Ipek Oguz

DTIPrep: quality control of diffusion-weighted images

In the last decade, diffusion MRI (dMRI) studies of the human and animal brain have been used to investigate a multitude of pathologies and drug-related effects in neuroscience research. Study after study identifies white matter (WM) degeneration as a crucial biomarker for all these diseases. The tool of choice for studying WM is dMRI. However, dMRI has inherently low signal-to-noise ratio and its acquisition requires a relatively long scan time; in fact, the high loads required occasionally stress scanner hardware past the point of physical failure. As a result, many types of artifacts implicate the quality of diffusion imagery. Using these complex scans containing artifacts without quality control (QC) can result in considerable error and bias in the subsequent analysis, negatively affecting the results of research studies using them. However, dMRI QC remains an under-recognized issue in the dMRI community as there are no user-friendly tools commonly available to comprehensively address the issue of dMRI QC. As a result, current dMRI studies often perform a poor job at dMRI QC. Thorough QC of dMRI will reduce measurement noise and improve reproducibility, and sensitivity in neuroimaging studies; this will allow researchers to more fully exploit the power of the dMRI technique and will ultimately advance neuroscience. Therefore, in this manuscript, we present our open-source software, DTIPrep, as a unified, user friendly platform for thorough QC of dMRI data. These include artifacts caused by eddy-currents, head motion, bed vibration and pulsation, venetian blind artifacts, as well as slice-wise and gradient-wise intensity inconsistencies. This paper summarizes a basic set of features of DTIPrep described earlier and focuses on newly added capabilities related to directional artifacts and bias analysis.

Ethanol-induced face-brain dysmorphology patterns are correlative and exposure-stage dependent.

Prenatal ethanol exposure is the leading preventable cause of congenital mental disability. Whereas a diagnosis of fetal alcohol syndrome (FAS) requires identification of a specific pattern of craniofacial dysmorphology, most individuals with behavioral and neurological sequelae of heavy prenatal ethanol exposure do not exhibit these defining facial characteristics. Here, a novel integration of MRI and dense surface modeling-based shape analysis was applied to characterize concurrent face-brain phenotypes in C57Bl/6J fetuses exposed to ethanol on gestational day (GD)7 or GD8.5. The facial phenotype resulting from ethanol exposure depended upon stage of insult and was predictive of unique patterns of corresponding brain abnormalities. Ethanol exposure on GD7 produced a constellation of dysmorphic facial features characteristic of human FAS, including severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum. In contrast, ethanol exposure on GD8.5 caused mild midfacial hypoplasia and palpebral fissure shortening, a shortened upper lip, and a preserved philtrum. These distinct, stage-specific facial phenotypes were associated with unique volumetric and shape abnormalities of the septal region, pituitary, and olfactory bulbs. By demonstrating that early prenatal ethanol exposure can cause more than one temporally-specific pattern of defects, these findings illustrate the need for an expansion of current diagnostic criteria to better capture the full range of facial and brain dysmorphology in fetal alcohol spectrum disorders.

Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility

Adolescents binge drink more than any other age group, increasing risk of disrupting the development of the frontal cortex. We hypothesized that adolescent binge drinking would lead to persistent alterations in adulthood. In this study, we modeled adolescent weekend underage binge-drinking, using adolescent mice (post-natal days [P] 28-37). The adolescent intermittent binge ethanol (AIE) treatment includes 6 binge intragastric doses of ethanol in an intermittent pattern across adolescence. Assessments were conducted in adulthood following extended abstinence to determine if there were persistent changes in adults. Reversal learning, open field and other behavioral assessments as well as brain structure using magnetic imaging and immunohistochemistry were determined. We found that AIE did not impact adult Barnes Maze learning. However, AIE did cause reversal learning deficits in adults. AIE also caused structural changes in the adult brain. AIE was associated with adulthood volume enlargements in specific brain regions without changes in total brain volume. Enlarged regions included the orbitofrontal cortex (OFC, 4%), cerebellum (4.5%), thalamus (2%), internal capsule (10%) and genu of the corpus callosum (7%). The enlarged OFC volume in adults after AIE is consistent with previous imaging studies in human adolescents. AIE treatment was associated with significant increases in the expression of several extracellular matrix (ECM) proteins in the adult OFC including WFA (55%), Brevican (32%), Neurocan (105%), Tenacin-C (25%), and HABP (5%). These findings are consistent with AIE causing persistent changes in brain structure that could contribute to a lack of behavioral flexibility.

Mechanically Induced Focal Adhesion Assembly Amplifies Anti‐Adipogenic Pathways in Mesenchymal Stem Cells

The fate of pluripotent mesenchymal stem cells (MSC) is determined through integration of chemical, spatial, and physical signals. The suppression of MSC adipogenesis by mechanical stimuli, which requires Akt‐induced inhibition of glycogen synthase kinase 3β (GSK3β) with β‐catenin activation, can be enhanced by repetitive dosing within a single day. Here, we demonstrate that reapplication of cyclic strain within a 24‐hour period leads to amplification of both Akt activation and its subsequent inhibition of GSK3β, such that total cycle number can be reduced while still inhibiting adipogenesis. Amplification of Akt signaling is facilitated by a dynamic restructuring of the cell in response to mechanical signals, as evidenced by a transient increase in focal adhesion (FA) number and increased RhoA activity. Preventing FA assembly or development of tension blocks activation of Akt by mechanical signals, but not by insulin. This indicates that the FA infrastructure is essential to the physical, but not necessarily the chemical, sensitivity, and responsiveness of the cell. Exploiting the transient nature of cytoskeletal remodeling may represent a process to enhance cell responsiveness to mechanical input and ultimately define the fate of MSCs with a minimal input. STEM CELLS 2011;29:1829–1836

Postnatal day 7 ethanol treatment causes persistent reductions in adult mouse brain volume and cortical neurons with sex specific effects on neurogenesis

Ethanol treatment on postnatal day seven (P7) causes robust brain cell death and is a model of late gestational alcohol exposure (Ikonomidou et al., 2000). To investigate the long-term effects of P7 ethanol treatment on adult brain, mice received either two doses of saline or ethanol on P7 (2.5 g/kg, s.c., 2 h apart) and were assessed as adults (P82) for brain volume (using postmortem MRI) and cellular architecture (using immunohistochemistry). Adult mice that received P7 ethanol had reduced MRI total brain volume (4%) with multiple brain regions being reduced in both males and females. Immunohistochemistry indicated reduced frontal cortical parvalbumin immunoreactive (PV + IR) interneurons (18-33%) and reduced Cux1+IR layer II pyramidal neurons (15%) in both sexes. Interestingly, markers of adult hippocampal neurogenesis differed between sexes, with only ethanol treated males showing increased doublecortin and Ki67 expression (52 and 57% respectively) in the dentate gyrus, consistent with increased neurogenesis compared to controls. These findings suggest that P7 ethanol treatment causes persistent reductions in adult brain volume and frontal cortical neurons in both males and females. Increased adult neurogenesis in males, but not females, is consistent with differential adaptive responses to P7 ethanol toxicity between the sexes. One day of ethanol exposure, e.g. P7, causes persistent adult brain dysmorphology.

Brain abnormalities in bipolar disorder detected by quantitative T1ρ mapping

Abnormal metabolism has been reported in bipolar disorder, however, these studies have been limited to specific regions of the brain. To investigate whole-brain changes potentially associated with these processes, we applied a magnetic resonance imaging technique novel to psychiatric research, quantitative mapping of T1 relaxation in the rotating frame (T1ρ). This method is sensitive to proton chemical exchange, which is affected by pH, metabolite concentrations and cellular density with high spatial resolution relative to alternative techniques such as magnetic resonance spectroscopy and positron emission tomography. Study participants included 15 patients with bipolar I disorder in the euthymic state and 25 normal controls balanced for age and gender. T1ρ maps were generated and compared between the bipolar and control groups using voxel-wise and regional analyses. T1ρ values were found to be elevated in the cerebral white matter and cerebellum in the bipolar group. However, volumes of these areas were normal as measured by high-resolution T1- and T2-weighted magnetic resonance imaging. Interestingly, the cerebellar T1ρ abnormalities were normalized in participants receiving lithium treatment. These findings are consistent with metabolic or microstructural abnormalities in bipolar disorder and draw attention to roles of the cerebral white matter and cerebellum. This study highlights the potential utility of high-resolution T1ρ mapping in psychiatric research.

3-dimensional diffusion tensor imaging (DTI) atlas of the rat brain.

Anatomical atlases play an important role in the analysis of neuroimaging data in rodent neuroimaging studies. Having a high resolution, detailed atlas not only can expand understanding of rodent brain anatomy, but also enables automatic segmentation of new images, thus greatly increasing the efficiency of future analysis when applied to new data. These atlases can be used to analyze new scans of individual cases using a variety of automated segmentation methods. This project seeks to develop a set of detailed 3D anatomical atlases of the brain at postnatal day 5 (P5), 14 (P14), and adults (P72) in Sprague-Dawley rats. Our methods consisted of first creating a template image based on fixed scans of control rats, then manually segmenting various individual brain regions on the template. Using itk-SNAP software, subcortical and cortical regions, including both white matter and gray matter structures, were manually segmented in the axial, sagittal, and coronal planes. The P5, P14, and P72 atlases had 39, 45, and 29 regions segmented, respectively. These atlases have been made available to the broader research community.

Peri-adolescent ethanol vapor exposure produces reductions in hippocampal volume that are correlated with deficits in prepulse inhibition of the startle.

BACKGROUND Epidemiological studies suggest that excessive alcohol consumption is prevalent among adolescents and may have lasting neurobehavioral consequences. The use of animal models allows for the separation of the effects of adolescent ethanol (EtOH) exposure from genetic background and other environmental insults. In this study, the effects of moderate EtOH vapor exposure, during adolescence, on structural diffusion tensor imaging (DTI) and behavioral measures were evaluated in adulthood. METHODS A total of 53 Wistar rats were received at postnatal day (PD) 21 and were randomly assigned to EtOH vapor (14 hours on/10 hours off/day) or air exposure for 35 days from PD 23 to 58 (average blood ethanol concentration: 169 mg%). Animals were received in 2 groups that were subsequently sacrificed at 2 time points following withdrawal from EtOH vapor: (i) at 72 days of age, 2 weeks following withdrawal or (ii) at day 128, 10 weeks following withdrawal. In the second group, behavior in the light/dark box and prepulse inhibition (PPI) of the startle was also evaluated. Fifteen animals in each group were scanned, postmortem, for structural DTI. RESULTS There were no significant differences in body weight between EtOH and control animals. Volumetric data demonstrated that total brain, hippocampal, corpus callosum but not ventricular volume were significantly larger in the 128-day-sacrificed animals as compared to the 72 day animals. The hippocampus was smaller and the ventricles larger at 128 days as compared to 72 days, in the EtOH-exposed animals, leading to a significant group × time effect. EtOH-exposed animals sacrificed at 128 days also had diminished PPI, and more rears in the light box were significantly correlated with hippocampal size. CONCLUSIONS These studies demonstrate that DTI volumetric measures of hippocampus are significantly impacted by age and peri-adolescent EtOH exposure and withdrawal in Wistar rats.

Finite volume flow simulations on arbitrary domains

We present a novel method for solving the incompressible Navier-Stokes equations that more accurately handles arbitrary boundary conditions and sharp geometric features in the fluid domain. It uses a space filling tetrahedral mesh, which can be created using many well-known methods, to represent the fluid domain. Examples of the methods strengths are illustrated by free surface fluid simulations and smoke simulations of flows around objects with complex geometry.

Corpus callosum subdivision based on a probabilistic model of inter-hemispheric connectivity

Statistical shape analysis has become of increasing interest to the neuroimaging community due to its potential to locate morphological changes. In this paper, we present the a novel combination of shape analysis and Diffusion Tensor Image (DTI) Tractography to the computation of a probabilistic, model based corpus callosum (CC) subdivision. The probabilistic subdivision is based on the distances of arc-length parameterized corpus callosum contour points to trans-callosal DTI fibers associated with an automatic lobe subdivision. Our proposed subdivision method is automatic and reproducible, Its results are more stable than the Witelson subdivision scheme or other commonly applied schemes based on the CC bounding box. We present the application of our subdivision method to a small scale study of regional CC area growth in healthy subjects from age 2 to 4 years.