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Back to [[DBP2:Main|NA-MIC DBP 2]]
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__NOTOC__
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= Overview of Harvard DBP 2 =
 +
== Velocardiofacial Syndrome (VCFS) as a Genetic Model for Schizophrenia ==
  
* '''Title:''' Velocardiofacial Syndrome (VCFS) as a genetic model for schizophrenia
+
VCFS is a genetic disorder characterized by a deletion of a small piece of chromosome-22. The features of this syndrome include deficits in neurological psychomotor and perceptual skills, as well as in cognitive domains such as learning and memory. Most importantly, up to 30% of VCFS patients develop schizophrenia, making it the most commonly known single risk factor for the development of psychosis and a unique model for studying neurodevelopmental changes leading to psychotic deficits. We plan to collect new, high resolution DTI, structural and fMRI data, and apply existing NAMIC tools, as well as help to develop new tools to investigate the contribution of genetic variation to brain and behavioral/cognitive abnormalities, thus bridging the gap between neuroimaging studies and genetics.
 +
The NAMIC community will gain access to de-identified imaging data (new, high resolution structural and diffusion data acquired on the 3T magnet at Brigham and Women’s Hospital). Unlike in schizophrenia, subjects with VCFS have concrete cognitive abnormalities, in addition to a well defined chromosomal abnormality, which, taken together, will make it easier to establish scientific protocols that reveal associated anatomical and functional brain abnormalities in this disorder. Interestingly, some anatomical abnormalities will be shared between VCFS and schizophrenia (e.g., connections within working memory circuits), and some will be not (e.g., sensory and motor paths). Neuropsychological and genetic data will also be collected for each individual as part of separate collaboration between PI and the Children's Hospital("Investigation of Genotype/Phenotype Correlations in Velocardiofacial and DiGeorge Syndromes”) and de-dentified dataset containing neuropsychological tests, clinical evaluations and genetic data will be provided to the PI. The NAMIC project with thus enable the PI to apply NAMIC tools to imaging VCFS data, a genetic disorder that is viewed as a genetically mediated subtype of schizophrenia. To date, there have only been a small number of neuroimaging studies of this disorder and no studies have combined neurocognitive, neuroimaging, and genetic investigations in the same study. Importantly, this research will also increase our understanding of schizophrenia, and will help establish a multimodal research project involving an important collaboration between computer scientists, cognitive neuroscientists, radiologists, psychiatrists, and geneticists. The focus on imaging and genes also affords a new window of opportunity for defining further the new area of “imaging genomics”. [[DBP2:Harvard:Introduction|More...]]
  
==Team and Institute==
+
Data is provided at the following link: '''[[Data:DBP2:Harvard|Harvard Data]]'''.
*PI: Marek Kubicki, MD, PhD, Contact: kubicki at bwh.harvard.edu
 
*NA-MIC Engineering Contact: Brad Davis, Kitware
 
*NA-MIC Algorithms Contact: Polina Golland, MIT
 
  
 +
= Harvard Roadmap Project =
  
* '''Affiliation/Institution:''' Harvard Medical School, Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital
+
{| cellpadding="10" border="1" style="background:lightblue;text-align:left;"
  
* '''Science:''' VCFS is a genetic disorder characterized by a deletion of a small piece of chromosome-22. The features of this syndrome include deficits in neurological psychomotor and perceptual skills, as well as in cognitive domains such as learning and memory. Most importantly, up to 30% of VCFS patients develop schizophrenia, making it the most commonly known single risk factor for the development of psychosis and a unique model for studying neurodevelopmental changes leading to psychotic deficits. We plan to collect new, high resolution DTI, structural and fMRI data, and apply existing NAMIC tools, as well as help to develop new tools to investigate the contribution of genetic variation to brain and behavioral/cognitive abnormalities, thus bridging the gap between neuroimaging studies and genetics.
+
| style="width:200px" | [[Image:Arcuate_new.png|200px]]
 +
| style="width:1300px" |
  
* '''Benefits to NA-MIC'''<nowiki>: The NAMIC community will gain access to new, high resolution diffusion and fMRI data acquired on the 3T magnet at Brigham and Women’s Hospital. Unlike in schizophrenia, subjects with VCFS have concrete cognitive abnormalities, in addition to a well defined chromosomal abnormality, which, taken together, will make it easier to establish scientific protocols that reveal associated anatomical and functional brain abnormalities in this disorder. Interestingly, some anatomical abnormalities will be shared between VCFS and schizophrenia (e.g., connections within working memory circuits), and some will be not (e.g., sensory and motor paths). Genetic data will also be collected for each individual and will also be available for further analyses with the imaging and neurocognitive data. This NAMIC collaboration with thus enable the PI to apply NAMIC tools to VCFS, a genetic disorder that is viewed as a genetically mediated subtype of schizophrenia. To date, there have only been a small number of neuroimaging studies of this disorder and no studies have combined neurocognitive, neuroimaging, and genetic investigations in the same study. Importantly, this research will also increase our understanding of schizophrenia, and will help establish a multimodal research project involving an important collaboration between computer scientists, cognitive neuroscientists, radiologists, psychiatrists, and geneticists. The focus on imaging and genes also affords a new window of opportunity for defining further the new area of “imaging genomics”. </nowiki>
+
== [[DBP2:Harvard:Brain_Segmentation_Roadmap|Stochastic Tractography for VCSF]] ==
  
Back to [[DBP2]]
+
The main goal of this project is to develop end-to-end application that would be used to characterize anatomical connectivity abnormalities in the
 +
brain of patients with velocardiofacial syndrome (VCFS), and to link this information with deficits in schizophrenia. [[DBP2:Harvard:Brain_Segmentation_Roadmap|More...]]
  
=Velocardiofacial Syndrome (VCFS) as a genetic model for schizophrenia=
+
<font color="red">'''New: '''</font>  12/10/2008 official release of the python Slicer 3 stochastic tractography module
==Team and Institute==
 
  
==Research Goals==
+
<font color="red">'''New: '''</font>  Collaborative Publication: "Reduced interhemispheric connectivity in schizophrenia-tractography based segmentation of the corpus callosum. Kubicki M, Styner M, Bouix S, Gerig G, Markant D, Smith K, Kikinis R, McCarley RW, Shenton ME. Schizophr Res. 2008 Dec;106(2-3):125-131. Epub 2008 Sep 30.
'''Clinical and Scientific Relevance''': The main goal of this application is to characterize “intermediate phenotypes”, such as anatomic and functional abnormalities in the brain of patients with velocardiofacial syndrome (VCFS), and to link this information with cognitive/behavioral deficits in schizophrenia and with genetic variations. This area of research represents a new frontier for making schizophrenia more tractable, as well as for shedding new light on the etiology of this devastating disorder.  
 
  
We propose to study patients with VCFS, a genetic disorder characterized by a deletion of a small piece of chromosome-22, in order to understand this disorder further as well as to evaluate VCFS as a genetic model for schizophrenia. The features of this syndrome include, among other things, deficits in neurological psychomotor and perceptual skills, as well as cognitive deficits in learning and memory. Importantly, up to 30% of VCFS patients develop schizophrenia, making it the most commonly known single risk factor for the development of psychosis and a unique model for studying neurodevelopmental changes leading to psychotic deficits. The deletion region contains about 30 to 40 genes, but only 3- PRODH, RTN4R and COMT have thus far been related to schizophrenia. COMT (catecholamine-O-methyl transferease) is a gene that is important for the catabolism of dopamine and maintaining appropriate levels of dopamine in the human brain, and several studies have associated this gene, or rather different COMT genotypes, with dorso-lateral prefrontal cortex and working memory, which are known to be disrupted in schizophrenia. RTN4R (known also as No-Go-66 receptor) gene, on the other hand, is much less studied than the COMT gene, but might be equally important in studies investigating schizophrenia. This gene mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system. Since dopamine regulation, as well as neuronal plasticity, are both investigated in schizophrenia, VCFS seems to be the perfect genetic model for schizophrenia.  
+
| style="width:200px" | [[Image:Corpus2.jpg|200px]]
  
We propose to combine genetic data and sophisticated neuroimaging data analysis. Gray matter regions previously implicated in both VCFS and schizophrenia research (frontal and temporal regions), as well as regions more commonly observed in schizophrenia (medial temporal and subcortical structures), will be delineated and analyzed including shape analysis. In addition, fiber tracts that show abnormalities in schizophrenia, such as the fornix, the cingulum bundle, the uncinate fasciculus, the corpus callosum (also implicated in VCFS studies), and the internal capsule, will be investigated using Diffusion Tensor Imaging, a technique sensitive to white matter fiber integrity. In addition, statistical as well as anatomical relationships between gray and white matter pathology, including anatomical connections between gray matter areas affected in VCFS and schizophrenia and cognitive and clinical symptoms will also be evaluated.
+
|}
  
We will scan 15 VCFS patients per year for a total of 45 subjects over the three-year grant period. Half of these subjects will have severe psychiatric symptoms, with a diagnosis of schizophrenia or schizophrenia-like symptoms, and half will have either no psychiatric symptoms or minimal symptoms and no Axis I disorder determined by standardized diagnostic interview. While not part of this project, we will have access to patients with schizophrenia and controls from a larger study of schizophrenia. We thus plan to evaluate N=45 control group, which will consist of healthy controls and schizophrenia subjects without VCFS, matched for age, gender, handedness, parental socio-economic status and IQ. The later control group is important, since most schizophrenia studies exclude low IQ participants, thus results of majority of schizophrenia studies might not be comparable with our VCFS population, which is characterized by IQ below normal. 
+
= Other Harvard-NAMIC Collaboration Projects =
  
The '''specific aims''' of this project are:
+
; <font color="firebrick" font size="4"> LMI / PNL, Brigham & Women's Hospital </font>
* To detect and localize possible gray and white matter disruptions common to VCFS and schizophrenia.
+
 
* To investigate the relationship among anatomical and between anatomical and functional abnormalities (later measured by clinical symptoms and neuropsychological tests).
+
{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
* To determine the extent to which anatomical as well as functional abnormalities observed in schizophrenia and anatomical and functional differences between VCFS patients with and without schizophrenia can be explained by VCFS genotype. (latter involving genetic haplotype analysis)
+
 
 +
| style="width:1700px" |
 +
 
 +
== [[Projects:WhiteMatterGeometryDTGradients| Local white matter geometry from diffusion tensor gradients]] ==
 +
We are investigating methods for computing local white matter geometrical properties using a differential analysis of diffusion tensor fields. We are also investigating their applications in the context of schizophrenia research.
 +
 
 +
[[http://pnl.bwh.harvard.edu/pub/papers_html/SavadjievNeuroImage10.html Local white matter geometry from diffusion tensor gradients. P. Savadjiev, G. L. Kindlmann, S. Bouix, M. E. Shenton, C-F Westin, NeuroImage 2010. ]]
 +
 
 +
|}
 +
 
 +
{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
 +
 
 +
| style="width:1700px" |
 +
 
 +
== [[Projects:MultiTensorTractography| Multi-Tensor Tractography]] ==
 +
We are developing a novel framework for performing simultaneous multi-fiber model estimation and tractography. This is a unified framework
 +
that allows for using any type of parametric or nonparametric model to perform tractography.
 +
 
 +
[[http://pnl.bwh.harvard.edu/pub/papers_html/MalcolmInfProc09.html Neural tractography using an unscented Kalman filter. J. Malcolm, M. E. Shenton and Y. Rathi]]
 +
 
 +
|}
 +
 
 +
; <font color="firebrick" font size="4"> GA Tech </font>
 +
 
 +
{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
 +
 
 +
| style="width:1700px" |
 +
 
 +
== [[Projects:OptimalMassTransportRegistration|EPI distortion correction using optimal mass transport.]] ==
 +
EPI distortion correction using optimal mass transport. (baseline vs. strct t2w). Goal is to use optimal registration for EPI distortion correction in diffusion weigthed scans.
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:GeodesicTractographySegmentation| Geodesic Tractography Segmentation]] ==
 +
We are currently investigating Cingulum Bundle fractional anisotropy (FA) differences between a population of 12 schizophrenics and 12 normal controls using this new methodology.
 +
 
 +
[[http://pnl.bwh.harvard.edu/pub/papers_html/MelmohanMICCAI07.html Finsler Tractography for White Matter Connectivity Analysis of the Cingulum Bundle J. Melonakos, V. Mohan, M. Niethammer, K. Smith, M. Kubicki, A. Tannenbaum miccai 2007 ]]
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:TubularSurfaceSegmentationPopStudy| Tubular Surface Segmentation Population Study]] ==
 +
We are currently investigating Cingulum Bundle white matter properties between a population of schizophrenics and controls using using the Tubular Surface Model.
 +
 
 +
[[http://www.na-mic.org/publications/item/view/1571 Niethammer M., Zach C., Melonakos J., Tannenbaum A. Near-tubular fiber bundle segmentation for diffusion weighted imaging: segmentation through frame reorientation. Neuroimage. 2009 Mar;45(1 Suppl):S123-32. PMID: 19101640. PMCID: PMC2774769. ]]
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:LabelSpace| A Coupled Multi-Shape Representation]] ==
 +
We are currently using this technique to build an unbiased atlas for segmentation.
 +
 
 +
[[http://users.ece.gatech.edu/~malcolm/pubs/malcolm_lss.pdf J. Malcolm, Y. Rathi, and A. Tannenbaum. "Label Space: A Multi-Object Shape Representation." In Combinatorial Image Analysis, 2008.]]
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:MultiscaleShapeAnalysis| Shape Analysis of the Caudate]] ==
 +
Multiscale shape analysis
 +
 
 +
[Y. Gao, D. Nain, M. Styner, M. Niethammer, J. J. Levitt, M E Shenton, G Gerig, A. Bobick, A. Tannenbaum. Framework for the Statistical Shape Analysis of Brain Structures using Spherical Wavelets. In preparation for the Insight Journal, February/March 2007]
 +
|}
 +
 
 +
; <font color="firebrick" font size="4"> MIT </font>
 +
 
 +
{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
 +
 
 +
 
 +
| style="width:1700px" |
 +
 
 +
== [[Projects:ShapeBasedSegmentationAndRegistration|Shape Based Segmentation and Registration]] ==
 +
We use this segmentation algorithm to process our entire data set.
 +
 
 +
[[http://pnl.bwh.harvard.edu/pub/papers_html/PohlIEEE07.html A Hierarchical Algorithm for MR Brain Image Parcellation, K. Pohl, S. Bouix, M. Nakamura, T. Rohlfing, R. McCarley, R. Kikinis, W. Grimson, M. E. Shenton, W. Wells, IEEE Transactions on Medical Imaging, Volume 26, Number 9, Pages 1201-1212, 2007 ]]
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:GroupwiseRegistration| Groupwise Registration]] ==
 +
The goal is to create unbiased atlases throught nonlinear (b-spline) group wise registration.
 +
 
 +
[[http://www.spl.harvard.edu/publications/item/view/1090 S.K. Balci, P. Golland, M.E. Shenton, W.M. Wells III. Free-Form B-spline Deformation Model for Groupwise Registration. In Proceedings of MICCAI 2007 Statistical Registration Workshop: Pair-wise and Group-wise Alignment and Atlas Formation, 23-30, 2007. ]]
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:DTIClustering| DTI Fiber Clustering and Fiber Based Analysis ]] ==
 +
The goal of this project is to provide structural description of the white matter architecture as a partition into coherent fiber bundles and clusters, and to use these bundles for quantitative measurement. We use this method in two ongoing projects- corpus callosum segmentation in chronic schizophrenia sample, and whole brain clustering in sample of first episode psychosis subjects.
 +
 
 +
[[http://pnl.bwh.harvard.edu/pub/papers_html/odonnellAJNR06.html A Method for Clustering White Matter Fiber Tracts; L. O'Donnell, Kubicki M, M. E. Shenton, M. Dreusicke, W. E. L. Grimson, C.-F. Westin, AJNR Volume 27, Number 5 2006 ]]
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:DTIModeling| Fiber Tract Modeling, Clustering, and Quantitative Analysis ]] ==
 +
The goal of this project is to segment and parametrize fiber bundles for more precise group comparison. We use this method to segment and compare between controls and chronic schizophrenia population tracts belonging to inferior semantic processing stream (Inferior Longitudinal fasciculus, Uncinate Fasciculus and Inferior Occipito-Frontal Fasciculus). Manuscript is in preparation. 
 +
 
 +
<font color="red">'''New: '''</font>[[http://pnl.bwh.harvard.edu/pub/papers_html/madahmiccai08.html Findings in Schizophrenia by Tract-Oriented DT-MRI Analysis, M. Maddah, M. Kubicki, W. Wells, C.F. Westin, M.E. Shenton, W.E. Grimson, miccai, Pages 917-924 September, 2008 ]]
 +
 
 +
|-
 +
| |
 +
 
 +
== [[Projects:fMRIClustering| fMRI clustering]] ==
 +
The goal of this project is to use resting state fMRI data and clustering algorythm to detect and separate specific functional brain networks. We are in the process of runing the method on group of chronic schizophrenia and matched control subjects.
 +
 
 +
|}
 +
 
 +
; <font color="firebrick" font size="4"> UNC </font>
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{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
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| style="width:1700px" |
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 +
== [[Projects:ShapeAnalysisFrameworkUsingSPHARMPDM| Shape Analysis Framework using SPHARM-PDM]] ==
 +
["Shape Abnormalities of Caudate Nucleus in Schizotypal Personality Disorder" has been accepted by Schizophrenia Research. James J. Levitt, Martin Styner, Marc Niethammer, Sylvain Bouix, Min-Seong Koo, Martina M. Voglmaier, Chandlee C. Dickey, Margaret A. Niznikiewicz, Ron Kikinis, Robert, W. McCarley, Martha E. Shenton.]
 +
<font color="lightgray">  </font>
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|}
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; <font color="firebrick" font size="4"> Utah 1 </font>
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{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
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 +
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| style="width:1700px" |
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 +
== [[Projects:DTIProcessingTools| Diffusion Tensor Image Processing Tools]] ==
 +
Testing and use of eddy current correction for our DWI scans. <font color="lightgray">  </font>
 +
 
 +
|}
 +
 
 +
; <font color="firebrick" font size="4"> Utah 2 </font>
 +
 
 +
{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
  
==Data description==
 
'''What kind of image data is associated with these goals (modality, resolution, quantity)?'''
 
 
   
 
   
To date, we have collected  DTI and Structural Data on the 1.5Tesla magnet on 6 VCFS patients. We are waiting for IRB approval to rescan these subjects, and to start collecting further prospective data on 3Tesla magnet, where we plan to use the following scan parameters:  
+
| style="width:1700px" |
  
* '''Diffusion Tensor MRI''': DTI scans will be acquired from a 3 Tesla GE system (General Electric Medical Systems, Milwaukee, WI) using an echo planar imaging (EPI) DTI Tensor sequence. We will use a double echo option in order to reduce eddy-current related distortions (Heid 2000; Alexander 1997). To reduce the impact of EPI spatial distortion, we will use an 8 Channel coil that will allow us to perform parallel imaging using ASSET (Array Spatial Sensitivity Encoding Techniques, GE) with a SENSE-factor (speed-up) of 2. We will acquire 51 directions with b=700, 8 baseline scans with b=0. The original GE sequence has been modified, in order to increase spatial resolution, and to further minimize image artifacts. The following scan parameters will be used: TR 17000 ms, TE 78 ms, FOV 24 cm, 144 x 144 encoding steps, 1.7-mm slice thickness. We will acquire 81 axial-oblique slices parallel to the AC-PC line and perpendicular to the interhemispheric fissure covering the whole brain. The total scan time for the sequence will be 17 minutes. After reconstruction, the diffusion-weighted images will be transferred to Linux workstations, where eigenvalues, eigenvectors and anisotropy indices of the diffusion tensor will be calculated.  
+
== [[Projects:DTIPopulationAnalysis| Population Analysis from Deformable Registration]] ==
 +
This project uses non-rigid registration of DTI images to produce a common coordinate system for hypothesis testing of diffusion properties. <font color="lightgray">  </font>
  
* '''Structural MRI''': For the Structural MRI volume and shape measurements, images will be acquired also using a 3T GE scanner (GE Medical Systems, Milwaukee). The acquisition protocol will include two MRI pulse sequences. The first sequence results in contiguous spoiled gradient-recalled acquisition (FastSPGR) with the following parameters; TR=7.5ms, TE=3ms, 15 degree flip angle, 25.6cm2 field of view, NEX=1.0, matrix=256x256. Similar to DTI, we will use an 8 Channel coil that will allow us to perform parallel imaging using ASSET (Array Spatial Sensitivity Encoding Techniques, GE) with a SENSE-factor (speed-up) of 2. The voxel dimensions are 1x1x1 mm. Data will be formatted in the axial plane and analyzed as 186 axial slices, and a total scan time is 4 minutes. The second acquisition sequence (Fast Spin Echo- FSE) produces an axial series of contiguous T2-weighted images (TR=6200ms, TE=103ms, Echo Train Length=16; 25.6cm2 field of view, interleaved acquisitions with 2.0mm slice thickness). The voxel dimensions are 1x1x2.0 mm. This latter pulse sequence is used to measure the volume of the total intracranial contents, used then as an independent factor in a regression procedure to account for the effect of head/brain size.
+
|}
  
'''What other kinds of data are involved (non-image)?
+
;
 +
== Registration Documentation ==
  
For all the subjects, we are also currently collecting:
+
{| cellpadding="10" border="1" style="background:lightgray;text-align:left;"
 +
 
 +
 +
| style="width:1700px" |
  
* '''Neuropsychological and Cognitive Data''': VCFS patients will be administered a standard battery of cognitive measures in major domains thought to be affected in VCFS and schizophrenic populations, including: general intellectual functioning, verbal intelligence and language functioning, working memory, visuo-spatial and perceptual functioning, executive functioning, and attention among others. In addition, psychiatric diagnostic evaluations will be carried out on all VCFS subjects, and include standardized assessment of general psychiatric symptoms with the Structured Clinical Interview for DSM-IV Axis I (SCID-I) as well as specific measures of positive and negative symptoms of psychosis and measures of schizotypy. It is expected that structural brain abnormalities will correlate with the presence or absence of psychiatric diagnoses in VCFS subjects (e.g., midline defects like cavum septum pellicidum/vergae or enlarged lateral ventricles in psychotic VCFS subjects) and various cognitive measures (e.g., impairment in executive functioning and attention correlated with prefrontal lobe cortex anomalies; arithmetic ability correlated with inferior parietal lobe anomalies; and verbal memory correlated with left superior temporal gyrus, and left amygdale-hippocampal complex).
+
== [[Projects:DBP2:Harvard:Registration_Documentation| Documentation of Slicer3 registration modules]] ==
 +
This page documents the results of using the various registration methods available in Slicer 3. <font color="lightgray">  </font>
  
* '''Genetic Measures''': As testing every putative genetic variant in every candidate gene that may contribute to the VCFS/DGS phenotype would be prohibitive in terms of time and money, haplotype based approaches offer an alternative. These approaches have contributed to the identification of Mendelian disease genes and are now beginning to help identify susceptibility genes for common, complex diseases. The International HapMap Consortium is constructing genome-wide maps of sequence variation that may facilitate large association studies (The International HapMap Consortium:http://www.hapmap.org/). It is predicted that these approaches will be a powerful tool for common diseases like schizophrenia that are thought to result from a small number of common variants (“common disease-common variant” hypothesis). We propose a pilot investigation of the role of genetic variation found in the 22q11-deleted region using “tag” SNPs that define the haplotype map of this region. Using around two tag SNPs per haplotype block we expect that we will genotype around 160 SNPs for subsequent association studies. Although genes outside 22q11 may have a modifying effect on the phenotypic spectrum, our current focus is on genes within the 22q11 region because we feel it is important to first assess the role of the genes within the 3Mb region of deletion. Once genotyping data are assembled, we will use a case-control study design to determine if any of the genes in the commonly deleted 3Mb region are associated with neuropsychiatric phenotypes. Specifically, we will use the identified tag SNPs to genotype a set of cases (VCFS patients with psychiatric symptoms) and a set of controls (VCFS patients without psychiatric symptoms).  Neurocognitive measures, or anatomical abnormalities will also be considered as phenotypes of interest. Both single SNP and haplotype analyses will be undertaken.
+
|}

Latest revision as of 17:04, 13 May 2010

Home < DBP2:Harvard
Back to NA-MIC DBP 2

Overview of Harvard DBP 2

Velocardiofacial Syndrome (VCFS) as a Genetic Model for Schizophrenia

VCFS is a genetic disorder characterized by a deletion of a small piece of chromosome-22. The features of this syndrome include deficits in neurological psychomotor and perceptual skills, as well as in cognitive domains such as learning and memory. Most importantly, up to 30% of VCFS patients develop schizophrenia, making it the most commonly known single risk factor for the development of psychosis and a unique model for studying neurodevelopmental changes leading to psychotic deficits. We plan to collect new, high resolution DTI, structural and fMRI data, and apply existing NAMIC tools, as well as help to develop new tools to investigate the contribution of genetic variation to brain and behavioral/cognitive abnormalities, thus bridging the gap between neuroimaging studies and genetics. The NAMIC community will gain access to de-identified imaging data (new, high resolution structural and diffusion data acquired on the 3T magnet at Brigham and Women’s Hospital). Unlike in schizophrenia, subjects with VCFS have concrete cognitive abnormalities, in addition to a well defined chromosomal abnormality, which, taken together, will make it easier to establish scientific protocols that reveal associated anatomical and functional brain abnormalities in this disorder. Interestingly, some anatomical abnormalities will be shared between VCFS and schizophrenia (e.g., connections within working memory circuits), and some will be not (e.g., sensory and motor paths). Neuropsychological and genetic data will also be collected for each individual as part of separate collaboration between PI and the Children's Hospital("Investigation of Genotype/Phenotype Correlations in Velocardiofacial and DiGeorge Syndromes”) and de-dentified dataset containing neuropsychological tests, clinical evaluations and genetic data will be provided to the PI. The NAMIC project with thus enable the PI to apply NAMIC tools to imaging VCFS data, a genetic disorder that is viewed as a genetically mediated subtype of schizophrenia. To date, there have only been a small number of neuroimaging studies of this disorder and no studies have combined neurocognitive, neuroimaging, and genetic investigations in the same study. Importantly, this research will also increase our understanding of schizophrenia, and will help establish a multimodal research project involving an important collaboration between computer scientists, cognitive neuroscientists, radiologists, psychiatrists, and geneticists. The focus on imaging and genes also affords a new window of opportunity for defining further the new area of “imaging genomics”. More...

Data is provided at the following link: Harvard Data.

Harvard Roadmap Project

Arcuate new.png

Stochastic Tractography for VCSF

The main goal of this project is to develop end-to-end application that would be used to characterize anatomical connectivity abnormalities in the brain of patients with velocardiofacial syndrome (VCFS), and to link this information with deficits in schizophrenia. More...

New: 12/10/2008 official release of the python Slicer 3 stochastic tractography module

New: Collaborative Publication: "Reduced interhemispheric connectivity in schizophrenia-tractography based segmentation of the corpus callosum. Kubicki M, Styner M, Bouix S, Gerig G, Markant D, Smith K, Kikinis R, McCarley RW, Shenton ME. Schizophr Res. 2008 Dec;106(2-3):125-131. Epub 2008 Sep 30.

Corpus2.jpg

Other Harvard-NAMIC Collaboration Projects

LMI / PNL, Brigham & Women's Hospital

Local white matter geometry from diffusion tensor gradients

We are investigating methods for computing local white matter geometrical properties using a differential analysis of diffusion tensor fields. We are also investigating their applications in the context of schizophrenia research.

[Local white matter geometry from diffusion tensor gradients. P. Savadjiev, G. L. Kindlmann, S. Bouix, M. E. Shenton, C-F Westin, NeuroImage 2010. ]

Multi-Tensor Tractography

We are developing a novel framework for performing simultaneous multi-fiber model estimation and tractography. This is a unified framework that allows for using any type of parametric or nonparametric model to perform tractography.

[Neural tractography using an unscented Kalman filter. J. Malcolm, M. E. Shenton and Y. Rathi]

GA Tech

EPI distortion correction using optimal mass transport.

EPI distortion correction using optimal mass transport. (baseline vs. strct t2w). Goal is to use optimal registration for EPI distortion correction in diffusion weigthed scans.

Geodesic Tractography Segmentation

We are currently investigating Cingulum Bundle fractional anisotropy (FA) differences between a population of 12 schizophrenics and 12 normal controls using this new methodology.

[Finsler Tractography for White Matter Connectivity Analysis of the Cingulum Bundle J. Melonakos, V. Mohan, M. Niethammer, K. Smith, M. Kubicki, A. Tannenbaum miccai 2007 ]

Tubular Surface Segmentation Population Study

We are currently investigating Cingulum Bundle white matter properties between a population of schizophrenics and controls using using the Tubular Surface Model.

[Niethammer M., Zach C., Melonakos J., Tannenbaum A. Near-tubular fiber bundle segmentation for diffusion weighted imaging: segmentation through frame reorientation. Neuroimage. 2009 Mar;45(1 Suppl):S123-32. PMID: 19101640. PMCID: PMC2774769. ]

A Coupled Multi-Shape Representation

We are currently using this technique to build an unbiased atlas for segmentation.

[J. Malcolm, Y. Rathi, and A. Tannenbaum. "Label Space: A Multi-Object Shape Representation." In Combinatorial Image Analysis, 2008.]

Shape Analysis of the Caudate

Multiscale shape analysis

[Y. Gao, D. Nain, M. Styner, M. Niethammer, J. J. Levitt, M E Shenton, G Gerig, A. Bobick, A. Tannenbaum. Framework for the Statistical Shape Analysis of Brain Structures using Spherical Wavelets. In preparation for the Insight Journal, February/March 2007]

MIT

Shape Based Segmentation and Registration

We use this segmentation algorithm to process our entire data set.

[A Hierarchical Algorithm for MR Brain Image Parcellation, K. Pohl, S. Bouix, M. Nakamura, T. Rohlfing, R. McCarley, R. Kikinis, W. Grimson, M. E. Shenton, W. Wells, IEEE Transactions on Medical Imaging, Volume 26, Number 9, Pages 1201-1212, 2007 ]

Groupwise Registration

The goal is to create unbiased atlases throught nonlinear (b-spline) group wise registration.

[S.K. Balci, P. Golland, M.E. Shenton, W.M. Wells III. Free-Form B-spline Deformation Model for Groupwise Registration. In Proceedings of MICCAI 2007 Statistical Registration Workshop: Pair-wise and Group-wise Alignment and Atlas Formation, 23-30, 2007. ]

DTI Fiber Clustering and Fiber Based Analysis

The goal of this project is to provide structural description of the white matter architecture as a partition into coherent fiber bundles and clusters, and to use these bundles for quantitative measurement. We use this method in two ongoing projects- corpus callosum segmentation in chronic schizophrenia sample, and whole brain clustering in sample of first episode psychosis subjects.

[A Method for Clustering White Matter Fiber Tracts; L. O'Donnell, Kubicki M, M. E. Shenton, M. Dreusicke, W. E. L. Grimson, C.-F. Westin, AJNR Volume 27, Number 5 2006 ]

Fiber Tract Modeling, Clustering, and Quantitative Analysis

The goal of this project is to segment and parametrize fiber bundles for more precise group comparison. We use this method to segment and compare between controls and chronic schizophrenia population tracts belonging to inferior semantic processing stream (Inferior Longitudinal fasciculus, Uncinate Fasciculus and Inferior Occipito-Frontal Fasciculus). Manuscript is in preparation.

New: [Findings in Schizophrenia by Tract-Oriented DT-MRI Analysis, M. Maddah, M. Kubicki, W. Wells, C.F. Westin, M.E. Shenton, W.E. Grimson, miccai, Pages 917-924 September, 2008 ]

fMRI clustering

The goal of this project is to use resting state fMRI data and clustering algorythm to detect and separate specific functional brain networks. We are in the process of runing the method on group of chronic schizophrenia and matched control subjects.

UNC

Shape Analysis Framework using SPHARM-PDM

["Shape Abnormalities of Caudate Nucleus in Schizotypal Personality Disorder" has been accepted by Schizophrenia Research. James J. Levitt, Martin Styner, Marc Niethammer, Sylvain Bouix, Min-Seong Koo, Martina M. Voglmaier, Chandlee C. Dickey, Margaret A. Niznikiewicz, Ron Kikinis, Robert, W. McCarley, Martha E. Shenton.]

Utah 1

Diffusion Tensor Image Processing Tools

Testing and use of eddy current correction for our DWI scans.

Utah 2

Population Analysis from Deformable Registration

This project uses non-rigid registration of DTI images to produce a common coordinate system for hypothesis testing of diffusion properties.

Registration Documentation

Documentation of Slicer3 registration modules

This page documents the results of using the various registration methods available in Slicer 3.