental disturbance(s), possibly a brain infection (or group of infections). I first read about the potential fitness costs that left-handers suffer in a passing remark of Harpending & Cochran (2006), although when I searched PubMed for "left-handed" and "longevity," I found that the results have been somewhat inconsistent. However, a new study in Epidemiology on longevity and handedness in a large, representative sample of Dutch women (Ramadhani et al. 2007) confirms the earlier reports of decreased longevity among left-handers. The Hazard Ratios for left-handers vs. right-handers showed that lefties were more likely to die of all causes, and even more so for specific causes such as colorectal cancer and cerebrovascular diseases (PDF pp. 2-3):

Table 2 shows that, after adjustment for age, SES, BMI, and cigarette smoking status, left-handed women had a 1.36 times higher risk of dying from all causes than non-left-handed women. The adjusted HR for total mortality, after excluding the first 5 years of follow-up time, was 1.58 (95% CI = 1.03--2.42). With regard to cancer mortality, left-handed women had a 1.7 times greater risk of dying from any type of cancer (CI = 1.0--2.7), a 4.6 times higher risk of dying from colorectal cancer (1.5--14), and a 2.0-fold higher risk of dying from breast cancer (0.83--4.6). Handedness was weakly associated with overall mortality from diseases of the circulatory system (1.3, 0.54--3.3), although left-handed women had a 3.7 times greater risk of dying from cerebrovascular diseases than non-left-handed women. Left-handedness was not associated with mortality attributable to causes other than the above-mentioned.

A separate study from the same group of researchers (Ramadhani et al. 2006) also found that the severity of a bacterial meningitis infection correlated with handedness, such that those with stronger infections were more likely to become left-handed and lower in IQ. They note that since the infection happens before the other events, the former likely contributes to causing the latter (pp. 2528-9):

Fig. 1 shows that children with a meningitis severity score above the median had a 6.2 times higher risk of becoming lefthanded at school age compared to those below the median (95% CI 2.0--18.6). Furthermore, those who contracted meningitis below the median age of 1.8 years had a 12.3 times higher risk (95% CI 2.6--58.0) compared to a 5.9 times higher risk (95% CI 1.6--21.7) among children who contracted meningitis at older age.
. . .
More specific analyses on cognitive function are shown in Table 3, with left-handed children generally performing worse on the cognitive tests. Left-handed children had an almost seven points lower IQ (p = 0.018), a one point lower vocabulary score of WISC-r (p = 0.061), and an almost five points lower Beery score (p = 0.069) than their non-left-handed counterparts.

Turning next to handedness among pedophiles, Bogaert (2001) examined a Kinsey Institute dataset for the handedness data of 286 criminal pedophiles (those who had a victim of either sex under age 12). His findings, where NRH means Non-Right-Handedness (pp. 467-8):

Although the effects were small, it should be noted that a 5% difference means about a 30% change in NRH (e.g. 15.7% in pedophiles vs. 11.5% in controls).
. . .
In contrast, education is not related to the handedness/pedophilia relationship. Pedophiles had elevated NRH relative to controls with or without controlling for education. This result suggests that, even though pedophiles have a rate of NRH comparable to other offenders (or perhaps slightly higher), there may be a different mechanism underlying the handedness/pedophile relationship than the handedness/(general) criminality relationship. Thus, elevated NRH in pedophiles probably does not merely represent a 'criminal/antisocial behavior' tendency, because of, for example, general cognitive and/or educational difficulties. Instead, these data may indicate that elevated NRH in pedophiles reflects [Central Nervous System] abnormalities that, in part, directly affects their sexual preference systems (see [24] for a review of CNS abnormalities in pedophiles).

Next are two studies done by Cantor and colleagues. In the first, Cantor et al. (2004) examined men who were referred to a clinic for inappropriate sexual behavior, using phallometric responses (which measure penile arousal) to various erotic stimuli in order to divide the men categorically into pedophiles (those attracted to children under 12), hebephiles (those attracted to 12-16 year-olds), and teleiophiles (those attracted to adults). They found (p. 8):

The group differences did not change appreciably after the addition of the covariates [i.e., Age and Wechsler Full Scale IQ; agnostic], F(2, 294) = 6.31, eta^2 = .041, p = .002, and simple effects contrasts showed that both the pedophilia group and the hebephilia group reported significantly less right-handedness than did the teleiophilia group, t(294) = -3.51, eta^2 = .040, p = .001 (twotailed), and t(294) = -2.14, eta^2 = .015, p = .033 (two-tailed), respectively.

The researchers then used a continuous measure of sexual interest, namely the degree to which they become aroused when viewing different stimuli (p. 8-9):

The results indicated that, in general, measures of cognitive ability correlated negatively with sexual response to children and positively with sexual response to adults. Handedness, however, was significantly related to phallometric response to children, only. [From Table 4, partial correlation of arousal by prepubescent stimuli and handedness = -.13, p less than .05, where negative handedness indicates left-handedness; agnostic.] There was little evidence of association between the neuropsychological variables and sexual response to stimuli depicting pubescents in the laboratory.

They conclude that the relationship between handedness, cognitive ability, and pedophilia is that they are all caused by an early collection of brain perturbations, not that poor cognitive ability leads one (probabilistically) to develop pedophilic interests, since IQ was controlled for. Their follow-up article (Cantor et al. 2005) has two studies, the first of which was a successful replication of their previous findings. The second study classified patients categorically as right-handed or non-right-handed, in contrast to their continuous measure in the 2004 study, so that they could report Odds Ratios, making their results more comparable to those of other studies. By measuring penile arousal to stimuli involving adults, pubescents, and prepubescents, as before, the authors slotted the patients into those primarily attracted to one of the three age groups, as well as which sex they were most attracted to.

The relationship between sexual preferences and handedness was only significant for those attracted to prepubescents (although there was a trend toward lower right-handedness among those attracted most to pubescents), with or without controlling for IQ. Their Table II shows that after controlling for IQ in their logistic regression, the B-coefficient for age preference in predicting handedness was 1.26 (SE = .34), and the Odds Ratio was 3.54 (95% CI = 1.84--6.81), p = 0.0002. Next the researchers categorized the patients based not on their penile response to stimuli, but on their actual sexual offenses against others, again sorting by age and sex of the victim. At first, there was a trend in the same direction as the results obtained from measuring genital response, but the trends were not significant.

They thought that incest cases might be confounding the results -- for example, men who commit crimes against intrafamilial individuals might be engaging in a facultative behavior similar to men who have sex with men in prison, rather than have obligate pedophilic preferences. After removing patients who had intrafamilial victims, the results became significant. In particular, their Table V shows that in a similar regression analysis as before, the best predictor of handedness was a preference for prebubescents, even controlling for IQ: B = 1.06 (SE = .47), OR = 2.9 (95% CI = 1.15--7.28), p = 0.02. Admittedly the results are less striking when measuring sexual preferences according to their actual sexual offenses than when measuring it by their arousal to erotic stimuli, but this may well be because the latter is a purer measure of preferences, since it doesn't involve the vagaries of choosing and offending against a real person.

In sum, there is a significant relationship between non-right-handedness and pedophilic preferences, and this is likely the result of an early developmental disturbance to the brain. Since these studies were conducted in modern Western countries, things like lack of proper nutrition in the mother are probably not what's going on. As hinted at in the study of meningitis and handedness, it is more likely that an infection causes the damage -- these are one of the sources of environmental insults whose effects we still have yet to curtail, beyond ameliorating some of the more horrendous cases like smallpox. Of course, the pathogen responsible for non-right-handedness doesn't have to be the same as that which causes pedophilia; the affected individual might have been born in an unusually high pathogen-load area, or have a weakened immune system in general, and so on.

One thing seems pretty clear, though: common cases of deviance from Darwinian fitness are most likely caused by environmental insults, with pathogens being the most obvious culprit (see Cochran, Ewald, & Cochran 2000 for the rationale). That result isn't guaranteed a priori, but it is a far more reasonable "working hypothesis" for a particular case than imagining how, for example, pedophilia might have been adaptive in the past, or how it represents the tail of a distribution for "caring for children," or how pedophilia-normal heterozygotes might enjoy a fitness advantage, and so on. Mental, financial, and time resources are all limited, so we should follow the course that all good detectives do: first look at the person you most suspect, based on the accumulated knowledge of similar past cases. Real life is not a Law & Order episode where the least likely culprit routinely turns out to be the one who dunnit. If they're cleared, then move on to the exotic suspects.

Related: Left-handedness post from the archives.


Bogaert, AF (2001). Handedness, criminality, and sexual offending. Neuropsychologia, 39, 465-9.

Cantor, JM, R Blanchard, BK Christensen, R Dickey, PE Klassen, AL Beckstead, T Blak, & ME Kuban (2004). Intelligence, memory, and handedness in pedophilia. Neuropsychology, 18, 3-14.

Cantor, JM, PE Klassen, R Dickey, BK Christensen, ME Kuban, T Blak, NS Williams, & R Blanchard (2005). Handedness in pedophilia and hebephilia. Archives of Sexual Behavior, 34, 447-59.

Cochran, GM, PW Ewald, & KD Cochran (2000). Infectious causation of disease: an evolutionary perspective. Perspectives in Biology and Medicine, 43, 406-48.

Harpending, H & G Cochran (2006). Genetic diversity and genetic burden in humans. Infection, Genetics, and Evolution, 6, 154-62.

Ramadhani, MK, SG Elias, PA van Noord,DE Grobbee, PH Peeters, & CS Uiterwaal (2007). Innate handedness and disease-specific mortality in women. Epidemiology, 18, 208-12.

Ramadhani, MK, I Koomen, DE Grobbee, CA van Donselaar, A Marceline van Furth, CS Uiterwaal (2006). Increased occurrence of left-handedness after severe childhood bacterial meningitis: support for the pathological left-handedness hypothesis. Neuropsychologia, 44, 2526-32.

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