Faculty Bibliography
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Department/Unit:Neuroscience Institute
Total Results:
13562
Guidelines for the use and interpretation of assays for monitoring autophagy [Guideline]
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
PMCID:3404883
PMID: 22966490
ISSN: 1554-8627
CID: 181862
Early cognitive experience prevents adult deficits in a neurodevelopmental schizophrenia model
Brain abnormalities acquired early in life may cause schizophrenia, characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments. Cognitive symptoms, like impaired cognitive control, are now recognized to be important treatment targets but cognition-promoting treatments are ineffective. We hypothesized that cognitive training during the adolescent period of neuroplastic development can tune compromised neural circuits to develop in the service of adult cognition and attenuate schizophrenia-related cognitive impairments that manifest in adulthood. We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia, that adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats. The early intervention also normalized brain function, enhancing cognition-associated synchrony of neural oscillations between the hippocampi, a measure of brain function that indexed cognitive ability. Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia.
PMCID:3437240
PMID: 22920261
ISSN: 0896-6273
CID: 182022
Uric Acid stones and hyperuricosuria
Recent work has highlighted the strong relationships among obesity, diabetes, and the metabolic syndrome as causes of low urinary pH. Low urinary pH in turn is the major urinary risk factor for uric acid stones. Unlike calcium stones, uric acid stones can be dissolved and easily prevented with adequate urinary alkalinization. Recognizing the relevant risk factors should lead to increased identification of these radiolucent stones. The cornerstone of therapy is raising urinary pH; xanthine dehydrogenase inhibitors should be used only when urinary alkalinization cannot be achieved.
PMID: 23089277
ISSN: 1548-5595
CID: 180732
The role of gray and white matter segmentation in quantitative proton MR spectroscopic imaging
Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's (1) H MR spectroscopy ((1) H-MRS) signal, reducing sensitivity to changes. While single-voxel (1) H-MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1-mm(3) resolution MRI into GM, WM and CSF masks that were co-registered with the MRSI grid to yield their partial volumes in approximately every 1 cm(3) spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i- metabolite's GM and WM concentrations C(i) (GM) , C(i) (WM) . With the voxels' GM and WM volumes as independent coefficients, the over-determined system of equations was solved for the global averaged C(i) (GM) and C(i) (WM) . Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N-acetylaspartate, creatine, choline and myo-inositol C(i) (GM) concentrations of 8.5 +/- 0.7, 6.9 +/- 0.6, 1.2 +/- 0.2, 5.3 +/- 0.6mM, respectively, and C(i) (WM) concentrations of 7.7 +/- 0.6, 4.9 +/- 0.5, 1.4 +/- 0.1 and 4.4 +/- 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5-10% (more for ratios), which can often double the sample size required to establish statistical significance
PMCID:3449040
PMID: 22714729
ISSN: 0952-3480
CID: 180362
Development of amygdala intrinsic functional connectivity in a rat model of maternal maltreatment [Meeting Abstract]
Background and Objectives: Maltreatment from the caregiver induces vulnerability to later life psychopathology. Animal models of early life stress suggest this is due to disruption of neural development of long-distance circuits linking amygdala to prefrontal cortex. Methods: We used a rat model of early life maltreatment to examine amygdala connectivity using resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by a mother provided with insufficient bedding for nest building or by one with abundant bedding from postnatal days (PND) 8 to 12. In adolescence (at PND 45) and in early adulthood (at PND 60), R-fMRI sessions were conducted under light (*1%) isofluorane anesthesia. Behavioral tests were obtained in animals reared under identical conditions to model negative affectivity, including the Forced Swim Test, Sucrose Preference Test, and Social Behavior Test. Results: Behaviors reflecting negative affectivity were seen in both adolescent and adult animals. Amygdala functional connectivity (FC) with frontal, parietal, and basal ganglia, including thalamus, increased significantly with increased age. By contrast, local amygdala FC decreased significantly with age. Additionally, we detected significant interactions between abuse condition and age. Local amygdala FC decreased between PND 45 and 60 in control rats, but increased significantly in abused rats. The reverse pattern was observed for amygdala FC with medial frontal cortex and parietal cortex. Conclusions: Translation of an in vivo longitudinal imaging approach to a rodent model of early caregiver maltreatment revealed enduring evidence of differences in brain functional connectivity in adulthood that likely underlies negative affectivity and vulnerability to internalizing psychopathology in humans
EMBASE:70892551
ISSN: 2158-0014
CID: 180100
The faster the better: Reliability of resting-state fMRI measures by multiband echo planar imaging [Meeting Abstract]
Objectives: An important recent advance in echo planar imaging is the emergence of multiband echo planar imaging (MB-EPI, Moeller et al., 2010; Xu et al., 2012), which can provide low TRs or small voxel size to optimize temporal or spatial resolution for fMRI, respectively. The reliability of resting-state fMRI (R-fMRI) analyses performed on MB-EPI data has yet to be established. Here we address the test-retest (TRT) reliability of MB-EPI using intra-class correlation (ICC) for a variety of R-fMRI metrics, including: seed-based functional connectivity (FC, Biswal et al., (Figure psented) 1995), amplitude of low frequency fluctuations (ALFF, Zang et al., 2007), fractional amplitude of low frequency fluctuations (fALFF, Zou et al., 2008) and regional homogeneity (ReHo, Zang et al., 2004). Materials and Methods: We conducted an analysis of R-fMRI data from NKI-RS Multiband Imaging Test-Retest Pilot Dataset (http://fcon-1000.projects.nitrc.org) which consists of 2 scanning sessions separated by one week. The dataset includes: 1) MB-EPI/ TR = 645 (3mm isotropic voxels, 10-min scan), 2) MB-EPI/ TR = 1400 (2 mm, 10-min), and 3) a standard EPI sequence/ TR = 2500 (3 mm, 5-min) for each session. R-fMRI data were preprocessed and derivative maps were generated for full-length data (see Fig. 1 for details). To match scan length of the sequences, first 5-min data were also extract from preprocessed MB data for the ICC analysis. Results: All R-fMRI sequences demonstrated moderate to high TRT reliability across the brain for all measures from both fulllength, and 5-min data (Fig. 2 & 3); ICC values were most impressive for the MB-EPI/TR = 645 ms sequence, especially for seed-based FC and fALFF measures - attesting to the increased utility and reliability of this state-of-the-art sequence with unparalleled sampling rates for full brain acquisition. Conclusion: In summary, the pilot TRT reliability dataset suggests improved TRT reliability for the MB-EPI/TR = 645 ms sequence. The MB-EPI/TR = 1400 ms sequence offers improved spatial resolution with little or no cost of TRT reliability. Further testing will perform on voxel-mirrored homotopic connectivity, degree centrality, ICA as well as FC for other seed regions
EMBASE:70892715
ISSN: 2158-0014
CID: 180119
The motion crisis in functional connectomics: Damage assessment and control for resting-state fMRI [Meeting Abstract]
Introduction: Recent work has demonstrated head motion contributes to artifactual differences in resting-state fMRI (R-fMRI) measures (Power et al., 2012a;Satterthwaite et al., 2012;Van Dijk et al., 2012). Here we explored how a broad array of R-fMRIbased intrinsic brain function measures are affected by head motion, and how such sensitivities and their test-retest (TRT) reliabilities are impacted by various motion correction strategies. Methods: After preprocessing publicly released developmental, young adult and TRT datasets, the following strategies were applied to correct head motion effects: regressing out 6 head motion parameters (Traditional 6), regressing out autoregressive models (Friston et al., 1996) (Friston 24), regressing out voxelspecific head motion regressors (Voxel-Specific 12), and data scrubbing at framewise displacement (FD) > 0.2 or 0.5mm. We then explored head motion effects and TRT reliability on amplitude of low frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity, voxel-mirrored homotopic connectivity, and functional connectivity of medial prefrontal cortex. Results: As previously suggested, head motion effects are stronger in developmental than adult data (Fig. 1 vs. Fig. 2). Among the measures, fALFF is least affected by head motion. Among head motion correction strategies, scrubbing at FD > 0.2 mm (Power et al., 2012b) cleared the most motion effect while creating artificial head motion effect in fALFF due to destruction of temporal structure. Scrubbing at FD > 0.2mm also diminished TRT reliability dramatically (Fig. 3); some subjects varied markedly in the number of time points excluded across sessions (e.g., (Figure Presented) 150 vs. 37). Importantly, head motion effects remained after all correction strategies (Figs. 1, 2) suggesting taking subject head motion into account at the group level is still necessary. Regressing out mean FD slightly decreased TRT reliability but preserved its structure (Fig. 4). Conclusion: Results suggest that head motion effects extend to all metrics when studying hyperkinetic populations. We suggest caution when using stringent scrubbing (e.g. FD > 0.2mm as recommend by Power et al. 2012b), as test-retest reliability can be compromised and frequency metrics made immeasurable. Correction for inter-individual differences in motion at the grouplevel appears to be necessary regardless of individual subject correction strategy
EMBASE:70892571
ISSN: 2158-0014
CID: 180122
Toward individually-based biomarkers of verbal proficiency in Autism [Meeting Abstract]
Question: Verbal proficiency in 6 year-olds with Autistic Disorder (AD) is a prognostic factor of long-term functioning. As a first step toward identifying biomarkers as early as the first identification of AD, we characterize the neuronal underpinnings of verbal proficiency in children with AD. By means of resting-state fMRI (R-fMRI), we first examined intrinsic functional connectivity (iFC) of language-based circuits in a sample of school-age children. Then, to explore the stability of the identified marker(s), we examined its relationship with verbal proficiency in an independent group of preschoolers with AD. Methods: Two samples of children with AD included: 34 schoolage kids (age 11 +/- 2yrs) completing an awake R-fMRI scan; and 20 preschoolers (age 60 +/- 10months) completing a R-fMRI scan during natural sleep. To examine iFC of language circuits we focused on the left inferior frontal gyrus (IFG): the pars triangularis (pt), pars opercularis and ventral premotor cortex. We indexed verbal proficiency with the Vineland Expressive Language (VEL) standard scores of expressive language skills. In the 34 school-age children with AD, we examined the relationship between VEL scores and inter-individual differences in iFC patterns associated with each of the IFG seeds, at the voxel-wise, wholebrain level (Z > 2.3, p < 0.05, Gaussian random field theory corrected). Then, we examined the relationship between iFC of circuit( s) identified in the first step with the individual VEL score in the preschoolers with AD. We plan to apply one-class support vector machine to examine whether pattern of iFC can classify verbal proficient children with AD from those with poor verbal proficiency. Results: Voxel-wise analyses showed a significant positive relationship between VEL scores and the iFC between left IFGpt and a cluster in the posterior aspects of the right superior temporal sulcus (STS) in the school-age kids.Guided by this finding, we correlated the iFC within this circuit with VEL scores of 20 preschoolers with AD.The iFC of this circuit explained 16% of the variance in verbal proficiency (r = 0.40). Conclusions: R-fMRI during natural sleep provides a feasible means for identifying loci of disconnection in autism that may serve to identify prognostic markers of verbal proficiency at the individual level at the time of first diagnosis
EMBASE:70892635
ISSN: 2158-0014
CID: 180121
Diffusion-Weighted Intravoxel Incoherent Motion Imaging of Renal Tumors With Histopathologic Correlation
PURPOSE: The aim of this study was to use intravoxel incoherent motion diffusion-weighted imaging to discriminate subtypes of renal neoplasms and to assess agreement between intravoxel incoherent motion (perfusion fraction, fp) and dynamic contrast-enhanced magnetic resonance imaging (MRI) metrics of tumor vascularity. SUBJECTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved prospective study, 26 patients were imaged at 1.5-T MRI using dynamic contrast-enhanced MRI with high temporal resolution and diffusion-weighted imaging using 8 b values (range, 0-800 s/mm). Perfusion fraction (fp), tissue diffusivity (Dt), and pseudodiffusivity (Dp) were calculated using biexponential fitting of the diffusion data. Apparent diffusion coefficient (ADC) was calculated with monoexponential fit using 3 b values of 0, 400, and 800 s/mm. Dynamic contrast-enhanced data were processed with a semiquantitative method to generate model-free parameter cumulative initial area under the curve of gadolinium concentration at 60 seconds (CIAUC60). Perfusion fraction, Dt, Dp, ADC, and CIAUC60 were compared between different subtypes of renal lesions. Perfusion fraction was correlated with CIAUC60. RESULTS: We examined 14 clear cell, 4 papillary, 5 chromophobe, and 3 cystic renal cell carcinomas (RCCs). Although fp had higher accuracy (area under the curve, 0.74) for a diagnosis of clear cell RCC compared with Dt or ADC, the combination of fp and Dt had the highest accuracy (area under the curve, 0.78). The combination of fp and Dt diagnosed papillary RCC and cystic RCC with 100% accuracy, and clear cell RCC and chromophobe RCC, with 86.5% accuracy. There was significant strong correlation between fp and CIAUC60 (r = 0.82; P < 0.001). CONCLUSION: Intravoxel incoherent motion parameters fp and Dt can discriminate renal tumor subtypes. Perfusion fraction demonstrates good correlation with CIAUC60 and can assess degree of tumor vascularity without the use of exogenous contrast agent.
PMID: 22996315
ISSN: 0020-9996
CID: 179984
Bilateral tubulocystic renal cell carcinomas associated with acquired end-stage renal disease: The first case report with cytogenetic and ultrastructural studies [Meeting Abstract]
Tubulocystic renal cell carcinoma (TC-RCC) is a rare, typically unilateral renal tumor. We report the first case of bilateral multifocal TC-RCC associated with end-stage renal disease with cytogenetic, immunohistochemical, and ultrastructural studies. A 62-year-old man with type 2 diabetes, hypertension, and end-stage renal disease on hemodialysis had bilateral complex renal masses smaller than 3.0 cm in greatest dimension found incidentally. Follow-up imaging studies demonstrated slowly enlarging masses. The patient underwent bilateral laparoscopic radical nephrectomy. Grossly, both kidneys had multifocal, unencapsulated, sharply demarcated, gray, spongy cystic lesions (0.3-2.5 cm) in cortex and medulla. The lesions contained clear serous fluid. Microscopically, the background kidneys showed end-stage changes with glomerulosclerosis and atrophic tubules. The well-delineated cystic lesions are composed of tightly packed tubules and cysts, separated by bland fibrous stroma. The lining cells are single-layer, flattened, cuboidal to columnar, with abundant eosinophilic cytoplasm, large round to oval nuclei, and prominent nucleoli. Hobnail cells are common. No desmoplastic reaction or cellular ovarian-like stroma is present. No solid growth or papilla is seen in either kidney. Immunohistochemically, the tumor cells showed diffuse and strong positivity for AMACR, AE1/AE3, CK8/18, CD10, and PAX2; focally strong positivity for CK7, EMA, vimentin, and 34BE12; and negativity for p63 and CK20. TC-RCC was diagnosed. Fuhrman nuclear grade was 2 to 3. Pathologic stage was pT1 on both kidneys. Fluorescence in situ hybridization shows gain of chromosome 7 and chromosome 17. Transmission electronic microscopy showed 2 types of epithelial cells: type I cells reminiscent of proximal tubular cells and lining the tubules and type II cells reminiscent of distal tubular cells lining the cysts. The patient was disease-free 3 years after radiologic detection and 12 months after bilateral nephrectomy. Our studies suggest TC-RCC is closely related to papillary RCC. This tumor appears to be low-grade with no metastasis
EMBASE:70889935
ISSN: 0002-9173
CID: 179310
