Publications by Year: 2014

Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann’s area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder.

Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30-100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann’s area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-β) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated.

PURPOSE OF REVIEW: Schizophrenia is a multifocal brain disease that involves abnormal brain connectivity. Diffusion Tensor Imaging is the most advanced imaging technique to investigate white matter connections in vivo. In this review, we focus on studies published in the last year with a high impact on our understanding of how changes in white matter may lead to better treatment. RECENT FINDINGS: Recent studies establish white matter changes at illness onset, and quite possibly before, wherein they constitute a risk factor. Some studies also suggest that white matter changes might not progress over time, even without treatment. Further, while genetic risk may be associated with neurodevelopmental changes related to either white matter geometry, or a different trajectory of aging, clinical risk may also be associated with more acute changes of tissue integrity. These latter changes may be inflammatory in nature at illness onset, and related to the cellular integrity of oligodendrocytes and/or astrocytes at later stages of illness. SUMMARY: Recent publications suggest new directions for research and lead to new hypotheses about the pathophysiology of schizophrenia involving white matter. When replicated on larger samples, this knowledge will likely lead to the development of new treatment strategies.

PURPOSE: To evaluate the ability of various software (SW) tools used for quantitative image analysis to properly account for source-specific image scaling employed by magnetic resonance imaging manufacturers. METHODS: A series of gadoteridol-doped distilled water solutions (0%, 0.5%, 1%, and 2% volume concentrations) was prepared for manual substitution into one (of three) phantom compartments to create "variable signal," whereas the other two compartments (containing mineral oil and 0.25% gadoteriol) were held unchanged. Pseudodynamic images were acquired over multiple series using four scanners such that the histogram of pixel intensities varied enough to provoke variable image scaling from series to series. Additional diffusion-weighted images were acquired of an ice-water phantom to generate scanner-specific apparent diffusion coefficient (ADC) maps. The resulting pseudodynamic images and ADC maps were analyzed by eight centers of the Quantitative Imaging Network using 16 different SW tools to measure compartment-specific region-of-interest intensity. RESULTS: Images generated by one of the scanners appeared to have additional intensity scaling that was not accounted for by the majority of tested quantitative image analysis SW tools. Incorrect image scaling leads to intensity measurement bias near 100%, compared to nonscaled images. CONCLUSION: Corrective actions for image scaling are suggested for manufacturers and quantitative imaging community.

BACKGROUND: TMS activations of white matter depend not only on the distance from the coil, but also on the orientation of the axons relative to the TMS-induced electric field, and especially on axonal bends that create strong local field gradient maxima. Therefore, tractography contains potentially useful information for TMS targeting. OBJECTIVE/METHODS: Here, we utilized 1-mm resolution diffusion and structural T1-weighted MRI to construct large-scale tractography models, and localized TMS white matter activations in motor cortex using electromagnetic forward modeling in a boundary element model (BEM). RESULTS: As expected, in sulcal walls, pyramidal cell axonal bends created preferred sites of activation that were not found in gyral crowns. The model agreed with the well-known coil orientation sensitivity of motor cortex, and also suggested unexpected activation distributions emerging from the E-field and tract configurations. We further propose a novel method for computing the optimal coil location and orientation to maximally stimulate a pre-determined axonal bundle. CONCLUSIONS: Diffusion MRI tractography with electromagnetic modeling may improve spatial specificity and efficacy of TMS.

Deformable image registration is used increasingly in image-guided interventions and other applications. However, validation and characterization of registration performance remain areas that require further study. We propose an analysis methodology for deriving tolerance limits on the initial conditions for deformable registration that reliably lead to a successful registration. This approach results in a concise summary of the probability of registration failure, while accounting for the variability in the test data. The (β, γ) tolerance limit can be interpreted as a value of the input parameter that leads to successful registration outcome in at least 100β% of cases with the 100γ% confidence. The utility of the methodology is illustrated by summarizing the performance of a deformable registration algorithm evaluated in three different experimental setups of increasing complexity. Our examples are based on clinical data collected during MRI-guided prostate biopsy registered using publicly available deformable registration tool. The results indicate that the proposed methodology can be used to generate concise graphical summaries of the experiments, as well as a probabilistic estimate of the registration outcome for a future sample. Its use may facilitate improved objective assessment, comparison and retrospective stress-testing of deformable.

Detailed analysis of spinal deformity is important within orthopaedic healthcare, in particular for assessment of idiopathic scoliosis. This paper addresses this challenge by proposing an image analysis method, capable of providing a full three-dimensional spine characterization. The proposed method is based on the registration of a highly detailed spine model to image data from computed tomography. The registration process provides an accurate segmentation of each individual vertebra and the ability to derive various measures describing the spinal deformity. The derived measures are estimated from landmarks attached to the spine model and transferred to the patient data according to the registration result. Evaluation of the method provides an average point-to-surface error of 0.9 mm ± 0.9 (comparing segmentations), and an average target registration error of 2.3 mm ± 1.7 (comparing landmarks). Comparing automatic and manual measurements of axial vertebral rotation provides a mean absolute difference of 2.5° ± 1.8, which is on a par with other computerized methods for assessing axial vertebral rotation. A significant advantage of our method, compared to other computerized methods for rotational measurements, is that it does not rely on vertebral symmetry for computing the rotational measures. The proposed method is fully automatic and computationally efficient, only requiring three to four minutes to process an entire image volume covering vertebrae L5 to T1. Given the use of landmarks, the method can be readily adapted to estimate other measures describing a spinal deformity by changing the set of employed landmarks. In addition, the method has the potential to be utilized for accurate segmentations of the vertebrae in routine computed tomography examinations, given the relatively low point-to-surface error.

The structure of the lamellar phase of aqueous pentaethylene glycol mono-n-dodecyl ether (C12E5) surfactant at various temperatures and molar fractions is studied by using united atom molecular dynamics simulations and nuclear magnetic resonance measurements. Namely, the simulation model is used to interpret the magnitude and temperature dependence of experimental C-H order parameter profiles in terms of the molecular conformation and orientation. Our simulations suggest that the low order parameters that are generally measured in poly(ethylene oxide) surfactant bilayers are due to the presence of bilayer pores throughout the entire lamellar phase region.

In this study we use high resolution Magnetic Resonance imaging (MRI) and apply rigorous manual tracing criteria in order to assess volumetrically the prefrontal cortex (PFC) in schizophrenia. Previous MRI studies suggested PFC is included in neural systems necessary for emotional processing and cognition, and regional PFC abnormalities might, thus, lead to specific negative symptoms, as well as a frequent association of poorer performance in category switching. The aim of this study was to use 3T imaging and reliable manual parcellation to determine if, as hypothesized, this higher precision would reveal additional MRI abnormalities in PFC in schizophrenia, and an association between PFC abnormalities and specific negative symptoms, as well as in category switching. Using 3-T MRI, 27 schizophrenia patients and 27 healthy controls were examined. PFC was manually parcellated into frontal pole, superior frontal gyrus (SFG), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG). Left SFG (p=0.004), bilateral MFG (left: p=0.007; right: p=0.007), and bilateral IFG (left: p

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.