The Psychological & Neuroscientific musings of sandygautam
schizophrenia
Autism and Schizophrenia: proof from comparative genomics
Dec 2nd
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I have blogged extensively about the Autism and Schizophrenia as opposites on a continuum theory. I remember first putting this theory in words in an article 3 yrs back on the mouse trap titled Autism and Schizophrenia: the two cultures. That 2006 article, in turn, was inspired by Daniel Nettle’s 2005 article in Journal of Research in Personality where Nettle had also proposed the dichotomy and that paper helped crystallize my thoughts on the subject, a theory which I had been building on my own and now supported by someone like Nettle who I respect a lot. Important to note that at that time I was blissfully unaware of Badcock or Crespi and their work. It is to the credit of Badcock that he had published in 2006 his own theory of Autism and Schizophrenia as opposites on a continuum based on parental imprinting of genes and proposed a mechanism. Crespi I guess got involved in Badcocks’s efforts later on and gave it more experimental and theoretic grounding. I firts became aware of Badcock and Crespi’s work in early 2008.
The wider world became aware of the Autism/Schizophrenia dichotomy sometime in late 2008 (November 2008) . at that time too, I was a little disappointed because most of the coverage did not mention Daniel Nettle, who I think should be credited for this work and line of reasoning too. As a consolation, some reports did mention Chris Frith who has also been partly supporting the thesis.
I wanted to give a historical perspective, because I am sure the recent Crespi article would be grabbed on by mainstream media and the pioneers Chris Frith/Nettle perhaps overlooked- but to me they too are heroes for having come up with such profound early insights. this is not to discredit teh work of Badcock and Crespi- they are doing a thorough job of convincing the skeptics and delineating the exact mechanism and genetics involved.
While we are on the topic of historical perspective , let me also pat myself on the back. In May 2008, a study came out that de novo Copy Number Variations’s (CNVs) were quite high in schizophrenics and they are in the same region as that for autistics who also have high CNVs in the same region. While some took that result to imply that Schizophrenia and Autism are same and are not different, I persisted and proposed a mechanism, whereby they could still be opposites : To quote:
Now as it happens 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.
Now one and half year later Crespi et al report the results of their study which has found exactly the same- that is, if deletions in some locus lead to autism, duplications lead to schizophrenia and vice versa. That to me is clinching evidence of my thesis. Who says Science does not happen on blogs- I proposed something to flow as a consequence of theory and exactly the same thing is found as per the hypothesis. I feel vindicated and emotional to some extent. Loves labor has not been lost to deaf ears.
Let us then return to the new and latest study that has sort of proven that Autism and Schizophrenia are opposites, genetically. Crespi et al, report in the latest PNAS edition that comparative genomics leads to that conclusion. What Crespi et al did was look at theCNV s and the locus whee CNV in both Autism and Schizophrenia are involved and sure enough they found the pattern I had proposed. I’ll now quote from the abstract and the article extensively:
We used data from studies of copy-number variants (CNVs), singlegene associations, growth-signaling pathways, and intermediate phenotypes associated with brain growth to evaluate four alternative hypotheses for the genomic and developmental relationships between autism and schizophrenia: (i) autism subsumed in schizophrenia, (ii) independence, (iii) diametric, and (iv) partialoverlap. Data from CNVs provides statistical support for the hypothesis that autism and schizophrenia are associated with reciprocal variants, such that at four loci, deletions predispose to one disorder, whereas duplications predispose to the other. Data from single-gene studies are inconsistent with a hypothesis based on independence, in that autism and schizophrenia share associated genes more often than expected by chance. However, differentiation between the partial overlap and diametric hypotheses using these data is precluded by limited overlap in the specific genetic markers analyzed in both autism and schizophrenia. Evidence from the effects of risk variants on growth-signaling pathways shows that autism-spectrum conditions tend to be associated with upregulation of pathways due to loss of function mutations in negative regulators, whereas schizophrenia is associated with reduced pathway activation. Finally, data from studies of head and brain size phenotypes indicate that autism is commonly associated with developmentally-enhanced brain growth, whereas schizophrenia is characterized, on average, by reduced brain growth.These convergent lines of evidence appear most compatible with the hypothesis that autism and schizophrenia represent diametric conditions with regard to their genomic underpinnings, neurodevelopmental bases, and phenotypic manifestations as reflecting under-development versus dysregulated over-development of the human social brain.
Copy Number Data. Rare copy-number variants (CNVs) at seven loci, 1q21.1, 15q13.3, 16p11.2, 16p13.1, 17p12, 22q11.21, and 22q13.3 (Tables S1 and S2), have been independently ascertained and associated with autism and schizophrenia in a sufficient number of microarray-based comparative genomic hybridization (aCGH) and SNP-based studies to allow statistical analysis of the frequencies of deletions versus duplications in these two conditions (Table 1, Tables S3–S9). For five of the loci (1q21.1, 16p11.2, 16p13.1, 22q11.21, and 22q13.3), specific risk variants have been statistically supported for both autism and schizophrenia using case-control comparisons, which allows direct evaluation of the alternative hypotheses in Fig. 1. One locus (16p13.1) supports a model of overlap, and four loci support the reciprocal model, such that deletions are associated with increased risk of autism and duplications with increased risk of schizophrenia (16p11.2, 22q13.3), or deletions are associated with increased risk of schizophrenia and duplications with increased risk of autism (1q21.1, 22q11.21). For 1q21.1 and 22q11.21, contingency table analyses also indicate highly significant differences in the frequencies of deletions compared with duplications for the two disorders, such that schizophrenia is differentially associated with deletions and autism with duplications. By contrast, for 16p11.2 and 22q13.3 such analyses show that autism is differentially associated with deletions and schizophrenia with duplications.
I cannot cut n paste the table, but a look at the table clears all doubts. They also look at gene association data and come to a similar conclusion ruling out model A (autism, subsumed in schizophrenia) or model B (autism and schizophrenia are independent of each other).
Models 1C (diametric) and 1D (overlapping) both predict broad overlap in risk genes between autism and schizophrenia, and do not necessarily predict an absence or paucity of genes affecting one condition but not the other. In theory, these models can be differentiated by using data on specific risk alleles for specific loci (such as single-nucleotide polymorphisms, haplotypes, or genotypes), which should be partially shared under the overlapping model but different under the diametric model. For the genes DAO, DISC1, GRIK2, GSTM1, and MTHFR, the same allele, genotype, or haplotype was associated with both autism and schizophrenia, and for the genes AHI1, APOE, DRD1, FOXP2, HLA-DRB1, and SHANK3, alternative alleles, genotypes, or haplotypes at the same loci appear to mediate risk of these two conditions (SI Text). For the other genes that have been associated with both conditions, heterogeneity in the genetic markers used, heterogeneity among results from multiple studies of the same genes, and the general lack of functional information preclude interpretation in terms of shared or alternative risk factors.
Models of autism as a subset of schizophrenia (Fig. 1A), and autism and schizophrenia as independent or separate (model 1B), can be rejected with some degree of confidence, but models involving diametric etiology (model 1C) or partial overlap (model 1D) cannot be clearly rejected. Taken together, most of the data and analyses described here appear to support the hypothesis of autism and schizophrenia as diametric conditions, based primarily on the findings that reciprocal variants at 1q21.1, 16p11.2, 22q11.21, and 22q13.3 represent statistically-supported, highly-penetrant risk factors for the two conditions (Table 1), and that for a number of genes, alternative alleles or haplotypes appear to mediate risk of autism versus schizophrenia. Additional lines of evidence supporting the diametric hypothesis, from previous studies of autism and schizophrenia, include:
- 1. Data showing notable rarity of familial coaggregation of autism with schizophrenia (38), in contrast, for example, to strong patterns of co-occurance within pedigrees of schizophrenia, schizoaffective disorder, and bipolar disorder (39).
- 2. Psychiatric contrasts of Smith-Magenis syndrome with Potocki-Lupski syndrome (due to the reciprocal duplication at the Smith-Magenis locus), Williams syndrome with cases of Williams-syndrome region duplication, and Klinefelter syndrome with Turner syndrome, each of which tends to involve psychotic-affective spectrum phenotypes in the former syndrome, and autistic spectrum conditions in the latter (5, 40).
- 3. Effects of autism and schizophrenia risk alleles on common growth-signaling pathways, such that autism has been associated with loss of function in genes, such as FMR1, NF1, PTEN, TSC1, and TSC2 that act as negative regulators of the PI3K, Akt, mTOR, or other growth-signaling pathways (41–45), whereas schizophrenia tends to be associated with reduced function or activity of genes that up-regulate the PI3K, Akt, and other growth-related pathways (46–49).
- 4. Increased average head size, childhood brain volume, or cortical thickness in individuals with: (i) idiopathic autism (50–53), (ii) the autism-associated duplications at 1q21.1 (17) and 16p13.1 (32) and the autism-associated deletions at 6p11.2 (31), and (iii) autism due to loss of function (or haploinsufficiency) of FMR1 (54), NF1 (55), PTEN (56) and RNF135 (57). By contrast, reduced average values for brain size and cortical thickness, due to some combination of reduced growth and accelerated gray matter loss, have been demonstrated with notable consistency across studies of schizophrenia (58–62), and such reduced head or brain size has also been associated with the schizophrenia-linked CNVs at 1q21.1 and 22q11.21 (17, 63, 64), and with deletions of 16p13.1 (65).
I am more than pleased with these results. Badcock too is. You can read his comments here. What about you? What would it take to convince you?
Crespi, B., Stead, P., & Elliot, M. (2009). Evolution in Health and Medicine Sackler Colloquium: Comparative genomics of autism and schizophrenia Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0906080106
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Mar 22nd
There is a new study in PLOS One that argues that we make reality-fictional distinction on the basis of how personally relevant the event in question is. To be fair, the study focuses on fictional, famous or familiar (friends and family) entities like Cinderella, Obama or our mother and based on the fact that these are arranged in increasing order of personal relevance, as well as represent fictional and real characters, tries to show that one of the means by which we try to distinguish fictional from real characters is by the degree of personal relevance these characters are able to invoke in us.
The authors build upon their previous work that showed that amPFC(anterior medial prefrontal cortex) and PCC (Posterior Cingulate cortex), which are part of the default brain network, are differentially recruited when people are exposed to contexts involving real as opposed to fictional entities. From this neural correlate of the regions involved in distinguishing fiction from reality, and from the known functions of these brain regions in self-referential thinking and autobiographical memory retrieval, the authors hypothesized that the reality-fictional distinction may be mediated by the relevance to self and this difference in self-relevance leads to differential engagement of these brain areas. I quote form the paper:
In the first attempt to tackle this issue using functional magnetic resonance imaging (fMRI), we aimed to uncover which brain regions were preferentially engaged when processing either real or fictional scenarios . The findings demonstrated that processing contexts containing real people (e.g., George Bush) compared to contexts containing fictional characters (e.g., Cinderella) led to activations in the anterior medial prefrontal cortex (amPFC) and the posterior cingulate cortex (PCC).
These findings were intriguing for two reasons. First, the identified brain areas have been previously implicated in self-referential thinking and autobiographical memory retrieval. This suggested that information about real people, in contrast to fictional characters, may be coded in a manner that leads to the triggering of automatic self-referential and autobiographical processing. This led to the hypothesis that information about real people may be coded in more personally relevant terms than that of fictional characters. We do, after all, occupy a common social world and have a wider range of associations in relation to famous people. These may be spontaneously triggered and processed further when reading about them. A logical extension of this premise would be that explicitly self-relevant information should therefore elicit such processing to an even greater extent.
To study the above hypothesis they used an experimental study that used behavioral measures like reaction time, correctness and perceived difficulty of judging propositions involving fictional, famous and close entities. Meanwhile they also measured , using fMRI, the differential recruitment of brain areas as the subjects performed under the different entity conditions. The experimental design is best summarized by having a look at the below figure.
What they found was that for the control condition and the fictional condition the reaction time , correctness and perceived difficulty associated with the proposition was signifciantkly different (lower RT, lower correctness and more perceived difficulty) than for the famous and friend entities condition. Thus, from the behavioral data is was apparent that real characters were judged faster , accurately and more easily than fictional characters. The FMRI data showed that , as hypothesiszed, amPFC and PCC were recruited significantly more in personal relevance contexts and showed a gradient in the expected direction. The below figure should summariz the findings:
In particular, in line with our predictions, regions in and near the amPFC (including the ventral mPFC) and PCC (including the retrosplenial cortex) were modulated by the degree of personal relevance associated with the presented entities. These regions were most strongly engaged when processing high personal relevance contexts (friend-real), secondarily for medium relevance contexts (famous-real) and least of all in the low personal relevance contexts (fiction) (high relevance>medium relevance>low relevance).
The amPFC and PCC regions are known to be commonly engaged during autobiographical and episodic memory retrieval as well as during self-referential processing. Regarding their specific roles, there is evidence indicating that amPFC is comparatively more selective for self-referential processing whereas the PCC/RSC is more selective for episodic memory retrieval . The results of the present study contribute to the understanding of processes implemented in these regions by showing that the demands on autobiographical retrieval processes and self-referential mentation are affected by the degree of personal relevance associated with a processed scenario. It should additionally be noted that the extension of the activations in anterior and ventral PFC regions into subgenual cingulate areas indicates that the degree of personal relevance also modulated responsiveness in affective or emotional regions of the brain .
Here is what the authors have to say about the wider ramifications:
That core regions of the brain’s default network are spontaneously modulated by the degree of stimulus-associated personal relevance is a consequential finding for two reasons. Firstly, the findings suggest that one of the factors that guide our implicit knowledge of what is real and unreal is the degree of coded personal relevance associated with a particular entity/character representation.
….
What this might translate to at a phenomenological level is that a real person feels more “real” to us than a fictional character because we automatically have access to far more comprehensive and multi-flavored conceptual knowledge in relation to the real people than fictional characters. This would also explain why a real person we know personally (a friend) feels more real to us than a real person who we do not know personally (George Bush).
I would say that there are other broader implications. First it is important to note that phenomenologically, Schizophrenia/psychosis is charachterized by an inability to distinguish reality from fiction. What is fictious also starts seeming real. A putative mechanism of why even fictional things start assuming ‘real’ dimensions may be the attribution of personal relevance or significance to those fictional entities. If something, even though fictional in nature, become highly personally relevant, then it would be easier to treat it as real. What ties things together is the fact that the default brain network is indeed overactive in the schizophrenics. If the PCC and amPFC are hyperactive, no wonder even fictional entities would be attributed personal relevance and incorporated into reality. I had earlier too discussed the delusions of reference with respect to default network hyperactivity in shizophrenics and this can be easily extended to now account for the loss of contact with reality , with the relevance and reality linkage in place. when everything is self relevant everything is real.
As always I am excited and would like some experiments done with schizophrnics/scizotypals using the same experimental paradigm and finding whether there is significant differences in the behavioral measures between controls and subjects and whether that is mediated by differential engagement of the default brain network. In autistics of course I hypothesize the opposite effects.
Needless to say I am grateful to Neuronarrative for reporting on this and helping me make one more puzzle piece fit in place.
Abraham, A., & von Cramon, D. (2009). Reality?=?Relevance? Insights from Spontaneous Modulations of the Brain’s Default Network when Telling Apart Reality from Fiction PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004741
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Mar 10th
A new article in PNAS by Grafman et al, argues that Religiosity can be broken down into three factors and the underlying machinery that these factors use are basic Theory Of Mind (ToM) circuitry, thus substantiating the claim that religion occurred as a byproduct of basic ToM related adaptations, although not ruling out that once established Religion may have provided adaptive advantage.
First a detour. I am more interested in this study as I had once claimed that Schizophrenics were more religious than Autistics and I have been maintaining that Religion is just one aspect of an underlying hyper-mentalizing to hyper-physicalism continuum on which these two spectrum disorders lie on opposite ends. The case for less ToM abilities in ASD seems to be fairly settled; its also becoming apparent that in Schizophrenia spectrum disorders you have excess of ToM abilities; This study by showing the ToM to Religion linkage, fills in the gaps and another puzzle piece falls in place.
On to the study. The authors first show that Religious Belief can be split into three factors. they use a novel (to me) technique of Multi Dimensional Scaling (MDS) to tease out the factors associated with religious belief. I have not checked how MDS works, but I assume it is similar to Factor analysis and can give us reliable factor structure underlying the data. They build on previous research and discovered the following three factors:
- God’s perceived level of involvement,
- God’s perceived emotion, and
- religious knowledge source.
The first factor refers to endowing intentionality to superantural agents like God; the second factor refers to endowing emotions to God an dthe thierd factor refers to the source of the religious beliefs- whether it is doctrinal or derived from experience. Thus the trinity of intention, emotion and belief – alos the trinity involved in ToM tasks. The authors do a good job of describing the factors, so I’ll let them do it.
Dimension 1 (D1) correlated negatively with God’s perceived level of involvement (–0.994), Dimension 2 (D2) correlated negatively with God’s perceived anger (–0.953) and positively with God’s perceived love (0.953), and Dimension 3 (D3) correlated positively with doctrinal (0.993) and negatively with experiential (–0.993) religious content. D1 represents a quantitative gradient of a single concept and we will be referring to it as ‘‘God’s perceived level of involvement.’’ D2 and D3 represent gradients of contrasting concepts; we will be referring to them as ‘‘God’s perceived emotion’’ (D2) and ‘‘religious knowledge source’’ (D3).
God’s perceived level of involvement (D1) organizes statements so that ‘‘God is removed from the world’’ or ‘‘Life has no higher purpose’’ have high positive coordinate values, while ‘‘God’s will guides my acts,’’ ‘‘God protects one’s life,’’ or ‘‘God is punishing’’ have high negative values. Generally speaking, on the positive end of the gradient lie statements implying the existence of uninvolved supernatural agents, and on the negative end lie statements implying involved supernatural agents.
God’s perceived emotion (D2) ranges from love to anger and organizes statements so that ‘‘God is forgiving’’ and ‘‘God protects all people’’ have high positive-coordinate values, while ‘‘God is wrathful’’ and ‘‘The afterlife will be punishing’’ have high negative values. Generally speaking, on the positive end of the gradient lie statements implying the existence of a loving (and potentially rewarding) supernatural agent, and on the negative end lie statements suggestive of wrathful (and potentially punishing) supernatural agent.
Religious knowledge (D3) ranges from doctrinal to experiential and organizes statements so that ‘‘God is ever-present’’ and ‘‘A source of creation exists’’ have high positive-coordinate values, while ‘‘Religion is directly involved in worldly affairs’’ and ‘‘Religion provides moral guiding’’ have high negative values. Generally speaking, on the positive end of the gradient lies theological content referring to abstract religious concepts, and on the negative end lies theological content with moral, social, or practical implications.
This breakup of religiosity into three factors is itself commendable, but then they go on to show, using fMRI data that these factors activate areas of brain associated with ToM abilities. I don’t really understand all their fMRI data, but the results seem interesting. Here is what they conclude:
The MDS results confirmed the validity of the proposed psychological structure of religious belief. The 2 psychological processes previously implicated in religious belief, assessment of God’s level of involvement and God’s level of anger (11), as well as the hypothesized doctrinal to experiential continuum for religious nowledge, were identifiable dimensions in our MDS analysis. In addition, the neural correlates of these psychological dimensions were revealed to be well-known brain networks, mediating evolutionary adaptive cognitive functions.
This study defines a psychological and neuroanatomical framework for the (predominately explicit) processing of religious belief. Within this framework, religious belief engages well-known brain networks performing abstract semantic processing, imagery, and intent-related and emotional ToM, processes known to occur at both implicit and explicit levels (36, 39, 50). Moreover, the process of adopting religious beliefs depends on cognitive-emotional interactions within the anterior insulae, particularly among religious subjects. The findings support the view that religiosity is integrated in cognitive processes and brain networks used in social cognition, rather than being sui generis (2–4). The evolution of these networks was likely driven by their primary roles in social cognition, language, and logical reasoning (1, 3, 4, 51). Religious cognition likely emerged as a unique combination of these several evolutionarily important cognitive processes (52). Measurable individual differences in these core competencies (ToM, imagination, and so forth) may predict specific patterns of brain activation in response to religious stimuli.
As always I am excited and would like to see some field work being carried out to determine religiosity in ASD and Schizophrenia spectrum groups and see if we get the same results (less religiosity in autism and more religiosity in schizophrenics) as predicted, based on their baseline ToM abilities.
PS: I was not able to use the DOI lookup fetaure of Research Blogging, but the DOI of article is * Dimitrios Kapogiannis,, * Aron K. Barbey,, * Michael Su,, * Giovanna Zamboni,, * Frank Krueger,, * and Jordan Grafman (2009). Cognitive and neural foundations of religious belief PNAS
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Mar 9th
I have been maintaining that Autism and Schizophrenia are opposites on a continuum and one dimension on which they differ is Agency , with autistics attributing too less agency to themselves (and others), while schizophrenics attributing too much agency to themselves (and others).
The case for people with ASD is fairly settled. They have deficits in theory Of Mind (ToM) and one mechanism by which this deficit seems to arise is via their attributing less agency to themselves as well as others.
For Schizophrenics too, it was speculated that they have problems with agency , but a clear illustration that they have an enhanced agency attribution device was not firmly established. This study, which dates back to 2003, in my opinion, establishes the fact that their is hyper-agency attribution (or hyper-self-menatlizing) in schizophrenics.
The study in question is one by Haggard et al , and it uses an experimental paradigm to illustrate that schizophrenics indeed have problems with self- agency attribution, and that too in the hypothesized direction.
Here is the abstract:
An abnormal sense of agency is among the most characteristic yet perplexing positive symptoms of schizophrenia. Schizophrenics may either attribute the consequences of their own actions to the intentions of others (delusions of influence), or may perceive themselves as causing events which they do not in fact control (megalomania).Previous reports have often described inaccurate agency judgments in schizophrenia, but have not identified the disordered neural mechanisms or psychological processes underlying these judgments.We report the perceived time of a voluntary action and its consequence in eight schizophrenic patients and matched controls.The patients showed an unusually strong binding effect between actions and consequences. Specifically, the temporal interval between action and consequence appeared shorter for patients than for controls. Patients may overassociate their actions with subsequent events, experiencing their actions as having unusual causal efficacy.Disorders of agency may reflect an underlying abnormality in the experience of voluntary action.
Now, let us pause and recollect that Chris Frith had postulated that the voluntary action mechanism in Scizophrenics is somewhat malformed and specifically there is a disconnect between intention attribution and voluntary action manifestation. He however had not clearly stated that there would be over-attribution of intention to voluntary actions. We all know that dopamine is associated with voluntary action (voluntary movements) and that baseline dopamine is in excess in schizophrenics. This paper ties things in together showing that excess dopamine secretion in basal ganglia and cortical areas may lead to greater biding between intentions and subsequent actions (consequences) and by this mechanism may lead to over-attribution of agency. Of course the paper doe snot establish this mechanism but just speculates on it as one of the possible mechanisms. It is also important to pause and note that schizophrenics have a jumping-to-conclusions bias and thus if an intention and action were more tightly bound (occurred in time in close proximity)_, then they are more likely to judge the two events to be related and the intention to cause the action.
Now let me get to the actual experiment. Haggard et al asked schizophrenics as well as matched controls to note subjective time (using Libets approach) when they decided to voluntarily press a computer key, and also subjective time when they first heard an auditory tone . The tone was presented 250 ms after their voluntary key press. As has been established earlier, and using controls in this experiment, people advance the key press in future (shift it towards future time from the exact time they actually pressed the key) so that subjectively the key press happens after some time form the objective key press and in the direction of the tone presentation. Thus, the effective subjective time between the key press and the tone is reduced. This binding between a voluntary action and its consequence , happens in normal individuals too, but in schizophrenics this happened significantly more in magnitude ans was dependent on two factors. first, like in normals , the voluntary key press was advanced in time towards the tone presentation, but this advance was significantly greater than in the case of controls. Secondly, the subjective auditory tone was sort of anticipated and shifted back in time towards the voluntary key press in schizophrenics. Thus, in schizophrenics, it seemed to them that the auditory tone had occurred prior to when it was actually presented. This lead to overall very significant reduction in subjective time experienced between the voluntary key press and the tone hearing, thus binding the two events strongly and leading to stronger agency inferred. to quantize the things a bit, in normal controls the voluntary key press was on the average occurring 26 ms from the actual key press, the auditory tone was heard 5 ms from the actual presentation and thus the subjective difference between the key press (intention) and tone (consequence) was 250-(26+5)= 239 ms. In schizophrenics, the key press was deemed to occur 60 ms after the actual key press, however most importantly the tone was not heard subjectively after its presentation, but was heard anticipatory 139 ms before its actual presentation, thus the actual perceived subjective time between the key press (intention) and the tone (consequence) was 250-60-139 = 51 ms only. Now , one can easily see, that if perceived subjective time between tow events is shortened in schizophrenia, then wont they end up falsely clubbing many coincidental things too together, because they seem to follow each other in close temporal proximity.
To appreciate the results, one needs to put these results in the broader context of what we know about agency in schizophrenics:
Previous laboratory studies have investigated agency using action attribution tasks. In these tasks, the patient is asked to perform an action, and is shown a visual image corresponding to that action, for example, a line drawn with a pen , a video of a hand making a manual posture , or a computerised image of a joystick moving. By introducing a mismatch between the performed action and the visual feedback, experimenters investigate the accuracy of attribution judgments. The subject has to attribute the viewed image either to an action he has just been instructed to make or to some other source. Interestingly, all these studies have found schizophrenics abnormally willing to attribute to themselves actions which in fact differ from the ones they performed. Thus, they are less sensitive than control subjects to spatial, temporal or kinematic mismatches between actions and visual feedback. The direction of these results points towards an excessive, rather than a reduced, sense of agency. Such results have been interpreted in the context of an internal forward model. Schizophrenic patients’ errors involve mostly over-attribution, implying a forward model with an unusually tolerant comparator.
Impaired judgement of agency can also be linked to the brain abnormalities underlying the disease. Agency involves forming a conscious mental association between one’s own intentional actions, and their consequences in the outside world. Thus, agency may be a conscious aspect of a more general system for instrumental or operant learning about environmental contingencies and rewards. Animal learning studies show that dopaminergic circuits, including the basal ganglia and medial forebrain are essential for associating actions with their effects, and for motivating behaviours. Brain imaging studies in man show that these same areas are active when a voluntary action produces a reward or other salient consequence . Moreover, these dopaminergic circuits are overactive in schizophrenia . Excessive dopaminergic activity might therefore explain abnormalities of conscious agency in schizophrenia, such as over-association between intentions and external events.
This is how they interpret their results:
More importantly, our schizophrenic patients seem to show an exaggerated version of the normal binding effect, or hyperbinding. These results could account for the findings of some action attribution experiments. Franck et al. asked patients and controls to move a joystick and then to observe their movements on a computer screen after a delay. The experimenters systematically varied the delay to investigate at what point the two groups ceased to accept the observed action as their own. Control subjects detected the temporal discrepancy between their action and the image with delays of around 100–150 ms. Schizophrenic subjects were much more tolerant, and accepted the viewed action as their own even for delays of 300 ms. Overall, the detection threshold for the relevant action was increased by about 150–200 ms for the patients compared to the controls. This value can be compared to the 180 ms difference between our patients and controls in the implied perceptual duration of the interval between action and tone.
The direction of the attribution effect is important: schizophrenics over-attributed events to their own agency. Our data suggests that schizophrenic patients have unusually strong associations between conscious representations of action and consequence. Thus, they might bind action and viewed image across the substantial delay periods imposed in the Franck et al. experiment, and be unaware of the artificially-induced lag between these events. There may be a critical period in which to perceive the consequence of an action. Actions and events falling in this period may be perceptually bound. A deficit in setting the duration of this critical period in schizophrenics could contribute to the shifts we found in their subjective temporal experience. This view would interpret abnormal conscious experience in schizophrenia as a problem in predicting the consequences of one’s own actions. Further work could investigate whether temporal analysis in schizophrenic patients is defective only when concerning their own actions, or also when observing actions made by others.
I am thrilled as usual and predict that if the same experimental paradigm is used with Autistic, then they will show very little or no forward movement of subjective time between their actual voluntary key-press and the subjective feel of when they decided to press the key. Also, there would be no anticipatory backwards movement of subjective time for when the tone was heard. Thus, Autistic would perceive the time gap as 250 ms only, or may even perceive the time to be more than 250 ms depending ion whether they move the voluntary key press subjective time back in time. No matter what they should show lesser binding between the intention (if they can form one) and consequence. Haggard P, Martin F, Taylor-Clarke M, Jeannerod M, Franck N. (2003). Awareness of action in schizophrenia Neuroreport, 14 (7), 1081-1085
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Feb 17th
Last week I wrote about the aberrant salience theory of psychosis, and luckily, this week itself a new study has surfaced that corroborates that theory with some preliminary evidence.
Thanks to BPS research digest, I have come across this open source research article in Psychological Medicine, that has found evidence for the aberrant salience hypothesis.
What Rosier et al did was to administer a Salience Attribution Test to both patients with Schizophrenia and normal controls, and to look for differences in the adaptive and aberrant salience. It is important to realize that most of the patients were medicated on anti-psychotics, and as per the theory advocated by Shitij Kapur, the anti-psychotics would dampen the normal adaptive salience too as psychosis is due to hyper reactivity of dopamine system and anti-psychotics are supposed to work by attenuating that behavior. More specifically, the predictions were:
It has been hypothesized that dopamine antagonists reduce both adaptive and aberrant salience, and that in the absence of effective treatment patients with schizophrenia exhibit aberrant salience (Kapur, 2003). Therefore, our first prediction was that that medicated patients with schizophrenia would exhibit reduced adaptive salience relative to controls, representing an undesirable side-effect of anti-psychotic medication. Our second prediction was that medicated patients with schizophrenia would exhibit equivalent aberrant salience to controls, representing the beneficial effect of anti-psychotic medication, which is hypothesized to normalize aberrant salience from a previously elevated level (Kapur, 2003). Our third prediction was that those patients with persistent positive symptoms, in whom medication is not entirely effective, would exhibit greater aberrant salience than patients without positive symptoms. Our fourth prediction was that in the controls, individual differences in aberrant salience would be related to the personality trait of schizotypy, considered to be an index of psychosis proneness (Chapman et al. 1994; Claridge, 1994; Stefanis et al. 2004).
All of their predictions were supported by the test results. The SAT paradigm is really simple and depends on reaction time measures following CS+ and CS-; with CS+ reaction times quantifying adaptive salience and CS- reaction times quantifying aberrant salience attribution. Read the methods section for more on the SAT.
Interestingly in patients, those with persisting delusions as well as those high on Negative symptoms exhibited higher aberrant salience as compared to patients/ controls without any delusional symptoms.Also, in controls the introverted anhedonia subscale of schizotypy correlated signficantly with the aberrant salience, thus indicating a role for negative symptom formation/ explanation too as apart of the aberrant salience. This is how the authors interpret their findings:
Aberrant salience and positive symptoms of schizophreniaOne explanation of increased aberrant salience in patients with positive symptoms concerns aberrant dopamine signalling. Contemporary accounts of reward learning suggest that phasic dopamine firing codes reward prediction errors (Schultz et al. 1997), for example, those arising from temporal difference models of reinforcement learning (Dayan & Balleine, 2002). Such models elegantly account for changes in both the firing patterns of ventral tegmental area dopamine neurons in monkeys (Schultz, 1997), and ventral striatal responses in humans (Pessiglione et al. 2006; Seymour et al. 2007), as reward-learning progresses. If phasic dopamine release signals reinforcement prediction errors, any large stochastic fluctuation in dopamine release may disrupt learning about stimulus–reinforcement associations, generating a state in which motivational salience could be misattributed to neutral stimuli, or what might be termed a ‘false-positive’ phasic dopamine signal; such events have been proposed to result in positive symptoms (Kapur, 2003).In the present study, patients for whom medication had effectively eliminated positive symptoms actually exhibited significantly less aberrant salience than controls, supporting the hypothesis that the beneficial effects of antipsychotic medications on positive symptoms are related to their ability to dampen-down aberrant salience (Kapur, 2003). However, independent of symptoms at the time of testing, the patients with schizophrenia exhibited significantly less adaptive salience than controls. Antipsychotic medication has long been considered to exacerbate negative symptoms in schizophrenia, which may be related to reduced adaptive salience [see discussion below and Schooler (1994) ]. Our findings support the suggestion of Kapur (2003) that this may be a necessary corollary to the beneficial effect of antipsychotic medication on positive symptoms.
Previous studies suggest that antipsychotic medication does not necessarily normalize abnormal dopamine signalling in psychotic patients. For example, functional neuroimaging studies have shown dopamine dysregulation in both medicated and unmedicated patients (Hietala et al. 1995; Abi-Dargham, 2004; McGowan et al. 2004). Therefore persistent symptoms in medicated patients might still be related to aberrant salience. Furthermore, the only other study investigating stimulus–reinforcement learning for appetitive outcomes in psychosis found that both medicated and unmedicated patients responded more quickly to a CS? than controls, a finding interpreted as aberrant salience (Murray et al. 2008). This study also reported that patients exhibited reduced haemodynamic correlates of reward prediction errors in the ventral striatum relative to controls, consistent with other findings in medicated patients (Juckel et al. 2006; Jensen et al. 2008). Nevertheless it will be important to confirm our findings in unmedicated patients.Aberrant salience and negative symptoms of schizophrenia
Although positive symptoms were associated with increased aberrant salience, our data also suggest a link between aberrant salience and negative symptoms. Aberrant salience correlated not only with negative symptoms in the patients, but also with O-LIFE introvertive anhedonia, which relates to reduced interest and social withdrawal, in the controls. If dopamine transmission is dysregulated in psychosis (Abi-Dargham, 2004), it is possible that ‘false negatives’ in the phasic dopamine signal might occur, i.e. a reinforcement-related stimulus fails to elicit a sufficiently large phasic dopamine response. False negatives would decrease the value of motivationally salient stimuli, possibly leading to symptoms such as avolition, apathy and social withdrawal. Consistent with this explanation, other studies that investigated responses to emotionally salient images in medicated patients with schizophrenia reported decreased responding for (Heerey & Gold, 2007) and ventral striatal responses to (Taylor et al. 2005) positive emotional stimuli relative to controls.
This explanation is also consistent with data from a functional magnetic resonance imaging study investigating the effects of d-amphetamine on reward processing in healthy volunteers. Knutson et al. (2004) found that amphetamine administration paradoxically decreased the magnitude of phasic ventral striatal haemodynamic responses in response to a CS+ that signalled reward (i.e. increasing the potential for a false negative). In the same study, amphetamine administration caused significant phasic haemodynamic responses in the ventral striatum following CS+ that signalled potential monetary loss, an effect that was absent under placebo, possibly reflecting a loss of specificity of dopamine signalling (i.e. increasing the potential for a false positive). The aberrant salience model might therefore explain both positive and negative symptoms by appealing to a common neurobiological mechanism, namely a loss of signal:noise ratio in the mesolimbic dopamine system, possibly as a result of increased tonic dopamine activity (Grace, 1991; Winterer & Weinberger, 2004).
I believe they are on to something, but the explanation for negative symptoms is still not fully fleshed out or convincing. and of course one has to remember that these results are juts with 20 patients so need to be replicated before being put to use/ accepted as orthodoxy.J. P. Roiser, K. E. Stephan, H. E. M. den Ouden, T. R. E. Barnes, K. J. Friston, E. M. Joyce (2008). Do patients with schizophrenia exhibit aberrant salience? Psychological Medicine, 39 (02) DOI: 10.1017/S0033291708003863
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