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1.  Mapping human brain fatty acid amide hydrolase activity with PET 
Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [11C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [11C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood sampling for 90 minutes. Kinetic parameters were estimated regionally using a one-tissue compartment model (TCM), a 2-TCM with and without irreversible trapping, and an irreversible 3-TCM. The 2-TCM with irreversible trapping provided the best identifiability of PET outcome measures among the approaches studied (coefficient of variation (COV) of the net influx constant Ki and the composite parameter λk3 (λ=K1/k2) <5%, and COV(k3)<10%). Reducing scan time to 60 minutes did not compromise the identifiability of rate constants. Arterial spin labeling measures of regional cerebral blood flow were only slightly correlated with Ki, but not with k3 or λk3. Our data suggest that λk3 is sensitive to changes in FAAH activity, therefore, optimal for PET quantification of FAAH activities with [11C]CURB. Simulations showed that [11C]CURB binding in healthy subjects is far from a flow-limited uptake.
PMCID: PMC3587811  PMID: 23211960
[11C]CURB; endocannabinoid; FAAH; fatty acid amide hydrolase; kinetic modeling; PET; positron emission tomography
2.  The ZNF804A Gene: Characterization of a Novel Neural Risk Mechanism for the Major Psychoses 
Neuropsychopharmacology  2011;36(9):1871-1878.
Schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant's potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant (‘A' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder.
PMCID: PMC3154105  PMID: 21525856
ZNF804A; cortical thickness; DTI; white matter; schizophrenia; bipolar disorder; schizophrenia/antipsychotics; depression; unipolar/bipolar; imaging; clinical or preclinical; neurogenetics; MRI; genetics; DTI; cortical thickness
3.  Age-related decline in white matter tract integrity and cognitive performance: A DTI tractography and structural equation modeling study 
Neurobiology of aging  2010;33(1):21-34.
Age-related decline in microstructural integrity of certain white matter tracts may explain cognitive decline associated with normal aging. Whole brain tractography and a clustering segmentation in 48 healthy individuals across the adult lifespan were used to examine: interhemispheric (corpus callosum), intrahemispheric association (cingulum, uncinate, arcuate, inferior longitudinal, inferior occipitofrontal), and projection (corticospinal) fibers. Principal components analysis reduced cognitive tests into 6 meaningful factors: (1) memory and executive function; (2) visuomotor dexterity; (3) motor speed; (4) attention and working memory; (5) set-shifting/flexibility; and (6) visuospatial construction. Using theory-based structural equation modeling, relationships among age, white matter tract integrity, and cognitive performance were investigated. Parsimonious model fit demonstrated relationships where decline in white matter integrity may explain age-related decline in cognitive performance: inferior longitudinal fasciculus (ILF) with visuomotor dexterity; the inferior occipitofrontal fasciculus with visuospatial construction; and posterior fibers (i.e., splenium) of the corpus callosum with memory and executive function. Our findings suggest that decline in the microstructural integrity of white matter fibers can account for cognitive decline in normal aging.
PMCID: PMC2945445  PMID: 20363050
Aging; Anisotropy; Cognition; Diffusion tensor imaging; White matter
4.  Diffusion tensor tractography findings in schizophrenia across the adult lifespan 
Brain  2010;133(5):1494-1504.
In healthy adult individuals, late life is a dynamic time of change with respect to the microstructural integrity of white matter tracts. Yet, elderly individuals are generally excluded from diffusion tensor imaging studies in schizophrenia. Therefore, we examined microstructural integrity of frontotemporal and interhemispheric white matter tracts in schizophrenia across the adult lifespan. Diffusion tensor imaging data from 25 younger schizophrenic patients (≤55 years), 25 younger controls, 25 older schizophrenic patients (≥56 years) and 25 older controls were analysed. Patients with schizophrenia in each group were individually matched to controls. Whole-brain tractography and clustering segmentation were employed to isolate white matter tracts. Groups were compared using repeated measures analysis of variance with 12 within-group measures of fractional anisotropy: (left and right) uncinate fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, inferior occipito-frontal fasciculus, cingulum bundle, and genu and splenium of the corpus callosum. For each white matter tract, fractional anisotropy was then regressed against age in patients and controls, and correlation coefficients compared. The main effect of group (F3,92 = 12.2, P < 0.001), and group by tract interactions (F26,832 = 1.68, P = 0.018) were evident for fractional anisotropy values. Younger patients had significantly lower fractional anisotropy than younger controls (Bonferonni-corrected alpha = 0.0042) in the left uncinate fasciculus (t48 = 3.7, P = 0.001) and right cingulum bundle (t48 = 3.6, P = 0.001), with considerable effect size, but the older groups did not differ. Schizophrenic patients did not demonstrate accelerated age-related decline compared with healthy controls in any white matter tract. To our knowledge, this is the first study to examine the microstructural integrity of frontotemporal white matter tracts across the adult lifespan in schizophrenia. The left uncinate fasciculus and right cingulum bundle are disrupted in younger chronic patients with schizophrenia compared with matched controls, suggesting that these white matter tracts are related to frontotemporal disconnectivity. The absence of accelerated age-related decline, or differences between older community-dwelling patients and controls, suggests that these patients may possess resilience to white matter disruption.
PMCID: PMC2859148  PMID: 20237131
schizophrenia; diffusion tensor; ageing; white matter fibre pathways
5.  Quantitative Examination of a Novel Clustering Method using Magnetic Resonance Diffusion Tensor Tractography 
NeuroImage  2008;45(2):370-376.
MR diffusion tensor imaging (DTI) can measure and visualize organization of white matter fibre tracts in vivo. DTI is a relatively new imaging technique, and new tools developed for quantifying fibre tracts require evaluation. The purpose of this study was to compare the reliability of a novel clustering approach with a multiple region of interest (MROI) approach in both healthy and disease (schizophrenia) populations. DTI images were acquired in 20 participants (n=10 patients with schizophrenia: 56 ± 15 years; n=10 controls: 51 ± 20 years) (1.5 Tesla GE system) with diffusion gradients applied in 23 non-collinear directions, repeated three times. Whole brain seeding and creation of fibre tracts were then performed. Interrater reliability of the clustering approach, and the MROI approach, were each evaluated and the methods compared. There was high spatial (voxel-based) agreement within and between the clustering and MROI methods. Fractional anisotropy, trace, and radial and axial diffusivity values showed high intraclass correlation (p<0.001 for all tracts) for each approach. Differences in scalar indices of diffusion between the clustering and MROI approach were minimal. The excellent interrater reliability of the clustering method and high agreement with the MROI method, quantitatively and spatially, indicates that the clustering method can be used with confidence. The clustering method avoids biases of ROI drawing and placement, and, not limited by a priori predictions, may be a more robust and efficient way to identify and measure white matter tracts of interest.
PMCID: PMC2646811  PMID: 19159690
diffusion tensor imaging; tractography; streamline; clustering; region of interest; schizophrenia
6.  Automatic segmentation of white matter hyperintensities in the elderly using FLAIR images at 3T 
To determine the precision and accuracy of an automated method for segmenting white matter hyperintensities (WMH) on fast fluid-attenuated inversion-recovery (FLAIR) images in elderly brains at 3T.
Materials and Methods
FLAIR images from 18 individuals (60–82 years, 9 females) with WMH burdens ranging from 1–80 cm3 were used. The protocol included the removal of clearly hyperintense voxels; two-class fuzzy C-means clustering (FCM); and thresholding to segment probable WMH. Two false-positive minimization (FPM) methods using white matter templates were tested. Precision was assessed by adding synthetic hyperintense voxels to brain slices. Accuracy was validated by comparing automatic and manual segmentations. Whole-brain, voxel-wise metrics of similarity, under- and overestimation were used to evaluate both precision and accuracy.
Precision was high, as the lowest accuracy in the synthetic datasets was 93%. Both FPM strategies successfully improved overall accuracy. Whole-brain accuracy for the FCM segmentation alone ranged from 45%–81%, which improved to 75%–85% using the FPM strategies.
The method was accurate across the range of WMH burden typically seen in the elderly. Accuracy levels achieved or exceeded those of other approaches using multispectral and/or more sophisticated pattern recognition methods. J. Magn. Reson. Imaging 2010;31:1311–1322. © 2010 Wiley-Liss, Inc.
PMCID: PMC2905619  PMID: 20512882
white matter hyperintensity; FLAIR; seg-mentation
7.  Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study 
PLoS ONE  2011;6(11):e28044.
Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.
Methods/Principal Findings
DTI scans were acquired for 19 children and adolescents with ASD (∼8–18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8–18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.
Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder.
PMCID: PMC3223195  PMID: 22132206

Results 1-7 (7)