Publications by authors named "Nathan N Ng"

7 Publications

  • Page 1 of 1

Brain Iron Assessment after Ferumoxytol-enhanced MRI in Children and Young Adults with Arteriovenous Malformations: A Case-Control Study.

Radiology 2020 Nov 15;297(2):438-446. Epub 2020 Sep 15.

From the Department of Radiology, Division of Neuroimaging and Neurointervention (M.I.), Department of Pathology (J.L.), Department of Radiology, Lucas Center (S.J.H., M.E.M., J.R.), and Department of Neurosurgery, Division of Pediatric Neurosurgery (G.A.G.), Stanford University, Stanford, Calif; Department of Radiology, Pediatric MRI and CT, Division of Pediatric Radiology, Lucile Packard Children's Hospital, Stanford University, 725 Welch Rd, Room G516, Palo Alto, CA 94304 (M.I., N.N.N., S.N., Y.Z., K.W.Y.); and Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT (S.H.C.). From the 2018 RSNA Annual Meeting.

Background Iron oxide nanoparticles are an alternative contrast agent for MRI. Gadolinium deposition has raised safety concerns, but it is unknown whether ferumoxytol administration also deposits in the brain. Purpose To investigate whether there are signal intensity changes in the brain at multiecho gradient imaging following ferumoxytol exposure in children and young adults. Materials and Methods This retrospective case-control study included children and young adults, matched for age and sex, with brain arteriovenous malformations who received at least one dose of ferumoxytol from January 2014 to January 2018. In participants who underwent at least two brain MRI examinations (subgroup), the first and last available examinations were analyzed. Regions of interests were placed around deep gray structures on quantitative susceptibility mapping and R2* images. Mean susceptibility and R2* values of regions of interests were recorded. Measurements were assessed by linear regression analyses: a between-group comparison of ferumoxytol-exposed and unexposed participants and a within-group (subgroup) comparison before and after exposure. Results Seventeen participants (mean age ± standard deviation, 13 years ± 5; nine male) were in the ferumoxytol-exposed (case) group, 21 (mean age, 14 years ± 5; 11 male) were in the control group, and nine (mean age, 12 years ± 6; four male) were in the subgroup. The mean number of ferumoxytol administrations was 2 ± 1 (range, one to four). Mean susceptibility (in parts per million [ppm]) and R2* (in inverse seconds [sec]) values of the dentate (case participants: 0.06 ppm ± 0.04 and 23.87 sec ± 4.13; control participants: 0.02 ppm ± 0.03 and 21.7 sec ± 5.26), substantia nigrae (case participants: 0.08 ppm ± 0.06 and 27.46 sec ± 5.58; control participants: 0.04 ppm ± 0.05 and 24.96 sec ± 5.3), globus pallidi (case participants: 0.14 ppm ± 0.05 and 30.75 sec ± 5.14; control participants: 0.08 ppm ± 0.07 and 28.82 sec ± 6.62), putamina (case participants: 0.03 ppm ± 0.02 and 20.63 sec ± 2.44; control participants: 0.02 ppm ± 0.02 and 19.65 sec ± 3.6), caudate (case participants: -0.1 ppm ± 0.04 and 18.21 sec ± 3.1; control participants: -0.06 ppm ± 0.05 and 18.83 sec ± 3.32), and thalami (case participants: 0 ppm ± 0.03 and 16.49 sec ± 3.6; control participants: 0.02 ppm ± 0.02 and 18.38 sec ± 2.09) did not differ between groups (susceptibility, = .21; R2*, = .24). For the subgroup, the mean interval between the first and last ferumoxytol administration was 14 months ± 8 (range, 1-25 months). Mean susceptibility and R2* values of the dentate (first MRI: 0.06 ppm ± 0.05 and 25.78 sec ± 5.9; last MRI: 0.06 ppm ± 0.02 and 25.55 sec ± 4.71), substantia nigrae (first MRI: 0.06 ppm ± 0.06 and 28.26 sec ± 9.56; last MRI: 0.07 ppm ± 0.06 and 25.65 sec ± 6.37), globus pallidi (first MRI: 0.13 ppm ± 0.07 and 27.53 sec ± 8.88; last MRI: 0.14 ppm ± 0.06 and 29.78 sec ± 6.54), putamina (first MRI: 0.03 ppm ± 0.03 and 19.78 sec ± 3.51; last MRI: 0.03 ppm ± 0.02 and 19.73 sec ± 3.01), caudate (first MRI: -0.09 ppm ± 0.05 and 21.38 sec ± 4.72; last MRI: -0.1 ppm ± 0.05 and 18.75 sec ± 2.68), and thalami (first MRI: 0.01 ppm ± 0.02 and 17.65 sec ± 5.16; last MRI: 0 ppm ± 0.02 and 15.32 sec ± 2.49) did not differ between the first and last MRI examinations (susceptibility, = .95; R2*, = .54). Conclusion No overall significant differences were found in susceptibility and R2* values of deep gray structures to suggest retained iron in the brain between ferumoxytol-exposed and unexposed children and young adults with arteriovenous malformations and in those exposed to ferumoxytol over time. © RSNA, 2020.
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http://dx.doi.org/10.1148/radiol.2020200378DOI Listing
November 2020

Cerebral volume and diffusion MRI changes in children with sensorineural hearing loss.

Neuroimage Clin 2020 25;27:102328. Epub 2020 Jun 25.

Department of Radiology, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA. Electronic address:

Purpose: Sensorineural hearing loss (SNHL) is the most prevalent congenital sensory deficit in children. Information regarding underlying brain microstructure could offer insight into neural development in deaf children and potentially guide therapies that optimize language development. We sought to quantitatively evaluate MRI-based cerebral volume and gray matter microstructure children with SNHL.

Methods & Materials: We conducted a retrospective study of children with SNHL who obtained brain MRI at 3 T. The study cohort comprised 63 children with congenital SNHL without known focal brain lesion or structural abnormality (33 males; mean age 5.3 years; age range 1 to 11.8 years) and 64 age-matched controls without neurological, developmental, or MRI-based brain macrostructure abnormality. An atlas-based analysis was used to extract quantitative volume and median diffusivity (ADC) in the following brain regions: cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. SNHL patients were further stratified by severity scores and hearing loss etiology.

Results: Children with SNHL showed higher median ADC of the cortex (p = .019), thalamus (p < .001), caudate (p = .005), and brainstem (p = .003) and smaller brainstem volumes (p = .007) compared to controls. Patients with profound bilateral SNHL did not show any significant differences compared to patients with milder bilateral SNHL, but both cohorts independently had smaller brainstem volumes compared to controls. Children with unilateral SNHL showed greater amygdala volumes compared to controls (p = .021), but no differences were found comparing unilateral SNHL to bilateral SNHL. Based on etiology for SNHL, patients with Pendrin mutations showed higher ADC values in the brainstem (p = .029, respectively); patients with Connexin 26 showed higher ADC values in both the thalamus (p < .001) and brainstem (p < .001) compared to controls.

Conclusion: SNHL patients showed significant differences in diffusion and volume in brain subregions, with region-specific findings for patients with Connexin 26 and Pendrin mutations. Future longitudinal studies could examine macro- and microstructure changes in children with SNHL over development and potential predictive role for MRI after interventions including cochlear implant outcome.
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http://dx.doi.org/10.1016/j.nicl.2020.102328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334366PMC
June 2020

Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging.

JAMA Netw Open 2020 05 1;3(5):e204063. Epub 2020 May 1.

Department of Radiology, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, California.

Importance: Epidemiological studies indicate a link between obsessive-compulsive disorder and infections, particularly streptococcal pharyngitis. Pediatric acute-onset neuropsychiatric syndrome (PANS) manifests suddenly with obsessions, compulsions, and other behavioral disturbances, often after an infectious trigger. The current working model suggests a unifying inflammatory process involving the central nervous system, particularly the basal ganglia.

Objective: To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS.

Design, Setting, And Participants: Case-control study performed at a single-center, multidisciplinary clinic in the United States focusing on the evaluation and treatment of children with PANS. Sixty consecutive patients who underwent 3 Tesla (T) magnetic resonance imaging (MRI) before immunomodulation from September 3, 2012, to March 30, 2018, were retrospectively reviewed for study inclusion. Six patients were excluded by blinded investigators because of imaging or motion artifacts, 3 patients for major pathologies, and 17 patients for suboptimal atlas image registration. In total, 34 patients with PANS before initiation of treatment were compared with 64 pediatric control participants.

Main Outcomes And Measures: Using atlas-based MRI analysis, regional brain volume, diffusion, and cerebral blood flow were measured in the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem. An age and sex-controlled multivariable analysis of covariance was used to compare patients with control participants.

Results: This study compared 34 patients with PANS (median age, 154 months; age range, 55-251 months; 17 girls and 17 boys) and 64 pediatric control participants (median age, 139 months; age range, 48-213 months); 41 girls and 23 boys). Multivariable analysis demonstrated a statistically significant difference in MRI parameters between patients with PANS and control participants (F21,74 = 6.91; P < .001; partial η2 = 0.662). All assessed brain regions had statistically significantly increased median diffusivity compared with 64 control participants. Specifically, the deep gray matter (eg, the thalamus, basal ganglia, and amygdala) demonstrated the most profound increases in diffusivity consistent with the cardinal clinical symptoms of obsessions, compulsions, emotional dysregulation, and sleep disturbances. No statistically significant differences were found regarding volume and cerebral blood flow.

Conclusions And Relevance: This study identifies cerebral microstructural differences in children with PANS in multiple brain structures, including the deep gray matter structures (eg, the thalamus, basal ganglia, and amygdala). Further study of MRI is warranted in prospective, clinical trials as a potential quantitative method for assessing patients under evaluation for PANS.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.4063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199120PMC
May 2020

Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation.

Neurobiol Dis 2020 02 28;134:104627. Epub 2019 Nov 28.

Department of Developmental and Cell Biology, University of California, Irvine, CA, United States of America. Electronic address:

Over 1250 mutations in SCN1A, the Nav1.1 voltage-gated sodium channel gene, are associated with seizure disorders including GEFS+. To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270T SCN1A mutation. The second pair is a GEFS+ patient line with the K1270T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270T mutation causes cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Comparisons within and between dual pairs of isogenic iPSC-derived neuronal cultures provide a novel platform for evaluating cellular mechanisms underlying a disease phenotype and for developing patient-specific anti-seizure therapies.
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http://dx.doi.org/10.1016/j.nbd.2019.104627DOI Listing
February 2020

Reproducible and efficient generation of functionally active neurons from human hiPSCs for preclinical disease modeling.

Stem Cell Res 2018 01 9;26:84-94. Epub 2017 Dec 9.

Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States. Electronic address:

The use of human induced pluripotent stem cell (hiPSC)-derived neuronal cultures to study the mechanisms of neurological disorders is often limited by low efficiency and high variability in differentiation of functional neurons. Here we compare the functional properties of neurons in cultures prepared with two hiPSC differentiation protocols, both plated on astroglial feeder layers. Using a protocol with an expandable intermediate stage, only a small percentage of cells with neuronal morphology were excitable by 21-23days in culture. In contrast, a direct differentiation strategy of the same hiPSC line produced cultures in which the majority of neurons fired action potentials as early as 4-5days. By 35-38days over 80% of the neurons fired repetitively and many fired spontaneously. Spontaneous post-synaptic currents were observed in ~40% of the neurons at 4-5days and in ~80% by 21-23days. The majority (75%) received both glutamatergic and GABAergic spontaneous postsynaptic currents. The rate and degree of maturation of excitability and synaptic activity was similar between multiple independent platings from a single hiPSC line, and between two different control hiPSC lines. Cultures of rapidly functional neurons will facilitate identification of cellular mechanisms underlying genetically defined neurological disorders and development of novel therapeutics.
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http://dx.doi.org/10.1016/j.scr.2017.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899925PMC
January 2018

Research Associates Program: Expanding clinical research productivity with undergraduate students.

SAGE Open Med 2017 11;5:2050312117730245. Epub 2017 Sep 11.

Department of Emergency Medicine, School of Medicine, University of California, Irvine, Orange, CA, USA.

Objectives: Clinical research is often time-consuming and difficult to conduct in busy academic institutions. Previous studies have proposed methods to integrate undergraduate students as a means to increase research productivity. The authors aimed to describe the possibility to enhance emergency department research productivity at an academic emergency department in the United States, using undergraduate students in an Emergency Medicine Research Associates Program.

Methods: The authors described the Emergency Medicine Research Associates Program curriculum and its implementation. We also conducted a retrospective study at a university-based emergency department from January 2005 to December 2014 to demonstrate the benefit of having an established Emergency Medicine Research Associates Program. The primary outcomes were number of Emergency Medicine Research Associates Program-related studies, number of enrolled patients, extramural/intramural funding, abstract presentations, and peer-reviewed publications. The authors analyzed the data using descriptive statistics.

Results: Over the 10-year period, 110 Emergency Medicine Research Associates Program-assisted research studies were conducted, with research associates enrolling 46,219 patients. These studies yielded a total of 31 peer-reviewed publications and 77 abstract presentations (13 international, 27 national, 37 state/regional). The Emergency Medicine Research Associates Program-related studies were used as pilot studies to obtain US$1,751,036 in extramural grant funding and US$31,047 in intramural grant funding.

Conclusion: The implementation of Emergency Medicine Research Associates Program can enhance emergency department clinical research productivity, and the inclusion of supplemental academic programs enhanced the undergraduate students' research experience.
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http://dx.doi.org/10.1177/2050312117730245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598797PMC
September 2017

Astrocyte-enriched feeder layers from cryopreserved cells support differentiation of spontaneously active networks of human iPSC-derived neurons.

J Neurosci Methods 2018 01 23;294:91-101. Epub 2017 Jul 23.

Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, United States. Electronic address:

Background: Human induced pluripotent stem cell (hiPSC)-derived neuronal cultures are a useful tool for studying the mechanisms of neurological disorders and developing novel therapeutics. While plating hiPSC-derived neuronal progenitors onto glial feeder layers prepared from rodent cortex has been reported to promote functional differentiation of neuronal networks, this has not been examined in detail.

New Method: Here we describe a method of using cryopreserved cells from primary cultures for generation of mouse astrocyte-enriched, neuron-free feeder layers that grow from 10% to 100% confluence in 1 week.

Results: Electrophysiological analysis demonstrated that compared to biochemical substrates alone, astrocyte-enriched feeder layers support more rapid differentiation of hiPSC-derived progenitors into excitable neurons that form spontaneously active networks in culture. There was a positive correlation between the degree of astroglial confluence at the time of progenitor plating and the average frequency of postsynaptic currents 3 weeks after plating. One disadvantage to plating on 100% confluent feeder layers was a high incidence of the astroglial layer with the overlying neurons detaching from the coverslips during transfer to the recording chamber.

Comparison With Existing Method(s): Prevailing methods using primary glial feeder layers can result in possible contamination with rodent neurons and an unpredictable rate of growth. We provide a reliable method of generating mouse astroglial feeder layers from cryopreserved primary cultures to support differentiation of hiPSC-derived neurons.

Conclusions: The ability to make astrocyte-enriched feeder layers of defined confluence from cryopreserved primary cultures will facilitate the use of human stem cell derived neuronal cultures for disease modeling.
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http://dx.doi.org/10.1016/j.jneumeth.2017.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776056PMC
January 2018