Friday, September 22, 2006

An "Endophenotype" For Sexual Orientation?

OR: The Neuroscience of Porn, according to The Frontal Cortex.

Wiktionary defines endophenotype as "any hereditary characteristic that is normally associated with some condition but is not a direct symptom of that condition."

Gottesman and Gould (2003) have this to say:
Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward—and successful—genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.

Gottesman II, Gould TD (2003). The endophenotype concept in psychiatry: Etymology and strategic intentions.
Am J Psychiatry 160:636-645.
However, for the study under discussion here, the "endophenotype" for sexual orientation is not diagnostic for a disorder of any sort, but merely for whether an individual (and his/her ventral premotor cortex) prefers to view pictures of the aroused genitals from one sex or the other. Do a Google seach for endophenotype, and the links are, in fact, mostly about disorders like schizophrenia, ADHD, autism, impulsivity, alcoholism, etc. Same for a PubMed search. Already we're dealing with a slightly loaded term, then, because the word endophenotype is associated with disorder.

But what about the pornography? Here it is,1 in NeuroImage:
Ponseti J, Bosinski HA, Wolff S, Peller M, Jansen O, Mehdorn HM, Buchel C, Siebner HR. A functional endophenotype for sexual orientation in humans. Neuroimage 2006 Sep 14; [Epub ahead of print]

Sexually arousing visual stimuli activate the human reward system and trigger sexual behavior. Here we performed event-related fMRI during visual processing of sexual core stimuli to pinpoint a neuronal correlate of sexual preference in humans. To dissociate gender of the stimulus from sexual preference, we studied male and female heterosexual and homosexual volunteers while they viewed sexual and nonsexual control stimuli. In contrast to previous work, we used core single-sex stimuli displaying male and female sexually aroused genitals. Since stimuli lacked any additional contextual information, they evoked no activity related to neuronal processing of faces, gestures or social interactions. Our prediction was that the sexual preference of the observer determines the neuronal responsiveness to pure male or female sexual stimuli in the human reward and motor system. Consistent with our prediction, the ventral striatum and the centromedian thalamus, showed a stronger neuronal response to preferred relative to non-preferred stimuli. Likewise, the ventral premotor cortex which is a key structure for imitative (mirror neurons) and tool-related (canonical neurons) actions showed a bilateral sexual preference-specific activation, suggesting that viewing sexually aroused genitals of the preferred sex triggers action representations of sexual behavior. The neuronal response of the ventral striatum, centromedian thalamus and ventral premotor cortex to preferred sexual stimuli was consistent across all groups. We propose that this invariant response pattern in core regions of the human reward and motor system represents a functional endophenotype for sexual orientation independent of the gender of the observer and gender of the stimulus.
OK, let's look at the study's German participants. There were 12 straight men, 12 straight women (0 or 1 on the Kinsey scale, meaning exclusively heterosexual or predominantly heterosexual) and 15 gay men, 14 gay women (Kinsey 6, meaning exclusively homosexual or 7... what's a Kinsey 7?? maybe they meant 5 and 6?). Anyway, those in the middle were excluded (sorry, all you bisexual Kinsey 2-4's out there, left out again). Below is the Kinsey Scale:




Exclusively heterosexual


Predominantly heterosexual, only incidentally homosexual


Predominantly heterosexual, but more than incidentally homosexual


Equally heterosexual and homosexual


Predominantly homosexual, but more than incidentally heterosexual


Predominantly homosexual, only incidentally heterosexual


Exclusively homosexual

So in the scanner, the participants viewed, in random order, 30 pictures of female genitals, 30 pics of male genitals, and 30 neutral stimuli. The task was to press a button when an oddball target stimulus appeared (a green square). Immediately after the scan, the subjects rated the visual stimuli on arousal and valence.

Arousal ratings conformed more or less to the predicted pattern. In Fig. 1 above, the post-hoc comparisons between nonsexual stimuli (gray bars) and preferred sexual stimuli (red bars) are significant for all groups (albeit to a smaller degree for the straight women). In general, ratings for preferred vs. nonpreferred sexual stimuli were more discrepant in men than in women (regardless of orientation).

For the fMRI results, the authors defined 3 regions of interest, based on a priori hypotheses:

1. Centromedian Thalamus (and adjacent ventral striatum) - reward system [striatum, yes, but thalamus??]

2. Orbitofrontal Cortex - reward system

3. Ventral Premotor Cortex (PMv) - "motor representations of sexual behavior" [genital mirror neurons??]

Note that the amygdala was not among the ROIs, even though others have observed greater amygdala activity when viewing sexual stimuli compared to neutral stimuli (e.g., Hamann et al., 2004; see the Comments section of Sweat, Urine, and Sexual Orientation for a review of sex differences in brain activity when viewing porn clips). Come to think of it, the hypothalamus wasn't selected as an ROI, either. Hmmm, makes one wonder whether the ROIs were a posteriori...

Anyway, the red bars in the figure above (preferred sexual stimuli) depict greater activity than the yellow bars (nonpreferred sexual stimuli), which held for all four groups in thalamic regions, PMv, left superior parietal lobule [hey, what's that about??], but not orbitofrontal cortex.

Here's a thought. According to Wikipedia,
a mirror neuron is a neuron which fires both when an animal performs an action and when the animal observes the same action performed by another (especially conspecific) animal. Thus, the neuron "mirrors" the behavior of another animal, as though the observer were himself performing the action.
The Neurocritic is as skeptical as anyone about the mirror neuron craze, but if the PMv activity in this experiment is really imitative in nature, or even "empathetic" (instead of motor imagery or motor preparation), then wouldn't same-sex genitals elicit greater activity than opposite-sex genitals, regardless of sexual orientation?

Never mind.
The foci of premotor activation closely corresponded to the site that was found to be activated by observation of hand or mouth movements (Buccino et al., 2001) and by the observation of action-related objects (Grezes et al., 2003).

The observation of sexually aroused genitals of the preferred sex may trigger neuronal activity of mirror neurons or canonical neurons in the PMv. Sexually aroused genitals of the preferred sex are targets of manipulative actions during mating. Thus, in analogy to tools [NOTE: !!], these stimuli can be conceptualized as action-related objects which may activate canonical neurons in the PMv. Beyond its significance as a tool-like target, a sexually aroused genital belongs to an agent and indicates the motivational and bodily state of the agent (i.e., the readiness to mate).
[NOTE: So what would happen if you showed pictures of sex toys or sexbots or or... never mind.]

Ventral premotor mirror neurons may be involved in understanding the intention of the sexually preferred agent and activating a repertoire of volitional sexual actions.
[Hmm, seems like you could program a robot that way...]

But here's the bottom line:

We propose that this response reflect the activation of motor representations of manual or oral sexual behavior.
They really don't discuss the endophenotype idea much more, except to say,

We show a strong relation between the neuronal response and sexual orientation in distinct structures of the human reward and motor neuron system. ...the specific activity pattern induced by preferred sexual stimuli was remarkably invariant across heterosexual and homosexual males and females. In contrast to sexual preference, the sex of the stimulus and of the observer had no influence on the neuronal response to sexually aroused genitals. Therefore, we propose that the observed response pattern represents a functional endophenotype for sexual orientation in humans.

OK, then. Here's a teaser for a future post.
Moulier V, Mouras H, Pelegrini-Issac M, Glutron D, Rouxel R, Grandjean B, Bittoun J, Stoleru S. Neuroanatomical correlates of penile erection evoked by photographic stimuli in human males. Neuroimage 2006 Sep 6; [Epub ahead of print]

The objective of this study was to identify the cerebral correlates of the early phase, and of low to moderate levels, of penile tumescence using for the first time a volumetric measure of the penile response. We hypothesized that (i) regions whose response had been found correlated with circumferential penile responses in previous studies would be identified with volumetric plethysmography and (ii) that other brain regions, including the amygdalae, would be found using the more sensitive volumetric measurement. In ten healthy males, functional magnetic resonance imaging (fMRI) was used to study brain responses to sexually stimulating photographs and to various categories of control photographs. Both ratings of perceived erection and penile plethysmography demonstrated an erectile response to the presentation of sexually stimulating photographs. Regions where the BOLD signal was correlated with penile volumetric responses included the right medial prefrontal cortex, the right and left orbitofrontal cortices, the insulae, the paracentral lobules, the right ventral lateral thalamic nucleus, the right anterior cingulate cortex and regions involved in motor imagery and motor preparation (supplementary motor areas, left ventral premotor area). This study suggests that the development of low levels of penile tumescence in response to static sexual stimuli is controlled by a network of frontal, parietal, insular and cingulate cortical areas and that penile tumescence reciprocally induces activation in somatosensory regions of the brain.

The paper did not provide any examples of the stimuli used in the experiment. The reviewers apparently missed out on the opportunity to request that such images appear in an Appendix. But here's the verbal description (Ponseti et al., 2006).

First, sexual stimuli had to be specific to one or the other sex. Second, sexual stimuli should lack any further context information to avoid confounding brain activation related to neuronal processing of faces, gestures or social interactions. To meet these constraints we used photographs of naked male or female trunks displaying signs of genital arousal without showing the head or distal limbs. In addition we presented matched nonsexual photographs of the International Affective Picture System (IAPS) (Lang et al., 1997) as control stimuli. Male sexual stimuli showed an erected penis, female sexual stimuli showed details of the vulva (labia, clitoris, moist). The torso was sometimes visible together with the genitals, but the face or the limbs were never displayed on the photographs.


Buccino G, Binkofski F, Fink GR, Fadiga L, Fogassi L, Gallese V, Seitz RJ, Zilles K, Rizzolatti G, Freund HJ (2001). Action observation activates premotor and parietal areas in a somatotopic manner: an fMRI study. Eur. J. Neurosci. 13: 400-404.

Grezes J, Armony JL, Rowe J, Passingham RE (2003). Activations related to "mirror" and "canonical" neurones in the human brain: an fMRI study. NeuroImage 18: 928-937.

Hamann S, Herman RA, Nolan CL, Wallen K. (2004). Men and women differ in amygdala response to visual sexual stimuli. Nat Neurosci. 7: 411-6.

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At September 28, 2006 3:37 PM, Blogger pneuro said...

Endophenotype? An interesting idea for psychiatry (thx for the great G+G snippet) – a simple and incidental clue for a complex genetic syndrome. G+G may have crossed a structure/function line when they include “cognitive and neuropsychological” data (e.g., behavior) with purely physical manifestations of genes. But that’s an issue for psychiatry, isn’t it? If I’m bipolar, perhaps genes are determining my behavior in some way. But now come Ponseti el al. to casually extend that determinism to all of us and our sexual orientations. Hold on a minute.

Right off the mat, the responses they are looking at are not simple and incidental clues; they are quite obviously advanced, learned behaviors. (Maybe the authors have found the neurological underpinnings to fetishism instead.) Remember a few years ago when it was briefly claimed that lesbians had a unique set of finger-lengths? Now THAT would have been an endophenotype.

OK, about their mirror neuron nonsense. They are so enthralled by the supposed evidence from tool use and eating, that they imagine mirror neurons must only apply to mouths and hands. Hey, if these things exist at all (rather than being manifestations of, say, networks by which we organize our understanding of self/others/the world), then they are going to reflect the activity of ANY bodily “tool !” (I mean knees and elbows and feet, silly.)

Next, a major issue with all fMRI work, what might be called the Subtraction Magic Problem. People designing these studies do their interpretive magic by the assumptions they build in to the subtractions of experimental events. Here, we are asked to believe that pictures of one aroused gender, but not the other, will be found stimulating, so that one set of reactions can be subtracted from the other. Hmm, seems like the authors are sneaking in some covert inhibitory effects here. Their idea of sexual orientation includes being turned OFF by the “wrong” stimulus. Anyone who isn’t, goes in the reject pile with the rest of us bi’s.

There sure is an fMRI bonanza going on. As usual, the deconstructions they yield are of the mind-set of the experimenters.

At September 28, 2006 10:35 PM, Blogger The Neurocritic said...

Thanks for the thoughtful comments, pneuro, you made many good points.

(Maybe the authors have found the neurological underpinnings to fetishism instead.)

Are you proposing a new fMRI experiment?? Doh! How do you suppose we solve the Subtraction Magic Problem (related to the glowing plastic tube effect)?

To follow up on the lesbian finger-length comment, now [supposedly] finger length is linked to female sporting potential.

Finally, hmmm, as far as being turned off by the "wrong" stimulus, isn't that [supposedly] less the case for women in general than for men? Or at least it is if you believe this article:

Chivers ML, Rieger G, Latty E, Bailey JM. (2004). A sex difference in the specificity of sexual arousal. Psychol Sci. 15:736-44.

Sexual arousal is category-specific in men; heterosexual men are more aroused by female than by male sexual stimuli, whereas homosexual men show the opposite pattern. There is reason to believe that female sexual arousal is organized differently. We assessed genital and subjective sexual arousal to male and female sexual stimuli in women, men, and postoperative male-to-female transsexuals. In contrast to men, women showed little category specificity on either the genital or the subjective measure. Both heterosexual and homosexual women experienced strong genital arousal to both male and female sexual stimuli. Transsexuals showed a category-specific pattern, demonstrating that category specificity can be detected in the neovagina using a photoplethysmographic measure of female genital sexual arousal. In a second study, we showed that our results for females are unlikely to be explained by ascertainment biases. These findings suggest that sexual arousal patterns play fundamentally different roles in male and female sexuality.

At September 30, 2006 9:10 PM, Anonymous Anonymous said...

The Neurocritic writes:

OK, let's look at the study's German participants. There were 12 straight men, 12 straight women (0 or 1 on the Kinsey scale, meaning exclusively heterosexual or predominantly heterosexual) and 15 gay men, 14 gay women (Kinsey 6, meaning exclusively homosexual or 7... what's a Kinsey 7?? maybe they meant 5 and 6?).

I guess you didn't get the memo, Neurocritic. Kinsey didn't have his scale go to 7, but it has since been extended to that point in order to accomodate what Kyle on South Park would refer to as "Liberace Gay". At least, that's the best theory I can come up with.

Now, as far as endophenotypes go...pneuro is correct that this is the sTuPiDeSt claimed endophenotype of all time. I think pneuro is being slightly hard on the "core" mirror neuron people (as opposed to the more loosely associating types like, well, Ramachandran, not that I wanted to drop that name), but there is clearly an abuse of the mirror concept in this case. (And I won't even get into the notion of self-abuse vis a vis mirror neurons here, even though I think it could be scientifically relevant, because this is a "family" blog.)

In other news, I think I know where to email the "Rise Robots Rise" mp3 if it can be confirmed that this would not overload the Neurocritic's email quota.

At October 01, 2006 8:24 PM, Blogger The Neurocritic said...

No, guess I didn't get the memo:

On the South Park episode "Chinpokomon", after the South Park kids are shown the fake commercial for Alabama Man (a Ken doll/action figure who goes bowling, chews tobacco, drinks beer, and beats up his wife), Kyle refers to the toy as "Liberace gay". - Kinsey 7?

And looks like it'll be All Mirror Neurons, All the Time" redux.

Finally, the robot mp3 will not overload my gmail e-mail quota. Thank you, Anonymous!

At October 19, 2006 3:38 PM, Blogger pneuro said...

Thank you, Neurocritic!
Yes! For our fetish experiment we would enroll avowed fetishists, and a matched group of naïve prudes. We would induce “Ponsetian arousal” in one group but not the other with innocuous fetish images (silk rope, feather duster, black lace garter), and vice-versa with matrimonial icons (bride-and-groom cake decoration, cans tied behind a car, blue satin garter). Then we would announce an endophenotype for sexual SYLE, on a 0 – 6 scale of missionary-to-pervert.

Experiment B would selectively recruit shoe, glove, and vampire fetishists. We would replicate Pulvermueller (TICS 2001), who found separate activation in foot, hand, and mouth areas, for words like “kick, hit, bite.” Of course, we’d be looking at foot, hand and NECK roi’s.

Mirror neurons. Look, Anonymous, I’ve enjoyed reading the MN literature as much as the next person. It’s been one of the fresher breaths of air blowing across the barren neuroscience landscape this past decade (Rama, too!). But I have a few basic questions.

For one, it seems to me that if your lab uses single-cell recording technology, then your discoveries are bound to be….single cells! I don’t see how the apparatus can tell if (as seems almost certain) the cell is firing as part of a distributed network.

The early work contrasted an animal doing something itself (reaching for food),. and SEEING another animal doing it, as tho the seeing should have been done instead by the visual system. But what we really have is NOTICING (in scientificalese, “focusing attention”). If the animal notices that another is doing something it does itself, then it already has that commonality in its meaning system, so why not some neural commonality? It sometimes seems that the researchers expect the second awareness (of others) to occur without neural events. But non-neural mentation = immaculate conception!

The Subtraction Surprise Problem in neuroimaging. What to do about it? To start with, I highlight the subtraction description in each article,and whatever justification is given. This is usually very little. I suspect it’s because the leap is inductive, and explanations of inductive reasoning tend to look tautological, so that they are usually subsumed under a tacit obviousness. I just saw an article that addresses the leap of faith implicit in neuroimaging studies, and hope that it turns out to be as good as its first impression: Van Lancker Sidtis, “Does functional neuroimaging solve the questions of neurolinguistics?” Brain and Language 98,3:276-290 (Sept. 2006). At least, the discussion begins.

At October 20, 2006 6:35 PM, Blogger The Neurocritic said...

Pneuro, we must start collaborating!

For Experiment A, we'd have to carefully screen for fetish enthusiasts who are pro-marriage (not as a fetish), they do exist. These individuals may score as 3's on the Pneuro scale, equally aroused by silk ropes and cans tied behind a car.

Experiment B is perfect! We could look for co-activation of the fetish-specific somatatopic Pulvermuellerian neuron web and the medial preoptic area/anterior hypothalamus using Dynamic Causal Modelling.

Uh, one last thing for now. Rama? A breath of fresh air??

At October 20, 2006 7:12 PM, Blogger Sandra said...

You could tie the cans to the car with silk ropes...

At October 20, 2006 8:12 PM, Blogger The Neurocritic said...

Oops, I put in the Pulvermüller link for Dynamic Causal Modelling (Friston et al., 2003).

At December 03, 2006 6:54 PM, Blogger jj_gunn said...

Hey there neurocritic. I just read the article and somehow the stars aligned and I had the absolute pleasure of running into your blog. I couldn't be more happy with your discussion. My initial response was --talk about generalizing beyond the results of the data. I have been consistently disappointed with the peer reviews in the neuroimaging arena. This is a good example of the need to be reserved in generalization especially if your talking about sexual orientation! I also think the authors should really have to come clean with their agenda. Why are they doing this work? What is the point in looking for the endophenotype? Thanks for pointing out the subtraction problem.

I can also help out with the network analysis. We can certain seed a partial least squares analysis with the Pulvermueller region and try to find co-activation of the fetish-specific somatatopic Pulvermuellerian network and the medial preoptic area/anterior hypothalamus.

At December 03, 2006 10:53 PM, Blogger The Neurocritic said...

Hey jj_gunn, thanks for stopping in for a visit. I sure could use your help with the network analysis...


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