They used fMRI to show that the brains of teenagers with autism showed no activation differences to looking at smiling happy faces, or afraid faces, compared to unemotional ones. In teens without autism, there was strong activation in many emotional and face-related brain regions. The unaffected brothers and sisters of the autistic people showed intermediate effects.This is a fine study. The finding that siblings of people with autism have weakened neural responses to emotional faces is quite important as it suggests that this finding correlates (to some degree) with your position on the autism "spectrum".
The abstract of the paper actually downplays this, and says "The response in unaffected siblings did not differ significantly from the response in autism". However, there was a significant linear trend of group, and looking at the graphs, it's clear the siblings were In The Middle, like Malcolm.
There's plenty more nice things you could do with these results, which is an unusally large and rich dataset (120 people - 40 in each group). You could see, for example, whether siblings tend to be similar in terms of neural response. You could see whether the siblings who are most alike in brain response, are closest in symptoms. Or just look a the structural data on brain size and shape to see if there are characteristic differences between siblings that make one of the autistic and the other not.
There are a few problems. Most of the analyses are subject to the non-independence problem, because they defined their regions of interest based on the areas that showed a significant happy vs neutral face effect in the control group. So it's no surprise that when they generated graphs from these areas, the control group showed the strongest effect. However, they also do whole-brain analyses which avoid this problem and I don't think it undermines the main results.
So it's a decent study. But is this a "biomarker", or "endophenotype", as the title of the paper has it?
These are both hot topics in neuroscience at the moment. As the authors put it (emphasis mine):
An endophenotype is a heritable feature associated with a condition, present in affected individuals regardless of whether their condition is manifested, which co-segregates with the condition in families and which is present in unaffected family members at a higher rate than in the general population.The idea, in other words, is that if we can find a difference in the brains of people with autism, and their unaffected relatives who (presumably) share some of the same genes, we might have found a mechanism by which the genes ultimately cause the symptoms.
In such family members, endophenotypes represent instances in which genes associated with a particular condition exert measurable effects in individuals in whom they are insufficient to cause the condition itself...
The promise of characterizing endophenotypes lies in their hypothesized intermediate position between genotype and phenotype... the etiology of the endophenotype is likely to be correspondingly simpler: it can be said to be ‘closer to the level of gene action’.
It might be easier, then, to find the genes for brain-not-lighting-up-to-happy-faces, than it will be to find genes for autism. Then once we've found those, we can use them to better understand autism.
My concern is that, while in theory endophenotypes seem "closer to the genetics" because they're "biological" rather than "behavioural", this is just a philosophical illusion based on the idea that the mind is not the brain.
We actually have no idea whether brain-not-lighting-up-to-happy-faces is closer to genetics than autistic behaviour. I'd say that our default assumption should be that everything is exactly the same "distance" from DNA, that is to say, everything is the product of complex interactions between genes and environment.
Some things are under the more or less exclusive control of a small number of genes, and these are called "genetic", but it's important not to assume that just because something's "in the brain", it's probably "more genetic" in this sense. The brain is a product of the environment as well.
If you scanned my brain while playing an audio recording of Urda love poetry, not much would happen. I don't know Urdu. In someone who did speak Urdu, all kinds of language and emotional areas would light up. That doesn't mean Urdu-brain-response is genetic. It's exactly as genetic as speaking-Urdu, which isn't genetic.
Spencer, M., Holt, R., Chura, L., Suckling, J., Calder, A., Bullmore, E., & Baron-Cohen, S. (2011). A novel functional brain imaging endophenotype of autism: the neural response to facial expression of emotion Translational Psychiatry, 1 (7) DOI: 10.1038/tp.2011.18
13 comments:
Hi,
interesting post. Does it necessarily hold that if some measure is "closer to the genes" that it must therefore be less influenced by the environment (as I think you are suggesting)?
My understanding of the endophenotype argument is that it is based on two assumptions. Firstly it assumes a hierarchical causal chain from genes to behaviour (you know gene alters protein expression alters synaptic functioning alters cognitive processes alters behaviour kind of thing). Secondly it assumes that the further from the gene a particular measure is along this hierarchy, the more complex the relationship between the genotype and the measure is likely to be. However I don't think that the added complexity is necessarily environmental-- it could equally be genetic (e.g. perhaps more genes influence a behaviour than influence expression of a protein).
Anyway, if my logic holds, then you could argue that this fMRI finding represents an endophenotype of ASD without making any assumptions about environmental influence. You'd only have to assume that alterations in a range of cognitive processes contribute to the behaviours characteristic of ASD.
I guess you could argue that the activity of face sensitive neural circuits in response to emotional expression is no less complex than the associated set of behaviours (social communication difficulties), although it seems reasonable to me to suggest that the former may be one mechanism underlying the later.
Regardless, great blog and really interesting post.
Mike Browning
The major limitation I can see is that they didn't conduct eyetracking during testing. Dalton et al 2005 (Nat Neurosci) found that abnormal brain responses to faces in autism were a function of how much the subjects were looking at the eyes.
In this study, the subjects had to sit and stare at the faces for 4 seconds each. The results could potentially be explained away just as differences in attention to the faces or scanning patterns. This would be moderately interesting in itself but would hardly constitute a biomarker.
Also interesting that they didn't find anything in the amygdala (even in controls). Any ideas why?
It has been shown that affected and unaffected family members (parents and siblings) may share many subtle qualitative similarities in social cognitive traits but there are enormous differences between affected and unaffected family members. Autistic like traits, or the Broad Autism Phenotype, is not associated with intellectual disability, seizures or atypical brain development.
Sir Michael Rutter is known as the father of modern child and adolescent pyschiatry and prior to his retirement served as the European editor of the Journal of Autism and Developmental Disorders a science journal founded by Leo Kanner, the first editor of the Journal of Autism and Developmental Disorders.
Rutter has proposed a novel theory called the 'two-hit' mechanism hypothesis:
http://www.youtube.com/watch?v=0MVLH4B0tEU&feature=related
The hypothesis states that the genes underlying broader autistic phenotype may not be the same as the genetic and environmental factors involved in the disruption of early brain development and the transition to the handicapping disorder.
In other words, autism may involve the synergy between two independant component parts, the genetic infuences underlying the broad autism phenotype and the genetic and environmental factors involed in the transition to the handicapping disorder.
The genetic and environmental risk factors associated with autism are not diagnosis specific at all. These same genetic and environmental risk factors have also been linked to a broad spectrum of neurodevelopmental and neuropsychiatric disorders (autism, ADDH, bi-polar disorder, schizophrenia, childhood language disorders etc.).
If autism is a two-hit mechanism the implications are enormous. First, the search for the needle in the haystack may actually involve different needles in different haystacks. Seond, if it is a two-hit mechanism caused by the synergy between two independant mechanisms what the twin studies may actually be reflecting is not autism per se but rather the heritable genetic influences underlying the broad autism phenotype which is assumed to be present in all accurately diagnosed cases and may involve common genetic polymorphisms that tend to cluster within the families but also extend very broadly throughout the general population.
I'm not sure it's wrong to treat brain responses differently than behavior, exactly because the brain is roughly the same as the mind.
Behavior is one level removed from what's going on in the mind. People can perform the same behavior (e.g., having difficulty reading) for different reasons. Seeing that someone has trouble reading doesn't tell you anything much because of all the visual, attentional, phonological, and semantic processing involved, any of which could be impaired. The brain is the observable face of the mind, so yes, it should give you a more specific effect to trace back to the genetic level. In fact, I would even argue if you just look at behavior, you don't have anything to trace back to the genetic level.
But I'm guessing this isn't what these researchers mean by "endophenotype?"
Endophenotypes - when you can't find a significant relationship with the disease state and you need a positive result for your paper.
Could this go (be sensationalised) in an unexpected direction? Unaffected siblings -> low empathy -> psychopathy <-. Antisocial and offending behaviours among unaffected siblings etc. Would need to be careful how unaffected siblings are portrayed to the public. There is enough stigma out there for the whole family as it is.
Michael Browning: That's a good point, but it seems to me that the endophenotype interpretation of these results assumes a lot.
It assumes that there are genes for face-response, which don't cause autism per se, and that in some way these genes can cause autism when added to other genes that cause the other symptoms.
However this is an assumption. It assumes (as far as I can tell) that autism is polygenic. It might well be but we don't know, and I'd be very surprised if it were true in all cases.
We know that there are (thus far uncommon) cases of autism caused, seemingly, by a mutation affecting one gene, or a small number of genes.
In which case face processing abnormalities could be a downstream consequence of the neurobiology of autism, not a "piece of the puzzle".
And as Jon Brock says, the downstream consequence might not even be connected to the genetic cause via a "biological" pathway, it could be related to behaviour like eye movements.
Neuroskeptic: Sure, I didn't mean to suggest that this particular finding provides watertight support for the neuroimaging abnormalities being endophenotypes of ASD, rather I was interested in your genes/environment angle on the endophenotype question (which I hadn't previously considered).
I agree with all your caveats about this particular study and also with some of the more general caveats about endophenotypes in psychiatric diagnoses-- For example I've always been struck by the Munafo & Flint review a few years back in Psychological Medicine which (if I remember correctly) suggested that only 25% of the variance in mRNA expression (as the most proximal measure to the genes) could be explained by differences in genotype. If this is correct it suggests (to me) that more distal measures such as functional neuroimaging may well have such a complex relationship with the genetics as to render them little better than phenotype.
However, I haven't yet achieved the zen like cynicism of pj, so I would also add that the underlying assumptions of the endophenotype argument seem reasonable to me (e.g. I think the genetic components of the majority of psychiatric problems with which patients present are likely to be polygenic). It also seems to me that the best way to improve the often woeful treatments in psychiatry is by improving our aetiological understanding of patients' problems and that identification of reliable endophenotypes would be a good first step in this process.
Although I am a psychiatrist so maybe I'm biased.
Mike
I like your allusion to the ethnocentrism of the studies. This is THE problem with almost very form of Diagnostic Criteria manual i've read/skipped through/cringed at.
They are overwhelmingly written up by western culture based minds.
The methods based thereon too, the software, hardware, test facilities, test setup's etc.
That way no diagnostic criterion, or results confirming/disproving them can ever be assumed universal.
Culture driven genetical adaptation is virtually invisible.
Nowadays with more intercultural breeding this can only obfuscate the matters even more.
PS
I hate those smiley faces, put me in that test and a whole other part of my brain lights up.
Petrossa:
These are examples of the stimuli they actually used.
Spencer et al reckon that people with autism have less empathy for these faces. Can't say I blame them.
Well that didn't work
http://2.bp.blogspot.com/_IA5nokOFh84/SVwdDyZMV3I/AAAAAAAACvU/gBuL02jem7Q/s1600-h/facialexpression.jpg
<<
pj said...
Endophenotypes - when you can't find a significant relationship with the disease state and you need a positive result for your paper.>>
Except, PJ, if you actually read the paper, the authors of this paper do report significant results for the disease state (i.e. autism versus controls) and for the endophenotype.
I think PJ was making a general comment about endophenotype studies...
Post a Comment