Person: Goldstein, Jill
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Goldstein
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Jill
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Goldstein, Jill
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Publication Fetal hormonal programming of sex differences in depression: linking women's mental health with sex differences in the brain across the lifespan(Frontiers Media S.A., 2014) Goldstein, Jill; Holsen, Laura; Handa, Robert; Tobet, StuartPublication Clinical high risk and first episode schizophrenia: Auditory event-related potentials(Elsevier BV, 2015) Del Re, Elisabetta; Spencer, Kevin; Oribe, Naoya; Mesholam-Gately, Raquelle; Goldstein, Jill; Shenton, Martha; Petryshen, Tracey L.; Seidman, Larry Joel; McCarley, Robert William; Niznikiewicz, MargaretThe clinical high risk (CHR) period is a phase denoting a risk for overt psychosis during which subacute symptoms often appear, and cognitive functions may deteriorate. To compare biological indices during this phase with those during first episode schizophrenia, we cross-sectionally examined sex- and age-matched clinical high risk (CHR, n=21), first episode schizophrenia patients (FESZ, n=20) and matched healthy controls (HC, n=25) on oddball and novelty paradigms and assessed the N100, P200, P3a and P3b as indices of perceptual, attentional and working memory processes. To our knowledge, this is the only such comparison using all of these event-related potentials (ERPs) in two paradigms. We hypothesized that the ERPs would differentiate between the three groups and allow prediction of a diagnostic group. The majority of ERPs were significantly affected in CHR and FESZ compared with controls, with similar effect sizes. Nonetheless, in logistic regression, only the P3a and N100 distinguished CHR and FESZ from healthy controls, suggesting that ERPs not associated with an overt task might be more sensitive to prediction of group membership.Publication Molecular Profiles of Parvalbumin-Immunoreactive Neurons in the Superior Temporal Cortex in Schizophrenia(Informa Healthcare, 2014) Pietersen, Charmaine Y.; Mauney, Sarah A.; Kim, Susie S.; Passeri, Eleonora; Lim, Maribel P.; Rooney, Robert J.; Goldstein, Jill; Petreyshen, Tracey L.; Seidman, Larry Joel; Shenton, Martha; McCarley, Robert William; Sonntag, Kai-Christian; Woo, Tsung-UngDysregulation 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 PVimmunolabeled 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.Publication Extensive white matter abnormalities in patients with first-episode schizophrenia: A diffusion tensor imaging (DTI) study(Elsevier BV, 2013) Lee, Sang-Hyuk; Kubicki, Marek; Asami, Takeshi; Seidman, Larry Joel; Goldstein, Jill; Mesholam-Gately, Raquelle; McCarley, Robert William; Shenton, MarthaBackground—Previous voxelwise Diffusion Tensor Imaging (DTI) investigations of white matter in first-episode schizophrenia (FESZ) have been limited to the analysis of Fractional Anisotropy (FA) and mean diffusivity (MD), with their findings inconsistent in terms of the anatomical locations and extent of abnormalities. This study examines white matter abnormalities in FESZ, compared with healthy controls, using a tract-based spatial statistics (TBSS) approach applied to multiple measures of tract integrity, and correlates these findings with symptom severity. Methods—Seventeen first-episode patients with schizophrenia and seventeen age- and gender matched healthy controls (HC) participated in this imaging study where FA, MD, and axial and radial diffusivity were compared between the two groups using TBSS. Results—First-episode patients with schizophrenia showed lower FA values in the genu and body of corpus callosum, the internal capsule, the external capsule, the fornix, the superior, inferior fronto-occipital fasciculus, the cingulum, and the uncinate fasciculus compared with HC. Increased MD and radial diffusivity were shown in virtually all white matter regions. There was no significant difference, however, observed for axial diffusivity between the two groups. Pearson correlation analysis showed that the FA values of the right inferior fronto-occipital fasciculus were positively correlated with positive symptoms, negative symptoms, and total correct items of the Wisconsin Card Sorting Test. FA values of right external capsule also showed significant positive correlation with category completed scores of the WCST. Conclusions—These data suggest extensive, possibly myelin related white matter disruptions in FESZ.Publication Biomarkers for Identifying First-Episode Schizophrenia Patients Using Diffusion Weighted Imaging(Springer Science + Business Media, 2010) Rathi, Yogesh; Malcolm, James; Michailovich, Oleg; Goldstein, Jill; Seidman, Larry Joel; McCarley, Robert William; Westin, Carl-Fredrik; Shenton, MarthaRecent advances in diffusion weighted MR imaging (dMRI) has made it a tool of choice for investigating white matter abnormalities of the brain and central nervous system. In this work, we design a system that detects abnormal features (biomarkers) of first-episode schizophrenia patients and then classifies them using these features. We use two different models of the dMRI data, namely, spherical harmonics and the two-tensor model. The algorithm works by first computing several diffusion measures from each model. An affine-invariant representation of each subject is then computed, thus avoiding the need for registration. This representation is used within a kernel based feature selection algorithm to determine the biomarkers that are statistically different between the two populations. Confirmation of how well these biomarkers identify each population is obtained by using several classifiers such as, k-nearest neighbors, Parzen window classifier, and support vector machines to separate 21 first-episode patients from 20 age-matched normal controls. Classification results using leave-many-out cross-validation scheme are given for each representation. This algorithm is a first step towards early detection of schizophrenia.Publication Frequency and pattern of childhood symptom onset reported by first episode schizophrenia and clinical high risk youth(Elsevier BV, 2014) Woodberry, Kristen; Serur, Rachael A.; Hallinan, Sean B.; Mesholam-Gately, Raquelle; Giuliano, Anthony J.; Wojcik, Joanne; Keshavan, Matcheri; Frazier, Jean A.; Goldstein, Jill; Shenton, Martha; McCarley, Robert William; Seidman, Larry JoelBackground—Psychosis prevention and early intervention efforts in schizophrenia have focused increasingly on sub-threshold psychotic symptoms in adolescents and young adults. Although many youth report symptom onset prior to adolescence, the childhood incidence of prodromal level symptoms in those with schizophrenia or related psychoses is largely unknown. Methods—This study reports on the retrospective recall of prodromal-level symptoms from 40 participants in a first-episode of schizophrenia (FES) and 40 participants at “clinical high risk” (CHR) for psychosis. Onset of positive and non-specific symptoms was captured using the Structured Interview for Prodromal Syndromes. Frequencies are reported according to onset during childhood (prior to age 13), adolescence (13–17), or adulthood (18 +). Results—Childhood-onset of attenuated psychotic symptoms was not rare. At least 11% of FES and 23% of CHR reported specific recall of childhood-onset of unusual or delusional ideas, suspiciousness, or perceptual abnormalities. Most recalled experiencing non-specific symptoms prior to positive symptoms. CHR and FES did not differ significantly in the timing of positive and non-specific symptom onset. Other than being younger at assessment, those with childhood onset did not differ demographically from those with later onset. Conclusion—Childhood-onset of initial psychotic-like symptoms may be more common than previous research has suggested. Improved characterization of these symptoms and a focus on their predictive value for subsequent schizophrenia and other major psychoses are needed to facilitate screening of children presenting with attenuated psychotic symptoms. Accurate detection of prodromal symptoms in children might facilitate even earlier intervention and the potential to alter pre-illness trajectories.Publication Excessive Extracellular Volume Reveals a Neurodegenerative Pattern in Schizophrenia Onset(Society for Neuroscience, 2012) Pasternak, Ofer; Westin, Carl-Fredrik; Bouix, Sylvain; Seidman, Larry Joel; Goldstein, Jill; Woo, Tsung-Ung; Petryshen, Tracey L.; Mesholam-Gately, Raquelle; McCarley, Robert William; Kikinis, Ron; Shenton, Martha; Kubicki, MarekDiffusion MRI has been successful in identifying the existence of white matter abnormalities in schizophrenia in vivo. However, the role of these abnormalities in the etiology of schizophrenia is not well understood. Accumulating evidence from imaging, histological, genetic, and immunochemical studies support the involvement of axonal degeneration and neuroinflammation—ubiquitous components of neurodegenerative disorders—as the underlying pathologies of these abnormalities. Nevertheless, the current imaging modalities cannot distinguish neuroinflammation from axonal degeneration, and therefore provide little specificity with respect to the pathophysiology progression and whether it is related to a neurodegenerative process. Free-water imaging is a new methodology that is sensitive to water molecules diffusing in the extracellular space. Excessive extracellular volume is a surrogate biomarker for neuroinflammation and can be separated out to reveal abnormalities such as axonal degeneration that affect diffusion characteristics in the tissue. We applied free-water imaging on diffusion MRI data acquired from schizophrenia-diagnosed human subjects with a first psychotic episode. We found a significant increase in the extracellular volume in both white and gray matter. In contrast, significant signs of axonal degeneration were limited to focal areas in the frontal lobe white matter. Our findings demonstrate that neuroinflammation is more prominent than axonal degeneration in the early stage of schizophrenia, revealing a pattern shared by many neurodegenerative disorders, in which prolonged inflammation leads to axonal degeneration. These findings promote anti-inflammatory treatment for early diagnosed schizophrenia patients.Publication White matter tract abnormalities between rostral middle frontal gyrus, inferior frontal gyrus and striatum in first-episode schizophrenia(Elsevier BV, 2013) Quan, Meina; Lee, Sang-Hyuk; Kubicki, Marek; Kikinis, Zora; Rathi, Yogesh; Seidman, Larry Joel; Mesholam-Gately, Raquelle; Goldstein, Jill; McCarley, Robert William; Shenton, Martha; Levitt, JamesBackground—Previous studies have shown that frontostriatal networks, especially those involving dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) mediate cognitive functions some of which are abnormal in schizophrenia. This study examines white matter integrity of the tracts connecting DLPFC/VLPFC and striatum in patients with firstepisode schizophrenia (FESZ), and their associations with cognitive and clinical correlates. Methods—Diffusion tensor and structural magnetic resonance images were acquired on a 3T GE Echospeed system from 16 FESZ and 18 demographically comparable healthy controls. FreeSurfer software was used to parcellate regions of interest. Two-tensor tractography was applied to extract fibers connecting striatum with rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC respectively. DTI indices, including fractional anisotropy (FA), trace, axial diffusivity (AD) and radial diffusivity (RD), were used for group comparisons. Additionally, correlations were evaluated between these diffusion indices and the Wisconsin Card Sorting Task (WCST) and the Brief Psychiatric Rating Scale (BPRS). Results—FA was significantly reduced in the left IFG-striatum tract, whereas trace and RD were significantly increased in rMFG-striatum and IFG-striatum tracts, bilaterally. The number of WCST categories completed correlated positively with FA of the right rMFG-striatum tract, and negatively with trace and RD of right rMFG-striatum and right IFG-striatum tracts in FESZ. The BPRS scores did not correlate with these indices. Conclusions—These data suggest that white matter tract abnormalities between rMFG/IFG and striatum are present in FESZ and appear to be significantly associated with executive dysfunction but not with symptom severity.Publication Statistical analysis of fiber bundles using multi-tensor tractography: application to first-episode schizophrenia(Elsevier BV, 2011) Rathi, Yogesh; Kubicki, Marek; Bouix, Sylvain; Westin, Carl-Fredrik; Goldstein, Jill; Seidman, Larry Joel; Mesholam-Gately, Raquelle; McCarley, Robert William; Shenton, MarthaThis work proposes a new method to detect abnormalities in fiber bundles of first-episode (FE) schizophrenia patients. Existing methods have either examined a particular region of interest (ROI) or used voxel based morphometry (VBM) or used tracts generated using the single tensor model for locating statistically different fiber bundles. Further, a two-sample t-test, which assumes a Gaussian distribution for each population, is the most widely used statistical hypothesis testing algorithm. In this study, we use the unscented Kalman filter based two-tensor tractography algorithm for tracing neural fiber bundles of the brain that connect 105 different cortical and subcortical regions. Next, fiber bundles with significant connectivity across the entire population were determined. Several diffusion measures derived from the two-tensor model were computed and used as features in the subsequent analysis. For each fiber bundle, an affine-invariant descriptor was computed, thus obviating the need for precise registration of patients to an atlas. A kernel based statistical hypothesis testing algorithm, that makes no assumption regarding the distribution of the underlying population, was then used to determine the abnormal diffusion properties of all fiber bundles for 20 FE patients and 20 age-matched healthy controls. Of the 1254 fiber bundles with significant connectivity, 740 fiber bundles were found to be significantly different in at least one diffusion measure after correcting for multiple comparisons. Thus, the changes affecting firstepisode patients seem to be global in nature (spread throughout the brain).Publication Molecular Profiles of Pyramidal Neurons in the Superior Temporal Cortex in Schizophrenia(Informa Healthcare, 2014) Pietersen, Charmaine Y.; Mauney, Sarah A.; Kim, Susie S.; Lim, Maribel P.; Rooney, Robert J.; Goldstein, Jill; Petryshen, Tracey L.; Seidman, Larry Joel; Shenton, Martha; McCarley, Robert William; Sonntag, Kai-C.; Woo, Tsung-UngDisrupted 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.