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Sandeep Gautam is a psychology and cognitive neuroscience enthusiast, whose basic grounding is in computer science.
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There is a recent article in Nature Neuroscience by Philpot et al regarding how experience-dependent synaptic plasticity is downregulated in Angelmans’ syndrome and perhaps in Autism too, as the Ube3a gene involved is implicated in both disorders.
First a little history about Angelman– it is a disorder caused by deletion/lack of a maternally imprinted UBE3a gene in chromosomal region 15q11-q13 . It is typically contrasted with Prader-Willi syndrome which is caused by a paternally imprinted gene malfunction in the same chromosomal region. Christopher Badcock has used this to contrast Autism (related to Angelman) and Psychosis (more common in PWS) to argue that Autism and Psychosis are due to a genomic imprinting tug of war between fathers and mothers genes.
I have written about Badcock’s and Crespi’s thesis before and how it fits in with my views on Autism and Psychosis; suffice it to say that I am seeing the new study primarily from this prism of Autism and Psychosis dichotomy.
First , let us see what the study tells us:
It uses mouse model that contains silenced maternal Ube3a genes (Ube3a m-p+ mouse), thus trying to make a mouse model of Angelman.
What it found was:
1) Ube3a expression was markedly reduced in Ube3am-/p+ mice compared with wild-type mice in all three brain regions (visual neocortex, hippocampus,cerebellam). Consistent with previous observations, this attenuation was brain specific, as Ube3a was highly expressed in the liver of both Ube3am+/p- and Ube3am-/p+ mice.
2) To determine the physiological consequences of Ube3a loss on neocortical development, we examined the developmental acquisition of spontaneous excitatory synaptic transmission by recording miniature excitatory postsynaptic currents (mEPSCs) in layer 2/3 pyramidal neurons of visual cortex (see Supplementary Table 1 online for intrinsic membrane properties of recorded neurons). Consistent with previous findings24, 25, mEPSC amplitudes decreased and frequency increased during development in wild-type mice . Just before eye opening (postnatal day 10, P10), mEPSC frequency and amplitude were indistinguishable between wild-type and Ube3am-/p+ mice . Thereafter, mEPSC frequency failed to develop normally in Ube3am-/p+ mice
3)Although dark rearing had no measurable effect on mEPSC amplitude in wild-type mice at P25 , sensory deprivation strongly attenuated the normal developmental increase in mEPSC frequency in wild-type mice . In contrast, dark rearing did not affect mEPSC amplitude or frequency in Ube3am-/p+ mice. Consequently, mEPSC frequency in normally reared Ube3am-/p+ mice was not significantly different from that of dark-reared wild-type mice . These findings demonstrate that, although Ube3a is not necessary for the initial sensory-independent establishment of synaptic connectivity, it is selectively required for experience-dependent maturation of excitatory circuits.
4)We therefore compared the properties of neocortical long-term depression (LTD) and LTP at layer 2/3 synapses in visual cortex of wild-type and Ube3am-/p+ mice at both young (P25) and adult (P100) ages. Because layer 2/3 pyramidal neurons receive major inputs from layer 4 pyramidal neurons, layer 2/3 field potentials were evoked by layer 4 stimulation . We began by measuring LTD in young mice using a standard stimulation protocol (1 Hz for 15 min). Although LTD was reliably induced in young wild-type mice, it was absent in young Ube3am-/p+ mice . We also observed deficits in LTP induction. A relatively weak induction protocol (three 1-s trains of 40-Hz stimulation) elicited LTP in young wild-type mice, but failed to reliably induce LTP in young Ube3am-/p+ mice . To test whether the neocortex of Ube3am-/p+ mice was capable of expressing LTP, we also applied a strong LTP stimulation protocol (two 1-s trains of 100-Hz stimulation). This protocol consistently induced LTP in both Ube3am-/p+ and wild-type mice. Thus, as with LTP deficits in hippocampus8, 9, the LTP induction machinery is impaired in the visual cortex of Ube3am-/p+ mice and this deficit in LTP can be overcome with strong stimulation.
5)To determine whether the plasticity deficits in Angelman syndrome mice persisted into adulthood, we tested LTD and LTP in adults (P100). In adult wild-type mice, LTD induced by 1-Hz stimulation was absent, as expected27, whereas LTP could be induced with strong stimulation. In adult Ube3am-/p+ mice, however, neither of these protocols were effective at modifying synaptic strength. These results indicate that wild-type mice show attenuated neocortical plasticity as they mature and that this attenuation of plasticity is more severe in the absence of Ube3a . Furthermore, these data indicate that plasticity defects in Angelman syndrome mice persist into adulthood.
..and so on (go read the full paper)
In a nutshell, what they found was that in presence of visual stimuli, the plasticity (measured by LTP/LTD ) of visual cortex was adversely affected. As sensory stimulus would normally be available while developing, this would adversely affect the plasticity in adolescence/ critical periods and also continue into adulthood.
Thus, Autism/ Angelman are charechterised by less synaptic plasticity in adulthood and during critical development periods. Paradoxically, this loss of synaptic plasticity is concomitant on their it being experience-dependent or having sensory stimuli. If the organism is sensory deprived, it may still retain the normal synaptic plasticity exhibited by similar sensory deprived normal people.
How does this relate to Psychosis? If my thesis is correct that autism and Psychosis are opposites, then I would predict that in either prader-willi or in Psychosis (scheziphrenia etc) there should be excessive experience-dependent plasticity. I was glad to learn that I am not the first one to make that proposition, but someone back in 1995 has argued for Hippocampal synaptic plasticity as an endophenotyoe for Episodic Psychosis. I now quote heavily form that article.
Here is the abstract:
Structural change in the hippocampal formation has become popular as a proposed neurobiological substrate for schizophrenic disorders. It is postulated that behavioral plasticity in the form of long-term potentiation of hippocampal synaptic transmission is an attractive putative mechanism for the mediation of transient psychosis. Moreover, the disturbed hippocampal neuroarchitecture found in schizophrenic brain may be susceptible to potentiation and dysfunctional to the degree that delusions and hallucinations develop. Partial and selective blockade of the receptors mediating potentiation may prove to be an efficient means of preventing psychotic episodes and avoiding further damage to the involved network. Basic research, utilizing experimental models such as intraventricular kainic acid injection, may help to clarify the anatomical and physiological substrate of psychosis.
The Main thesis of the paper is:
1. Anatomical, physiological, pharmacological, and behavioral findings are most consistent with the view that neuropathological changes within the limbic system, specifically within the hippocampal formation, may represent a biological substrate of schizophrenia.
2. The biological mechanism underlying transient psychosis may be long-term potentiation (LTP) of synaptic transmission within the hippocampal formation.
3. The effects of dopamine manipulation on these behaviors may be mediated by direct actions on the compromised limbic system of the psychotic patient.
Associative plasticity within hippocampus occurs in the form of long-term potentiation (LTP), an experience-dependent increase in synaptic efficacy. Experimentally, LTP is produced by tetanic stimulation of afferent systems (Bliss and Lomo 1973) and has been shown to facilitate simple associative learning (Berger 1984) but disrupt more complex forms of associative plasticity (Robinson et al 1989). Hippocampal LTP has been observed to occur as a consequence of stimulus pairings in classical conditioning (Weisz et al 1984) and appears to be mediated by N-methyl-Daspartate (NMDA) receptors (Harris et al 1984). Pharmacological blockade of NMDA receptors has been shown to disrupt learning and memory in a variety of forms, including simple associations (Stillwell and Robinson 1990), spatial learning (Morris et al 1986; Heale and Harley 1990; Shapiro and Caramanos 1990), conditioned fear (Miserendino et al 1990; Kim et al 1991), olfactory memory (Staubli et al 1989) and gustatory memory (Welzl et al 1990). Some evidence, however, suggests that deficits involve motor impairment as well as disrupted learning (Keith and Rudy 1990)
Hippocampal function is particularly sensitive to neurochemical modulation, and the expression of monoamine receptors in the temporal lobe is altered in schizophrenics (Joyce 1993). Antipsychotics that reduce endogenous dopamine levels (Losonczy et al 1987) exert significant effects on the hippocampus and LTP. Trifluoperazine inhibits induction of LTP in hippocampus (Finn et al 1980), whereas the dopamine antagonist domperidone has been shown to prevent the maintenance of LTP (Frey et al 1990). Long-term effects of antipsychotic drugs include functional supersensitivity of hippocampal pyramidal neurons (Bijak and Smialowski 1989). Thus, individuals with deranged hippocampal neuroarchitecture would be prone to cognitive dysfunction (including, perhaps, perceptual distortion and other schizophrenic symptoms), differentially susceptible to stress, and responsive to amelioration of symptoms via dopamine antagonism. It may be more than coincidence that the time lag between administration of antipsychotic medication (which results in near immediate decrement in dopamine levels) and the attenuation of psychotic symptoms weeks later (Kane 1987) is remarkably consistent with the time parameters of LTP decay (Douglas and Goddard 1975). Also, the selective disruption of “weak” associative responses by antipsychotic drugs (van der Heyden and Bradford 1988) is consistent with interactions between NMDA-receptor blockade and stimulation intensity on induction of LTP (Reed and Robinson 1991).
From the above, at least to me, it is clear that anti-psychotics may work by decreasing LTP/LTD that is enhanced in episodic psychosis. A propensity towards increased experience-dependent enhancement of synaptic palsticty may be at work here and paradoxically the same approach of sensory deprivation, as in Angelman/ Autism may work here too.
Here is the summary:
In summary, potentiation of hippocampal synaptic transmission may be the neurophysiological basis of episodic psychosis. (Post  has proposed a similar process in the amygdala as a useful model in understanding the progression of recurrent affective disorders.) More selective blockade of the NMDA receptor, which mediates LTP, may prove an effective means of attenuating positive symptoms and preventing further accrual of cellular damage in hippocampus.
In my own summation, I am convinced that we would find more synaptic plasticity in Psychotic people and that hyper-plasticity to hypo-plasticity is another dimension on which the autistics and psychotics differ and this again is a result of the genomic imprinting mediated tug-pf-war between the maternal and paternal genomes.
PORT, R., & SEYBOLD, K. (1995). Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis Biological Psychiatry, 37 (5), 318-324 DOI: 10.1016/0006-3223(94)00128-P
Koji Yashiro, Thorfinn T Riday, Kathryn H Condon, Adam C Roberts, Danilo R Bernardo, Rohit Prakash, Richard J Weinberg, Michael D Ehlers & Benjamin D Philpot (2009). Ube3a is required for experience-dependent maturation of the neocortex Nature Neuroscience
I have installed a widget in my sidebar from skribit.com that lets you have a say in what article reviews/topics you would like to see me blog about. I am sure that I have a mature audience and the topic/article reviews requested would be related to my field of expertise, so do go ahead and have your say; I don’t promise that I would be able to write on every suggested topic, but as an experimentation I will try my best. You can suggest a topic like “OCEAN theory of personality” or a peer-reviewed/pre-print article(open access article..or be prepared to send the article to me, if it is behind a subscription firewall). I hope this takes off and we have a true two-way communication. By the way, for this you would have to visit my web page and look at the sidebar or you may try this link if it works.
Well, the cluster goes together. Previous research has found that Low LI and psychosis (schizophrenia) and creativity are related; previous research has also found that psychotic /some types of creative people have more faith in intuition; and this research ties things by showing that Low LI and high faith in intuition are correlated.
The research under question is by Kaufman and in it he explores the dual-process theories of cognition- the popular slow high road of deliberate conscious reasoning and the fast low road of unconscious processing. I would rather have the high road consist of both cognitive and affective factors and similarly the unconscious low road consist of both cognitive and affective factors. Kaufman focuses on the unconscious low road and his factor analysis reveal three factors: Faith in intuition: a meta cognition about ones tendency to use intuition; Holistic intuition: the cognitive factor; and affective intuition: the affective factor. with this in mind let us see what Kaufman’s thesis is:
He first introduces the low road and the high road:
In recent years, dual-process theories of cognition have become increasingly popular in explaining cognitive, personality, and social processes (Evans & Frankish, 2009). Although individual differences in the controlled, deliberate, reflective processes that underlay System 2 are strongly related to psychometric intelligence (Spearman, 1904) and working memory (Conway, Jarrold, Kane, Miyake, & Towse, 2007), few research studies have investigated individual differences in the automatic, associative, nonconscious processes that underlay System 1. Creativity and intelligence researchers might benefit from taking into account dual-process theories of cognition in their models and research, especially when exploring individual differences in nonconscious cognitive processes.
Then he explain LI:
Here I present new data, using a measure of implicit processing called latent inhibition (LI; Lubow, Ingberg-Sachs, Zalstein-Orda, & Gewirtz, 1992). LI reflects the brain’s capacity to screen from current attentional focus stimuli previously tagged as irrelevant (Lubow, 1989). LI is often characterized as a preconscious gating mechanism that automatically inhibits stimuli that have been previously experienced as irrelevant from entering awareness, and those with increased LI show higher levels of this form of inhibition (Peterson, Smith, & Carson, 2002). Variation in LI has been documented across a variety of mammalian species and, at least in other animals, has a known biological basis (Lubow & Gerwirtz, 1995). LI is surely important in people’s everyday lives—if people had to consciously decide at all times what stimuli to ignore, they would quickly become overstimulated.
Indeed, prior research has documented an association between decreased LI and acute-phase schizophrenia (Baruch, Hemsley, & Gray, 1988a, 1988b; Lubow et al., 1992). It is known, however, that schizophrenia is also associated with low executive functioning (Barch, 2005). Recent research has suggested that in highfunctioning individuals (in this case, Harvard students) with high IQs, decreased LI is associated with increased creative achievement (Carson et al., 2003). Therefore, decreased LI may make an individual more likely to perceive and make connections that others do not see and, in combination with high executive functioning, may lead to the highest levels of creative achievement. Indeed, the link between low LI and creativity is part of Eysenck’s (1995) model of creative potential, and Martindale (1999) has argued that a major contributor to creative thought is cognitive disinhibition.
He then relates this to intuition and presents his thesis:
A concept related to LI is intuition. Jung’s (1923/1971, p. 538) original conception of intuition is “perception via the unconscious.” Two of the most widely used measures of individual differences in the tendency to rely on an intuitive information-processing style are Epstein’s Rational- Experiential Inventory (REI; Pacini & Epstein, 1999) and the Myers-Briggs Type Indicator (MBTI) Intuition/Sensation subscale (Myers, McCaulley, Quenk, & Hammer, 1998). Both of these measures have demonstrated correlations with openness to experience (Keller, Bohner, & Erb, 2000; McCrae, 1994; Pacini & Epstein, 1999), a construct that has in turn shown associations with a reduced LI (Peterson & Carson, 2000; Peterson et al., 2002), as well as with divergent thinking (McCrae, 1987) and creative achievement.
The main hypothesis was that intuitive cognitive style is associated with decreased latent inhibition.
He found support for the hypothesis from his data. It seemed people with low LI were high in faith in intuition factor. Here is what he discusses:
The results of the current study suggest that faith in intuition, as assessed by the REI and the MBTI Thinking/Feeling subscale, is associated with decreased LI. Furthermore, a factor consisting of abstract, conceptual, holistic thought is not related to LI. Consistent with Pretz and Totz (2007), exploratory factor analysis revealed a distinction between a factor consisting of REI Experiential and MBTI Thinking/Feeling and a factor consisting of MBTI Intuition/Sensation and REI Rational Favorability. This further supports Epstein’s (1994) theory that the experiential system is directly tied to affect. The finding that MBTI Intuition/Sensation and REI Rational Favorability loaded on the same factor supports the idea that the type of intuition that is being measured by these tasks is affect neutral and more related to abstract, conceptual, holistic thought than to the gut feelings that are part of the Faith in Intuition factor.
Here are the broader implications:
The current study adds to a growing literature on the potential benefits of a decreased LI for creative cognition. Hopefully, with further research on the biological basis of LI, as well as its associated behaviors, including interactions with IQ and working memory, we can develop a more nuanced understanding of creative cognition. There is already promising theoretical progress in this direction.
Peterson et al. (2002) and Peterson and Carson (2000) found a significant relationship between low LI and three personality measures relating to an approach-oriented response and sensation-seeking behavior: openness to experience, psychoticism, and extraversion. Peterson et al. found that a combined measure of openness and extraversion (which was referred to as plasticity) provided a more differentiated prediction of decreased LI.
Peterson et al. (2002) argued that individual differences in a tendency toward exploratory behavior and cognition may be related to the activity of the mesolimbic dopamine system and predispose an individual to perceive even preexposed stimuli as interesting and novel, resulting in low LI. Moreover, under stressful or novel conditions, the dopamine system in these individuals will become more activated and the individual will instigate exploratory behavior. Under such conditions, decreased LI could help the individual by allowing him or her more options for reconsideration and thereby more ways to resolve the incongruity. It could also be disadvantageous in that the stressed individual risks becoming overwhelmed with possibilities. Research has shown that the combination of high IQ and reduced LI predicts creative achievement (Carson et al., 2003). Therefore, the individual predisposed to schizophrenia may suffer from an influx of experiential sensations and possess insufficient executive functioning to cope with the influx, whereas the healthy individual low in LI and open to experience (particularly an openness and faith in his or her gut feelings) may be better able to use the information effectively while not becoming overwhelmed or stressed out by the incongruity of the situation. Clearly, further research will need to investigate these ideas, but an understanding of the biological basis of individual differences in different forms of implicit processing and their relationship to openness to experience and intuition will surely increase our understanding of how certain individuals attain the highest levels of creative accomplishment.
To me this is exciting, the triad of creative/psychotic cognitive style, intuition and Latent Inhibition seem to gel together. the only grip eI have is that the author could also have measured intuition directly by using some insight problems requiring ‘aha’ solutions; maybe that is a project for future!
Kaufman, S. (2009). Faith in intuition is associated with decreased latent inhibition in a sample of high-achieving adolescents. Psychology of Aesthetics, Creativity, and the Arts, 3 (1), 28-34 DOI: 10.1037/a0014822
Chris Patil , of Ouroboros , and Vivian Siegel have an interesting and thought-provoking op-ed in DMM, on the issue of the promise and the not-so-promising actuality of science 2.0.
They are right when they say that they doubt if science 2.0 wold attract more scientists than the currently active science bloggers and the likes; and I share their skepticism. However, while they believe that all the tools for online collaboration are already in place, I on the other hand think we need a more formalized one-stop system for scientists, where all their sharing, networking and collaborating needs are met. It doesn’t really attract me that much if I have to collaborate using FrinedFeed, share using twitter , learn using google reader, disseminate using blogger, or network using acaedmia.org etc. I am sure a scientific virtual water-cooler will soon emerge , but till that time I am skeptical of actual practicing scientists using science 2.0 in their day-to-day life; of course how the current breed of science bloggers use these tools and the kind of successful collaborations they can demonstrate would easily and likely define the way science 2.0 shapes up. Needless to say I am excited to be part of the early adopters and while twitter/ FF have not lived to their promise, the relatively older sibling of blogging , has managed to land me virtual collaborations, where I am discussing research ideas with persons who actually perform experiments (I am by circumstances an armchair scientist). For an example see comments by Kim on my last post on action selection, which has also led to some offline discussion and a possible future collaboration. For me science 2.0 works perfectly because I am not in the competitive business of being the first to publish a paper or to secure tenure etc and thus can put my ‘ideas to the world’ as freely as they come. At the same time, I am more than aware that the apprehensions scientists have over being stolen from are genuine and need more thought and care while designing the science 2.0 tools.
I will now like to quote some passages from the op-ed that I liked the most.
Suppose that your unique combination of training and expertise leads you to ask a novel question that you are not currently able to address. You advertise your idea to the world, seeking others who might be able to help. You find that Miranda has an idle machine, built for another purpose, that could be modified just so to help answer your question, if only she had a few samples from an appropriate patient. Hugo, busy with clinical responsibilities, has no time, but has a freezer full of biopsy tissues from such patients. Steve has the time and inclination to modify Miranda’s machine and to write the scripts to drive the analysis. Polly watches the whole process to make sure that the study has sufficient statistical power. Correspondence among the interested parties could be recorded in a publicly available forum, along with data and analysis as they emerge – allowing the entire scientific world to look on and to offer advice on the framing of the question, the design of the machine, the processing of the samples and the interpretation of the results.
In other words, what if you could think a thought at the world and have the world think back? What if everyone in the world were in your lab – a ‘hive mind’ of sorts, but composed of countless creative intellects rather than mindless worker ants, and one in which resources, reagents and effort could be shared, along with ideas, in a manner not dictated by institutional and geographical constraints?
What if, in the process, you could do actual scientific research? Granted, it would be research for which no one person (or group) could take credit, but research all the same. Progress might even occur more rapidly than it does in our world, where new knowledge is shared in the form of highly refined distillates of years of work.
I fit perfectly the person who can ask novel questions, experimental suggestions, but lacks expertise / time/ resources/ sanctity to run them. to me this hive mind would be god-send. If only, it could take off!! But then they provide a reality check:
Beyond raising concerns about the philosophy of communication, our utopian fantasy ignores important aspects of human nature. In any real world, finding collaborators would require a great deal more than shooting questions into the void and cocking an ear for the echo. In particular, in order to find a colleague with exactly the right complement of skills, interest and dependability, we need not only openness but trust. Within a laboratory group (at least, in a functional one), trust is part and parcel of lab citizenship; we and our colleagues voluntarily suspend our competitive urges in order to create a cooperative (and mutually beneficial) environment. In the wider world, however, the presumption is reversed: we tend to be cagey and suspicious in our interactions with other scientists. When we step outside the laboratory door, we transform from Musketeers (‘All for one…!’) to Mulder and Scully (‘Trust no one.’).
Oh , how I hate them to have burst my fantasy bubble by providing this reality check!! But thankfully not being bound to any laboratory I am at least immune form this cooperate or compete dilemma. I just hope there are more people like me (or enuff foolish scientists not really bothered about plagiarism) to reach a critical mass and snowball science 2.0. and then they touch on some subtle aspects of the above:
Another clash between utopia and human nature occurs at the level of publicly sharing preliminary data. In particular, during the period of transition between the status quo and the glorious future, openness may be provably irrational from a game-theoretical standpoint. If I share my data but my competitors do not, I’ve laid all of my cards out on the table, whereas others play theirs close to the vest – a bad bet under any circumstances. At best, my openness allows my adversaries to strategize; at worst, it allows them to steal my ideas. Perhaps the term ‘stealing’ is too harsh: in the words of our estimable thesis advisor, Peter Walter, ‘you can’t unthink a thought.’ Once an idea is in the field, can anyone be blamed for reacting to it in a way that is personally optimal? We already live with this moral conundrum every time we agree to review papers and need to balance the expectation of confidentiality with our own desire to shape our own future plans on the basis of the best and most current information. Radical sharing will require ways for individuals to protect themselves from the occasionally deleterious consequences of rational self-interest.
Perhaps most importantly from a practical perspective: information doesn’t share itself. From establishing an open record of preliminary discussions to freely disseminating experimental results, each step in the process requires an infrastructure. A framework, composed of software and web tools, is necessary in order to empower individual scientists to share information without each of them having to write the enabling code from scratch.
The weakest part of the article in my opinion, is when they argue that the tools are already available. I beleive we are still in the early stages of experimenting; new concepts and sites like biomedexperts need to be experimented with and I am sure we will soon be there. The authors suggest several sites where scientists in science 2.0 purportedly hang and then they point to reasons why that model has not succeeded yet:
Social networking tools also suffer from a variant of the ‘no one will go there until everyone goes there’ problem – the ‘me too’ dilution factor. Just as in the social/job space (Facebook, LinkedIn, MySpace, Bebo), there are myriad networks to choose from and many are too similar to distinguish. To a new user with limited time, it’s not obvious whether to try and join multiple networks, arbitrarily choose one, or wait for a clear winner to emerge.
Here’s praying that a clear victor emerges soon!
Patil, C., & Siegel, V. (2009). This revolution will be digitized: online tools for radical collaboration Disease Models and Mechanisms, 2 (5-6), 201-205 DOI: 10.1242/dmm.003285