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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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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'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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Psychology of Facebook: chance to participate

Dr. B J Fogg, who teaches the Psychology of Facebook course at Stanford , has kindly written by way of a comment to an earlier post, that Mouse Trap readers who wish to know more about the project and want to participate, can join the Facebook group for that course. They keep everything updated on the group page and you can read about what they are doing and how you can participate there.
I, myself, have subscribed to the group as I being a web 2.0 enthusiast too, find the topic to be pertinent and interesting.

They also keep a blog and it is worth checking out. For example one of the recent entries shows how the facebook community is a sucker for apps titled "Share the Love"; but are put off by apps titled 'Declare war'. Apparently web2.0 is all about sharing, caring and making love and not about making war or competing.

By the way, I have seen a trend among bloggers to have a group page on facebook regarding their blog. I'm not sure of the utility of such a page, but an opportunity to connect is always welcome. In case some of you are keen, we can start a mouse trap community on facebook.

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God is just a type I error!

Yes, believe me God is an error and that too a type I error. But before we appreciate the subtleties of that argument, we have to first learn a bit about error management theory ( not to be confused with the TMT or terror management theory about which too I have blogged previously). EMT in simple terms is an evolutionary theory that posits that we do not minimize the number of errors that are possible when we are faced with ambiguous situations and corresponding ambiguous decisions to make; but that we minimize the total costs associated with making the errors. To simplify, whenever we make a decision about reality that is based on our inferences then we can make two types of errors : in type I errors we assume/ infer something to be real, while the phenomenon is itself unreal (this is a false positive);l while in type II errors we assume/infer something to be unreal while the phenomenon is real.

To take by the way of an example , if we are in a jungle and hear a sound in a bush ; then if the sound was from a lion and we inferred that it was not from a lion we make a type II error; if the sound was not from a lion, but we infer that it was from a lion we make a type I error. Obviously in this case it is best to make a type I error as a type II error can mean death. Evolution would thus select for a behavior that is biased towards the flase positive inferences in this case.

I'll now let Haselton define the theory and give examples:

Error management theory proposes that the direction of a bias in social judgment is tied to how costly different kinds of errors are. For example, consider how smoke alarms are designed. Failures to detect fires (false negative errors) are extremely costly, whereas false alarms (false positives) are usually just inconvenient. So, when engineers make smoke alarms, they tend design them to be biased away from the more costly false negative error by setting a low threshold for fire detection. As a consequence, smoke alarms will tend to be systematically biased toward false positive errors (false alarms). A low threshold for fire detection will cause smoke alarms to make more errors overall, but it will minimize the cost of errors when they inevitably occur (i.e., the errors will tend to be false alarms rather than missed fires).

Error management theory proposes that the same principle of design applies to the evolution of judgment mechanisms in the human mind. Ancestrally, in many areas of social judgment, the costs of false positive and false negative errors differed. When the costs of false negatives are greater, error management theory predicts a bias toward false positives (as in the smoke alarm example); when the costs of false positives are greater, error management theory predicts a bias toward false negatives.

One example of a false-positive bias is in men’s estimations of women’s sexual interest. For an ancestral man, failing to detect sexual interest in a woman resulted in a missed reproductive opportunity, which was highly costly to his reproductive success. The opposite error (believing that a woman was interested when she was not) was perhaps a bit embarrassing, but probably was less costly overall. Thus, error management theory predicts that natural selection designed a bias in men toward slightly overestimating a woman’s sexual interest in order to reduce the likelihood of a missed sexual opportunity; this leads modern men to “overpercieve” women’s sexual interest.

Satoshi Kanazawa, who has applied the error management theory to the above men-think-women-are-attracted-to-them behavior has a two part post over at his psychology today blog that is worth reading in entirety. There he argues that we believe in god, because of an inbuilt bias to detect agency. He says that detecting agency when none is there can only lead to paranoia in the worst case, while not detecting agency when there was one could lead to death. He has a beautiful figure illustrating the same and I post it here.

Different theorists call this innate human tendency to commit false-positive errors rather than false-negative errors (and as a consequence be a bit paranoid) “animistic bias” or “the agency-detector mechanism.” These theorists argue that the evolutionary origins of religious beliefs in supernatural forces may have come from such an innate cognitive bias to commit false-positive errors rather than false-negative errors, and thus overinfer personal, intentional, and animate forces behind otherwise perfectly natural phenomena.

You see a bush on fire. It could have been caused by an impersonal, inanimate, and unintentional force (lightning striking the bush and setting it on fire), or it could have been caused by a personal, animate, and intentional force (God trying to communicate with you). The “animistic bias” or “agency-detector mechanism” predisposes you to opt for the latter explanation rather than the former. It predisposes you to see the hands of God at work behind natural, physical phenomena whose exact causes are unknown.

In this view, religiosity (the human capacity for belief in supernatural beings) is not an evolved tendency per se; after all, religion in itself is not adaptive. It is instead a byproduct of animistic bias or the agency-detector mechanism, the tendency to be paranoid, which is adaptive because it can save your life. Humans did not evolve to be religious; they evolved to be paranoid. And humans are religious because they are paranoid

It is interesting to note that Kanazawa mentions the research of Nettle as I am myself a big fan of his work, but never knew that he had contributed to the EMT too. I myself have speculated on the close association of religiosity with psychosis and the Kanzawa post just bolsters the arguments there.

To sum up, it is perhaps better to be paranoid and suffer from the God delusion! You would at least survive to pass your genes along!!

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Antidepressants and neurogenesis / plasticity

It is relatively less well known that much of the anti-depressant effect of medications like Prozac may be due to them leading to better neurogenesis in the brain/ hippocampus. It is more well known that depression may itself be caused due to reduced neurogenesis. What is most well known is the scientifically unproved 'serotonin' theory of depression and how SSRIs work by increasing the level of serotonin in the brain.

Now a new research paper shows that Prozac has a non-specific effect on plasticity ion the brain and can even be used to treat Ambylopia, a defect of visual system, by rewiring the brain. Here is the abstract:

We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.

Now this brings me to an important conclusion. We have shown earlier that depression is associated with a bland sense of taste and a bland sense of smell. I have also heard of anecdotal evidence (including from readers of this blog) that depression leads to loss of fine sensation capabilities in other realms too including loss of an ability to discern pitch. Thus, to me it seems that the reason one has bland sensations in depressive states may have to do with reduced neurogeneisis and loss of neurons in the sensory areas. Anti-depressants also restore the sense acuity back, so apparently they are able to induce neurogenisis and plasticity in other barin regions than the hippocampus and their anti-depressant effects may largely be due to this factor. I had hypothesized earlier that depressed people should have diminished sense in other areas too - like that of vision and it will be interesting to see if data exists to support this view. Are there disorders similar to the 'lazy eye' that are more common in depressed people than in normal controls ; if so they would definitely be cured by prozac and one reason why people may be getting better due to medication may be because they can feel the world as vivid again. I theorize that while everything seems more vivid in mania, the reverse is true for depression and the underlying reason may be the anomalous neurogenesis. If so, there is hope for people who get their senses diminished as a result of depression- with an insight into how anti-depressants work - by improving neurogenisis and plasticity- we may be able to make better drugs that benefit them.

I'll be watching this anti-depressant as a general enhancer of plasticity theory very keenly in the future and would love any pointers to research on the same lines from my readers.

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The facebook persuasion methods

There is a  recent article  on BBC that covers The Psychology Of Facebook course of professor B J Fogg a persuasion psychologist from Stanford. This is a bold attempt to teach psychology of persuasion by taking a real world of Facebook and its viral growth as well as the growth of applications on Facebook.

He says: "When Facebook came along I was one of the developers at the
launch and what struck me was how there was this new form of
persuasion. This mass interpersonal persuasion."

Professor Fogg says the pivotal moment came when he watched an
application on the site go from "literally zero to more than a million
users in a week".

"Where on earth could you get a million customers in a week? That was
when I said 'I want to learn more about this' and I thought the best
way was to teach a class and look at how persuasion happens."

There is an interesting case study of why people upload their profile photos:

Today the focus is on the use of profile pictures, the photograph on the front page of every Facebook entry.

The discussion is lead by Psychology Senior Richard Barton, who
maintains Facebook's high strike rate in this area has to do with the
default picture it puts up if you don't post your own.

"Who wants a question mark in place of their face and what questions
does that raise about you? Like, why are you on Facebook? And so
basically Facebook sets up an environment where your friends do the
persuading to get you to post a picture."

This is interesting. Others before Facebook have tried various measures for persuading users to reveal their true identities. A case in point is the tongue-in-cheek 'anonymous coward' that is displayed as your user name on slashdot if you do not sign in and give your real user name. I don't know whether it was the question mark, or because I normally do not value anonymity, but I posted my photo on Facebook as soon as I joined.

BTW, for those of you who want to connect: here is my Facebook profile page and I'll love to get connected with my readers. Also in case someone is interested my twitter id is sandygautam and you can also follow me there.

 

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Art and Insanity: is there risk involved in artistic creation?

William Schultz has just posted a blog entry regarding how artistic creation may have an associated risk of suicide/ depression/ psychosis and how exploring the depths of one's psyche may lead one to the downward spiral that ends with taking one;s own life. He gives Sylvia Plath and Diane Arbus as examples and I agree with his basic premise that writers/ artists are especially vulnerable to extreme mental states as they try to explore the depths of human experience by imagining the extremes that are possible.

I ,myself, consider myself to have moderately good writing talent, and have found that when I write literature , be it poems or short stroies or novellas, the theme of the creation starts taking its hold. this is most apparent when for example I recently added a few sonnets to my epic-in-making The Fools Quest. The initial sonnets depict a person who is on a brink of new journey, somewhat facing an existential angst and in general questioning both his past and his future. now, though, I myself am very well adjusted and happy with my life as it is going, just creating in myself the protagonists mindset led to a state where I myself started feeling restless, unsatisfied and in general more eager for change and willing to rock the boat. This may seem anecdotal evidence, but there is good statistics showing prevalence of mental health disorders in artists in general and writers in particular.

I would now quote a bit from Schultz' post (italics mine):

What's going on here? It's more than a little uncanny. As Wendell Berry once said: "To go in the dark with a light is to know the light. To know the dark, go dark." Both Plath and Arbus knew the dark, but this knowing came at a massive price. The dark stayed dark. Forever. Some artists--not all--do not survive the hero's quest. Maybe, when the moment comes, they lack the requisite "ego strength" to re-compose after the decompensation that a certain category of art requires. Or else: once they achieve genius, the question becomes: Where do I go from here? Having reached the top of the mountain, there is nothing left but the descent, and the idea of descending is simply intolerable, ultimately depressing.

I don't know, whether my quest is a hero's quest or a fool's quest , but I definitely know that I have slowed down as I saw that the quest was affecting my mood. Hopefully, as the quest moves to more adventurous phases and away from the initial dilemmas , it would have more uplifting effects. Hopefully, I wont fall from the cliff like my Fool is planning to!

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