Tuesday, May 20, 2008

CNVs and Autism/ Schizophrenia

I had been meaning to comment on a recent paper that found that rare and de novo Copy Number Variants (CNVs) were more common in schizophrenics as compared to controls.

Copy number Variants is a type of variation in the genome of two individuals. Whole genes or big chunks of DNA may get deleted or duplicated in individuals leading to CNVs. It is important to stress that each individual has two copies of a gene. Now it might happen that the whole gene from one of the parents gets deleted leaving the individual with only one functional gene. It may also happen that one of the DNA strands, instead of having a single gene sequence, has multiple such sequences leading to duplication. These sort of duplications and deletions can also have deleterious effects. this type of variation between genomes of individuals is as opposed to the Single Nucleotide Polyphormism (SNPs) in which normally only a single base changes and this may or may not lead to change in amino acid being transcribed. The two variants of genes that differ by such a single base change are referred to alleles and we have dominant or recessive genetic disorders based on whether both genes have to be of the same deviant mutation to confer susceptibility to disease.

CNVs on the other hand present a different model of disease. One can have one or more types of CNVs (deletions, duplications, multiple duplications etc) associated with the same genetic code sequence and this in my view would lead to spectrum like diseases where one may find variations along a continuum on a particular trait- based on how many copies of the genetic sequence one has. One would remember that I adhere to a spectrum based view of schizophrenia/psychosis and also a spectrum based view of Autism. Moreover I believe that Schizophrenia and Autism are the opposite ends of the spectrum, whose middle is normalcy and that the appropriate traits may have to do with social brain, creativity etc.

now as it happen previous research has also found that CNVs are also found to a higher extent in autistics. Moreover, research has indicated that the same chromosomal regions have CNVs in both Autism and Schizophrenia. To me this is exciting news. Probably the chromosomal region (neurexin related is one such region) commonly involved in both schizophrenia and autism is related to cognitive style, creativity and social thinking. Qualitatively (deletions as opposed to duplications) and quantitatively (more duplications) different type of CNVs may lead to differential eruption of either Schizophrenia or Autism as the same underlying neural circuit gets affected due to CNVs, though in a different qualitative and quantitative way.

One of the readers of this blog, 'concerned heart', in a comment on an earlier post ,though has taken the new finding to imply that autism and Schizophrenia (especially childhood onset schizophrenia) is one and the same. Nothing could be farther from the truth. They are the same spectrum conditions and both are due to deficits in the same brain circuit/ mind module. Yet the deficits in one are the reverse of that found in the other and they are opposite ends of the spectrum. The mere fact that both involve CNVs and that too near the same chromosomal region, is not sufficient to warrant that they are the same. It would be akin to saying that because both sickle cell anemia and Huntington disease are due to SNPs , they are the same disorder. Nothing could be farther from the truth. I'm stretching the analogy too far, but this is just to stress that the role of CNVs in both the diseases do not imply that both diseases are same. However, some overlap , or even the same gene, could be involved in both Autism and Schizophrenia as they indeed are opposite ends of a spectrum. It may be like a gene for height (although life is not so simple that there is only one gene for height) ---one sort of disruption of the gene may lead to dwarfism ; while the other may lead to an unusually high height.

However, I do not claim to fully understand the significance of CNVs or how they can have deleterious effects; but it is heartening to note that CNV mechanism may be a viable alternative to multiple genes coming together additively to bring about complex effects. If I understand correctly rare de novo CNV is equivalent to shearing of a single gene and could lead to deleterious effects on the scale of complex symptomatology like that of autism or schizophrenia. I'll be watching this CNV business quite keenly, but meanwhile I stand by my position that this in no way proves that Autism and schizophrenia are the same condition.If at all it juts bolsters the argument that they are opposite disorders of the same gene/ loci/ trait/ brain system.

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Monday, May 19, 2008

Autism and Schizophrenia: Chris Frith on my side

I was reading the excellent new book by Chris Frith titled " Making up the mind: how the brain creates our mental world" and was delighted to discover that Chris Frith, a leading world authority on Schizophrenia (and whose wife Uta Firth is a world authority on Autism) also contrasts Autism and Schizophrenia along the social, mind-reading dimension.

To quote from his book:

We understand that people’s behavior is controlled by beliefs even if these beliefs are false. And we soon learn that we can control people’s behavior by giving them false beliefs. This is the dark side of communication.

Without this awareness that behavior can be controlled by beliefs, even when these are false, deliberate deception and lying are impossible. In autism this awareness seems to be lacking, and people with autism can be incapable of deception. At first thought the inability of the autistic person to lie seems to be a charming and desirable trait. But this trait is part of a wider failure to communicate, which also makes people with autism seem rude and difficult. It can often make them lonely and friendless. In practice, friendly interactions are maintained by frequent little deceptions and circumlocutions that sometimes hide our true feelings.

At the other extreme from autism lies the person with paranoid schizophrenia who is aware of intentions that are invisible to rest of us. For the person with paranoia every statement can be a deception or a hidden message that has to be interpreted. Hostile statements can be interpreted as friendly. Friendly statements can be interpreted as hostile.

One person heard voices saying “Kill yourself ” and “He’s a fool.” He described these voices as two benevolent spirits who wanted him to go to a better world. Another person heard voices saying “Be careful” and “Try harder.” These were “powerful witches who used to be my neighbours . . . punishing me.”

This hyperawareness of the intentions and feelings of other people can be so intense as to be overwhelming.

The walk of a stranger in the street could be a “sign” to me that I must interpret. Every face in the windows of a passing street car would be engraved on my mind, all of them concentrating on me and trying to pass me some kind of message. . . . The significance of the real or imagined feelings of people was very painful. To feel that a stranger passing on the street knows your innermost soul is disconcerting. I was sure that the girl in the office on my right was jealous of me. I felt that the girl in the office on my left wanted to be my friend but I made her feel depressed. . . . The intensity with which I felt [these impressions] made the air fairly crackle when the typists in question came into my office. Work in a situation like that is too difficult to be endured at all. I withdrew farther and farther.


In such a state the possibility of meeting other minds has been temporarily lost. This vivid experience of the minds of others no longer corresponds to reality. Like the person with autism, the person with paranoia is alone.

It is important to pause here and note that there are two issue involved in the concept of the social brain. In words of Frith himself:

Perhaps the most important attribute of the social brain is that it allows us to make predictions about people’s actions on the basis of their mental states. This assumption that behaviour is caused by mental states has been called taking an ‘intentional stance’ (Dennett 1987) or ‘having a theory of mind’ (Premack & Woodruff 1978). The largely automatic process by which we ‘read’ the mental states of others is called mentalizing.


Thus, the deficits (and the excesses) in Autism (and schizophrenia) with relation to the social mind may arise from deficits in both of the processes involved. I have argued earlier that Schizophrenics/ Psychotics have too much of an intentional stance and have an animistic bias, while the reverse is true of Autistics. Similarly others , based on Mirror Neuron deficits have argued that the capacity to mentalize or infer mental states of other is impaired in Autism. The capacity to infer mental state sof others may be enhanced in schizophrenics/ psychotics (thus making them better artists/ writers).

To me having the Friths on my side is very important. Chris Frith is a very engaging author and I highly recommend his book Making up the Mind to all the readers of this blog. He doesn't tackle the question of consciousness; but on the other hand shows brilliantly - how, effortlessly and unconsciously, our brain helps us navigate the physical as well as the social world.

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Friday, May 02, 2008

'A' is for a RED apple and 'V' is for a PURPLE van!

New research has unearthed that the grapheme-color synesthesia is not idiosyncratic , but follows some typical patterns. Grapheme - color synesthesia is one of the common types of synesthesia wherein one sees color associated with visualizing an alphabet / letter. Thus, whenever one see the alphabet 'A' one may also have a perception of color 'red'. Till now, it was believed that this association of colors with alphabets was random and idiosyncratic; but new research has now revealed that it follows a pattern with most synesthetes more likely to associate typical colors with alphabets and for example report 'A' as red and V as 'purple'.

Jamie Ward's team that found this phenomenon speculates that the hue could be associated with the frequency of the word. Thus, as 'A' is a frequently used word it is associated with a common color 'red'. 'V' which is infrequently used in the lexicon is associated with a similar infrequently encountered color purple. I am not sure how their new study is different from their earlier study that also found thus association and I believe that there would be some truth to their theory. however, the science daily article also talks about saturation. So I though I would jump in.

Colors can be conceptualized as per the HSV/ HSL or HSB system and understood in terms of hue , saturation and value/ brightness. I would personally be inclined to interpret the 'A' is red and 'V' is purple mapping as the outcome of a mapping of the alphabet order (a, b, c, ....x, y, z) to the color order in the rainbow / hue dimension (VIBGYOR). 'A' is one end ofthe spec trim and thus red in color, while 'V' is on another end of spectrum and thus more likely to be 'violet' in color. The frequency of usage of the alphabet should ideally map to brightness/ value of the synesthete color as in color space value is mapped to the amount of light reflected. saturation or 'purity' of color is a bit difficult to map onto the alphabet; but one could venture forth and suggest it has to do with how 'pure' the alphabet is ....is it always pronounced in one way....or are their multiple pronunciations associated with the same alphabet.

Mapping a linear progression of hues along VIBGYOR axis to alphabet order or numeral oredr is not that hard to envisage or visualize. If neurons of adjacent colorotopic and lexicotopic maps (assuming there are such maps for color and lexicon in the brain) in the brain overlap/ cross-over we would have the phenomenon of grapheme-color synestehesia that accounted for the commonalities in hues and alphabet association. However, we just know of retinotopic sort of maps in brains and these fit in with our existing knowledge. How the brain stores information about saturation/ value and correspondingly frequency and purity of alphabets and maps between the too, can lead to novel insights as to how information is stored in the brain.

I am excited and believe that we are on verge of breaking new ground ( I haven't read the new Jamie ward paper though yet) and I have my own theories on why color is so important and may provide us many more clues (color and music are two most interesting phenomenon I believe). Are you excited? Do you have any theories?

PS: I just found that Jamie Ward is writing a book called "The Frog who Croaked Blue: Synaesthesia and the Mixing of the Senses” in which he recounts the experience of a synesthete who heard frog croaks as blue and chirping of cricket as red. To me this immediately conjures up the colortopic map with red at one end (high, feminine, shrill noises) and blue at the other (more manly, bass noise). This mapping of sound with colors may again follow the hue, saturation and value (three dimensions) with loudness of sound being proportional to the value of color being perceived and the hue and pitch mapped. Also , this may be an idiosyncratic experience, or this may be true of the species as a whole that we map more shrill noises to red and soothing and duller sounds to blue/ violet.

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