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Write for me good dissertation online interesting capstone topics ´╗┐okay so I'm going to be talking today about some of that more basic research that Alan touched on in his introduction sort of looking at the underlying neurobiology of fragile x syndrome and specifically longitudinal development in fragile x not quite sure how to advance yeah I tried all those maybe up anywhere okay so eating the clicker at that it's okay all right got it okay great so as I know I'm sure we're all familiar fragile X is associated with greatly reduced fmr p which results in neurobiological and cognitive deficits as well as social deficits that overlap with the characteristics of autism spectrum disorders there has been a lot of research in fact I'm sure you'll hear about some of this today research that is looking to develop targeted treatments for fragile x syndrome what I'm going to talk about in my talk is how the underlying neurobiology can help us really design the most effective targeted treatments so neuroimaging is able to help us design effective treatments because we can really target the neurobiological systems that are affected in fragile x instead of or in conjunction with targeting behavioral systems or symptoms neuroimaging can also help us identify objective metrics of treatment efficacy so we can actually look at neuroimaging biomarkers so the volume of a region for example in conjunction with or instead of behavioral or cognitive functioning metrics and then finally longitudinal studies are able to help us identify particular developmental windows when specific treatments may be maximally effective so the study I will be describing today is a longitudinal investigation a large investigation of boys from ages 1 through 13 and i'll be talking about our investigation of brain development behavior development and some brain behavior relationships so longitudinal brain development is what I'll start with and first I'm going to show you here this lovely a bit messy but also I think very lovely graph of brain volume changes in the bilateral caudate so you can see the caudate volume is on the y-axis and ages on the so we're tracking caudate volume from age 1 through 13 / 14 and the thin lines represent individual data points so that's one individuals growth trajectory and the thick lines represent groupwise estimates of growth trajectories so the first thing you might notice well first also point out that the fragile x group is colored in green and the red group is our autism spectrum disorders group so this is individuals with idiopathic autism spectrum disorders that we're sort of using as a comparison sort of a symptom match to the fragile x syndrome group so the first thing you'll notice is a great separation of all the green and all the red lines which is quite unique for a neuroimaging result like this and that is because the caudate is well known to be greatly enlarged in fragile x syndrome and so this is not a new finding for fragile x in large caudate however what's unique about this graph in these results is that we can see that in the same individuals caudate is in fact enlarged across these years ages 1 through 13 and next I'm going to highlight a few other regions showing longitudinal growth curves so the bilateral hippocampus and the amygdala which are both involved in important for the study of fragile x syndrome the hippocampus of course is critical for learning and memory it's a region that's known to be enriched in FM RP very early in on in development we can see the match symptom group this time first of all we can see quite a divergence in the trajectory so the shape of the two lines again the fragile x group is in green and the symptom match symptom comparison group is in red we can see a roughly linear steady growth in the comparison group versus the much more curved and delayed growth in the fragile x group but they do start to catch up starting around age 7 they have some rapid increase in growth and the red asterisks indicate that ages 3 5 7 and 9 are ages in which there is a significant difference in volume there is no significant difference in volume at age 11 through 13 so again quite different growth trajectories here for the hippocampus for the amygdala as we know as the key plays a key player in the social brain you can see these trajectories look roughly more similar and are much flatter than the previous one I showed you so here there's actually no significant differences in volume across these ages measured and there also is no significant difference in trajectory now what's interesting is that the groups do seem to divergency starting around age 9 and I think it will be interesting to follow these individuals further out in time to see if this trend does in fact continue although both let's see and it's also interesting that both groups do start to increase around age 7 significant increase in amygdala volume now switching gears I am going to talk a bit about longitudinal behavior development so the other side of things here so here we're looking at the same kind of growth trajectories but this time on the y-axis is the a dose as we know the sort of gold standard for measuring autism symptoms and again it's from ages 13 13 fragile X is in green first you might notice much more overlap in the green and red lines which is from my experience anyway much more typical of looking at behavior it's it's a little more fuzzy sometimes than the brain imaging but we can see that around the toddler age there seems to be quite a large difference between the two groups whereas later on around 10 through 13 the group seemed to be to look more similar and also we notice the fragile x syndrome group is increasing in autism symptoms so this measure is actually if you score worse on this measure that's indicative of higher levels of and more severe autism symptoms so higher score worse outcome so as you can see fragile X starts off somewhat better than the asd group but they end up increasing in autism symptoms over time this might suggest that early interventions could be particularly important for individuals with fragile X syndrome add that early toddler age before they even though at that age they may not be meeting clinical thresholds for autism as we can see there is likely to be an increase in symptoms over time and now I want to talk about putting the brain with the behavior so looking at early brain structure measured early in development can we use that to predict later outcome the answer is yes so I looked at early brain structure the volume of the caudate measured at age one through three as a predictor of later a das scores a das score being measured at ages 10 through 14 I'm so it's a single time point within the age 10 through 14 but that was the age of the participants and it turns out that caudate volume accounts for roughly thirty three percent of the variants in later aid off scores and this is significant after accounting for total brain volume suggesting that caudate volume may be a reliable useful specific biomarker for later outcome and this relationship was only found for the fragile x group so when we look at a match symptom comparison group that has the same or even perhaps more autism symptoms as you saw in the last graph this relationship does not hold of course the caudate is just one region of the brain we have to still look at various other regions and perhaps methods that can include variation of the whole brain as a potential biomarker but this is a an important first step and that so just to briefly summarize the caudate is enlarged early in life and remain so through age 13 behavior growth trajectory suggested that early interventions are very important in fragile x syndrome especially for later behavioral outcome early brain structure significantly predicts later behavior outcome and early brain measures could be useful biomarkers and finally I just want to underscore that these types of results are really only possible with longitudinal with a longitudinal design so following the same individuals throughout development is real critical to understanding these neurobiological differences and then in turn informing treatments that are perhaps going to target neurobiology and of course I'd like to thank everyone who worked on this project so many much of the work was done at Stanford we're also working in collaboration with the University of North Carolina and also El Camino Hospital this is one of our star participants who is indicating with his thumbs up that he enjoyed his experience visiting Stanford and I think we have time for questions if anyone would like to ask one a propaganda yes yes mm-hmm that's a great question I'm so the question was about medications influencing outcomes and as you alluded the numbers are quite small what I can say is that most of these kids are on medications of some sort and that that is an area that we do want to look in my inclination is that yes of course medication is affecting brain growth and behavior and we'll have to see how that pans out what I point out for the end let's say on go back to the behavior development growth curves um what i can say with a little bit more certainty is that I'm this autism group I can hypothesize why they're showing a decrease in autism symptoms over time so this is a unique group that was brought to us very early in their development ages 1 through 3 so they were most likely very brought to the attention of clinicians and researchers and clinicians and were targeted for early intervention so they likely had more behavioral intensive behavioral early interventions and that is likely to have caused that decrease so if we can apply the same thing too fragile X could be quite useful in conjunction with I mean of course that would not replace any kind of pharmacological target but it could be useful on its own or in conjunction with a farm illogical yes so so I have a question from the chat from George uncle um is a hiatus core indicative of someone on a higher behavioral problem that is correct a higher score on this measure indicates more and more and or more severe problems so basically this is a social behavioral assessment where an experimenter engages in play type activities with a child and basically provides opportunities for social interaction a score of zero means totally perfectly normal social interaction most people would probably score you know one or two because we're not all put totally perfect but basically you're getting a point for every abnormal social thing that you either do or fail to do and also does a large caudate indicate a higher a Doss score well I'm going to argue yes it does in the fragile x syndrome group so this is what my analysis using regression showed that a larger caudate volume at age one two three yes was indicative of a higher 80 score which indicates worse outcome and if you remember the graph from couple slides back the higher fragile X as a whole is associated with having higher caudate volumes so okay oh this is actually working alright so I was just whispering to see if I could get it to respond so i think Amy you were saying that are if you go to the graph of the any of them yeah like with the spaghetti plots on him our little guys are they're usually almost never on medication right if anything maybe they're on stimulants some a few a handful well so now that's really interesting following up on Mike's kana can you but go back to the hippocampus three slide so as you point out Jen the hippocampus is of interest for a variety of reasons too fragile X just from a basic brain behavioral standpoint from the standpoint of gene expression fmr1 gene expression and early in development but the other reason I've always thought the hippocampus is really interesting in fragile X is because it's a one of the regions of the brain certainly not the only one that is vulnerable to stress induced insult so to speak and you know in some ways you might think about fragile x syndrome particularly as kids get into school age years maybe even before and certainly after as a hairy traumatic stress disorder it's not post because there's it there's that tendency for hyper arousal that really starts to amplify around school age years and into adolescence where the stress response as measured by behavior by psychophysiology by cortisol they're all indicative that individuals with fragile X respond to stress but they overshoot and they have a much more difficult time reestablishing a stress response post stress response homeostasis so now looking at looking at that getting the point that the hippocampus one of the things that has been proposed to be actually a mechanism of antidepressant response to serotonin selective serotonin reuptake inhibitors is the generation of neurogenesis in the hippocampus it's very interesting and so you know following Mike's point we should probably look our kids get put on SSRIs that might account for some of that change in hippocampal morphology because that that could be pretty interesting I i actually have wondered for a long time about this balance between the tendency for overgrowth in the brain overall in fragile x syndrome most of it neuro pile but and the fact that the hippocampus is smaller and wondered if in fact the hippocampi in individuals with fragile X are being insulted by chronic stress and their physiology that doesn't allow them to adapt appropriately and so when I see something like this it really makes me wonder about all those different pieces thrown in the stress response possible insulted hippocampus SSRIs neurogenesis and so this is something we should really think about I don't have any great insights today other than to say we really need to think about yeah agree and the other thing that would just point out when looking at these graphs is that there is no curve on here for typical development so we don't know if are they catching up to the fragile X syndrome group is increasing but are they catching up to what's typical are they still quite delayed there what we do have those weeks it's not on this crash no I was gonna say yes we have the desert 80 is yes to be added any other questions okay you how many references for a 20000 dissertation State University of New York College at Oneonta.

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