Person: Kubicki, Marek
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Kubicki
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Marek
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Kubicki, Marek
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Publication Diagnostic value of structural and diffusion imaging measures in schizophrenia(Elsevier, 2018) Lee, Jungsun; Chon, Myong-Wuk; Kim, Harin; Rathi, Yogesh; Bouix, Sylvain; Shenton, Martha; Kubicki, MarekObjectives: Many studies have attempted to discriminate patients with schizophrenia from healthy controls by machine learning using structural or functional MRI. We included both structural and diffusion MRI (dMRI) and performed random forest (RF) and support vector machine (SVM) in this study. Methods: We evaluated the performance of classifying schizophrenia using RF method and SVM with 504 features (volume and/or fractional anisotropy and trace) from 184 brain regions. We enrolled 47 patients and 23 age- and sex-matched healthy controls and resampled our data into a balanced dataset using a Synthetic Minority Oversampling Technique method. We randomly permuted the classification of all participants as a patient or healthy control 100 times and ran the RF and SVM with leave one out cross validation for each permutation. We then compared the sensitivity and specificity of the original dataset and the permuted dataset. Results: Classification using RF with 504 features showed a significantly higher rate of performance compared to classification by chance: sensitivity (87.6% vs. 47.0%) and specificity (95.9 vs. 48.4%) performed by RF, sensitivity (89.5% vs. 48.0%) and specificity (94.5% vs. 47.1%) performed by SVM. Conclusions: Machine learning using RF and SVM with both volume and diffusion measures can discriminate patients with schizophrenia with a high degree of performance. Further replications are required.Publication Greater Extracellular Free Water in First-Episode Psychosis Predicts Better Neurocognitive Functioning(2017) Lyall, Amanda; Pasternak, Ofer; Robinson, Delbert G.; Newell, Dominick; Trampush, Joey W.; Gallego, Juan A.; Fava, Maurizio; Malhotra, Anil K.; Karlsgodt, Katherine H.; Kubicki, Marek; Szeszko, Philip R.Free Water Imaging is a novel diffusion magnetic reasonance imaging (MRI) method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, it’s clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MRI data and the Tract-Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared to healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. This is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome.Publication T201. THE STUDY OF WHITE MATTER MATURATION IN THREE POPULATIONS OF GENETIC HIGH RISK FOR SCHIZOPHRENIA INDIVIDUALS SPANNING THE DEVELOPMENTAL TIMELINE(Oxford University Press, 2018) Lyall, Amanda; Somes, Nathaniel; Zhang, Fan; Robertson, James; O’Donnell, Lauren J; Rathi, Yogesh; Pasternak, Ofer; Savadjiev, Peter; Styner, Martin; Fitzgerald, Zachary; Mesholam-Gately, Raquelle; Thermenos, Heidi; Whitfield-Gabrieli, Susan; Keshavan, Matcheri; DeLisi, Lynn; Gilmore, John; Seidman, Larry J; Kubicki, MarekAbstract Background: While the etiology of schizophrenia (SZ) is still unclear, it has been characterized as a neurodevelopmental disorder because patients exhibit deviations from normal maturational trajectories that are evident prior to the onset of psychotic symptoms. White matter (WM) has been purported to play a central role in the development of SZ, however, the timing and nature of WM changes in SZ is still poorly understood. This study uses diffusion imaging from three independent Genetic High Risk (GHR) populations spanning the developmental timeline from infancy to young adulthood. The aim of this study is to understand the extent and the time-course of WM maturational pathologies as a function of age and genetic risk for psychosis. Methods: Two datasets of 3T diffusion-weighted images of children aged 7 to 12 (24 HC and 16 at GHR) and young adults aged 19 to 29 (26 HC and 43 GHR) were collected at the Massachusetts Institute of Technology. The third dataset of 3T images of infants aged 2 years (35 HC and 18 GHR) was collected at the University of North Carolina – Chapel Hill. Whole brain two-tensor tractography was performed and 4 bilateral WM tracts (arcuate fasciculus (AF); inferior longitudinal fasciculus (ILF); cingulum bundle (CB); superior longitudinal fasciculus-ii (SLF-ii)), were extracted utilizing an atlas-guided fiber clustering algorithm. The fractional anisotropy of the tissue (FA-t) was obtained. We carried out group comparisons of FA-t between GHR and HCs utilizing Mann-Whitney-U tests and Cohen’s d effect sizes for each WM tract. Results: Preliminary analyses reveal significant reductions in FAt between GHR and HC in the right CB (p = 0.013) in the child GHR population. This is mirrored by medium to large effect sizes in the bilateral CB in GHR children (CB-left, d = 0.51; CB-right, d = 0.79). Reductions in FAt in the adult GHR population within the right CB was the largest effect observed in the adult analysis (CB-right, d = 0.46). Effect sizes in the bilateral CB were minimal in the infant GHR population (CB-left, d = 0.14, CB-right, d = 0.11). Significant decreases were also seen in the right SLF-ii in the adult GHR population (p = 0.012), but not in the infant or child GHR populations, though the reductions in FAt in the child GHR population exhibited a small effect (d = 0.35). All other white matter tracts in the adult analysis showed minor effects ranging from d = 0.033 (ILF-right) to 0.28 (ILF-left). The children and infant population also exhibited small effect sizes for all other tracts, with the child GHR dataset ranging from 0.036 (ILF-left) to 0.41 (ILF-right) and the infant GHR dataset ranging from d = 0.038 (SLF-left) to 0.34 (ILF-left). Discussion Our preliminary results suggest that abnormal WM maturation may occur in the right CB and right SLF-ii in individuals with increased genetic risk for SZ, specifically after early childhood (7 to 12 years) and into adulthood (19 to 29 years). The CB and SLF-ii are highly implicated in working memory performance, an ability that retrospective studies have shown begins to decline during the peripubertal period in those that develop SZ (~7 to 9 years). The lack of structural findings in GHR infants, may suggest that WM alterations are more likely to arise later in development, thereby possibly identifying childhood as a vulnerable period. Taken together, the preliminary results of this study provide possible evidence of subtle divergences from a healthy WM maturational trajectory in the right CB and right SLF-ii in early to late childhood that may persist into adulthood and these deviations may contribute to cognitive phenotypes described in other studies.Publication Schizophrenia as a Disorder of Communication(Hindawi Publishing Corporation, 2013) Niznikiewicz, Margaret; Kubicki, Marek; Mulert, Christoph; Condray, RuthPublication COMT Val158Met, but not BDNF Val66Met, is associated with white matter abnormalities of the temporal lobe in patients with first-episode, treatment-naïve major depressive disorder: a diffusion tensor imaging study(Dove Medical Press, 2014) Hayashi, Kenji; Yoshimura, Reiji; Kakeda, Shingo; Kishi, Taro; Abe, Osamu; Umene-Nakano, Wakako; Katsuki, Asuka; Hori, Hikaru; Ikenouchi-Sugita, Atsuko; Watanabe, Keita; Ide, Satoru; Ueda, Issei; Moriya, Junji; Iwata, Nakao; Korogi, Yukunori; Kubicki, Marek; Nakamura, JunWe investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. These results suggest an association between the COMT gene Val158Met and the white matter abnormalities found in the temporal lobe of patients with MDD.Publication Localized abnormalities in the cingulum bundle in patients with schizophrenia: A Diffusion Tensor tractography study(Elsevier, 2014) Whitford, T; Lee, Sun Woo; Oh, Jungsu S.; de Luis-Garcia, Rodrigo; Savadjiev, Peter; Alvarado, Jorge L.; Westin, Carl-Fredrik; Niznikiewicz, Margaret; Nestor, Paul; McCarley, Robert William; Kubicki, Marek; Shenton, MarthaThe cingulum bundle (CB) connects gray matter structures of the limbic system and as such has been implicated in the etiology of schizophrenia. There is growing evidence to suggest that the CB is actually comprised of a conglomeration of discrete sub-connections. The present study aimed to use Diffusion Tensor tractography to subdivide the CB into its constituent sub-connections, and to investigate the structural integrity of these sub-connections in patients with schizophrenia and matched healthy controls. Diffusion Tensor Imaging scans were acquired from 24 patients diagnosed with chronic schizophrenia and 26 matched healthy controls. Deterministic tractography was used in conjunction with FreeSurfer-based regions-of-interest to subdivide the CB into 5 sub-connections (I1 to I5). The patients with schizophrenia exhibited subnormal levels of FA in two cingulum sub-connections, specifically the fibers connecting the rostral and caudal anterior cingulate gyrus (I1) and the fibers connecting the isthmus of the cingulate with the parahippocampal cortex (I4). Furthermore, while FA in the I1 sub-connection was correlated with the severity of patients' positive symptoms (specifically hallucinations and delusions), FA in the I4 sub-connection was correlated with the severity of patients' negative symptoms (specifically affective flattening and anhedonia/asociality). These results support the notion that the CB is a conglomeration of structurally interconnected yet functionally distinct sub-connections, of which only a subset are abnormal in patients with schizophrenia. Furthermore, while acknowledging the fact that the present study only investigated the CB, these results suggest that the positive and negative symptoms of schizophrenia may have distinct neurobiological underpinnings.Publication Medial Frontal White and Gray Matter Contributions to General Intelligence(Public Library of Science, 2014) Ohtani, Toshiyuki; Nestor, Paul; Bouix, Sylvain; Saito, Yukiko; Hosokawa, Taiga; Kubicki, MarekThe medial orbitofrontal cortex (mOFC) and rostral anterior cingulate cortex (rACC) are part of a wider neural network that plays an important role in general intelligence and executive function. We used structural brain imaging to quantify magnetic resonance gray matter volume and diffusion tensor white matter integrity of the mOFC-rACC network in 26 healthy participants who also completed neuropsychological tests of intellectual abilities and executive function. Stochastic tractography, the most effective Diffusion Tensor Imaging method for examining white matter connections between adjacent gray matter regions, was employed to assess the integrity of mOFC-rACC pathways. Fractional anisotropy (FA), which reflects the integrity of white matter connections, was calculated. Results indicated that higher intelligence correlated with greater gray matter volumes for both mOFC and rACC, as well as with increased FA for left posterior mOFC-rACC connectivity. Hierarchical regression analyses revealed that DTI-derived FA of left posterior mOFC-rACC uniquely accounted for 29%–34% of the variance in IQ, in comparison to 11%–16% uniquely explained by gray matter volume of the left rACC. Together, left rACC gray matter volume and white matter connectivity between left posterior mOFC and rACC accounted for up to 50% of the variance in general intelligence. This study is to our knowledge the first to examine white matter connectivity between OFC and ACC, two gray matter regions of interests that are very close in physical proximity, and underscores the important independent contributions of variations in rACC gray matter volume and mOFC-rACC white matter connectivity to individual differences in general intelligence.Publication Method for Combining Information from White Matter Fiber Tracking and Gray Matter Parcellation(American Society of Neuroradiology, 2004) Park, Hae-Jeong; Kubicki, Marek; Westin, Carl-Fredrik; Talos, Ion-Florin; Brun, Anders; Peiper, Steve; Kikinis, Ron; Jolesz, Ference A.; McCarley, Robert William; Shenton, MarthaWe introduce a method for combining fiber tracking from diffusion-tensor (DT) imaging with cortical gray matter parcellation from structural high-spatial-resolution 3D spoiled gradient-recalled acquisition in the steady state images. We applied this method to a tumor case to determine the impact of the tumor on white matter architecture. We conclude that this new method for combining structural and DT imaging data is useful for understanding cortical connectivity and the localization of fiber tracts and their relationship with cortical anatomy and brain abnormalities.Publication Voxel-Based Morphometric Analysis of Gray Matter in First Episode Schizophrenia(Elsevier BV, 2002) Kubicki, Marek; Shenton, Martha; Salisbury, D.F.; Hirayasu, Y; Kasai, Kazue; Kikinis, Ron; Jolesz, Ferenc; McCarley, Robert WilliamVoxel-based morphometry (VBM) may afford a more rapid and extensive survey of gray matter abnormalities in schizophrenia than manually drawn region of interest (ROI) analysis, the current gold standard in structural MRI. Unfortunately, VBM has not been validated by comparison with ROI analyses, nor used in first-episode patients with schizophrenia or affective psychosis, who lack structural changes associated with chronicity. An SPM99-based implementation of VBM was used to compare a group of 16 patients with first-episode schizophrenia and a group of 18 normal controls and, as a further comparison, 16 first-episode patients with affective psychosis. All groups were matched for age and handedness. High spatial resolution structural images were normalized to the SPM99 template and then segmented, smoothed, and subjected to an ANCOVA. Schizophrenia vs control group comparisons: Voxel-by-voxel comparison of gray matter densities showed that only the left STG region was significantly different when corrected for multiple comparisons P < .05), consistent with our previously reported manual ROI results. Analysis of the extent of voxel clusters, replicated with permutation analyses, revealed group differences in bilateral anterior cingulate gyri and insula (not previously examined by us with manually drawn ROI) and unilateral parietal lobe, but not in medial temporal lobe (where our ROI analysis had shown differences). However, use of a smaller smoothing kernel and a small volume correction revealed left-sided hippocampal group differences. Affective psychosis comparisons: When the same statistical thresholding criteria were used, no significant differences between affective psychosis patients and controls were noted. Since a major interest was whether patients with affective psychosis shared some anatomical abnormalities with schizophrenia, we applied a small volume correction and searched within the regions that were significantly less dense in schizophrenia compared to control subjects. With this statistical correction, the insula showed, bilaterally, the same pattern of differences in affective disorder subjects as that in schizophrenic subjects, whereas both left STG and left hippocampus showed statistical differences between affectives and schizophrenics, indicating the abnormalities specific to first-episode schizophrenia. These findings suggest both the promise and utility of VBM in evaluating gray matter abnormalities. They further suggest the importance of comparing VBM findings with more traditional ROI analyses until the reasons for the differences between methods are determined.Publication Uncinate Fasciculus Findings in Schizophrenia: A Magnetic Resonance Diffusion Tensor Imaging Study(American Psychiatric Publishing, 2002) Kubicki, Marek; Westin, Carl-Fredrik; Maier, Stephan; Frumin, Melissa; Nestor, Paul; Salisbury, Dean F.; Kikinis, Ron; Jolesz, Ferenc; McCarley, Robert William; Shenton, MarthaObjective: Disruptions in connectivity between the frontal and temporal lobes may explain some of the symptoms observed in schizophrenia. Conventional magnetic resonance imaging (MRI) studies, however, have not shown compelling evidence for white matter abnormalities, because white matter fiber tracts cannot be visualized by conventional MRI. Diffusion tensor imaging is a relatively new technique that can detect subtle white matter abnormalities in vivo by assessing the degree to which directionally organized fibers have lost their normal integrity. The first three diffusion tensor imaging studies in schizophrenia showed lower anisotropic diffusion, relative to comparison subjects, in whole-brain white matter, prefrontal and temporal white matter, and the corpus callosum, respectively. Here the authors focus on fiber tracts forming temporal-frontal connections. Method: Anisotropic diffusion was assessed in the uncinate fasciculus, the most prominent white matter tract connecting temporal and frontal brain regions, in 15 patients with chronic schizophrenia and 18 normal comparison subjects. A 1.5-T GE Echospeed system was used to acquire 4-mm-thick coronal line-scan diffusion tensor images. Maps of the fractional anisotropy were generated to quantify the water diffusion within the uncinate fasciculus. Results: Findings revealed a group-by-side interaction for fractional anisotropy and for uncinate fasciculus area, derived from automatic segmentation. The patients with schizophrenia showed a lack of normal left-greater-than-right asymmetry seen in the comparison subjects. Conclusions: These findings demonstrate the importance of investigating white matter tracts in vivo in schizophrenia and support the hypothesis of a disruption in the normal pattern of connectivity between temporal and frontal brain regions in schizophrenia.