Publications by authors named "Cheddhi Thomas"

14 Publications

  • Page 1 of 1

Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma.

J Neuropathol Exp Neurol 2020 08;79(8):880-890

Department of Neuropathology, New York University Langone Health, New York, New York.

Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7-32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.
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http://dx.doi.org/10.1093/jnen/nlaa051DOI Listing
August 2020

Single Solitary Fibrous Tumor Brain Metastasis in a Patient with Simultaneous Adenocarcinoma of the Lung: Case Report and Review of the Literature.

Case Rep Med 2020 7;2020:3938270. Epub 2020 Apr 7.

Department of Radiation Oncology, Cancer Care Northwest and Gamma Knife of Spokane, Spokane, WA, USA.

We present a unique case of a patient simultaneously diagnosed with solitary fibrous tumor (SFT) and unrelated adenocarcinoma of the lung, both proven with separate pathology. It was subsequently found that the SFT had metastasized to the brain by additional pathology, and not the predicted adenocarcinoma. SFTs are a rare mesenchymal neoplasm that accounts for less than 2% of all reported soft tissue tumors. SFTs most commonly arise in the thoracic cavity, but are frequently found in various locations throughout the body, and rarely metastasize to the brain. This case highlights that rare neoplasms, such as SFT, should not be ruled out as a potential cause of metastasis. Due to the rarity of this clinical situation, we also provide a review and discussion of previously reported SFT cases and the use of postoperative radiation therapy. The optimal treatment for individual patients remains unclear in this unique situation. Surgical resection followed by adjuvant Gamma Knife radiation therapy to the surgical bed appears to be a safe option for local treatment of SFT in select patients. Further studies are needed of this rare clinical situation in order to better understand and optimize future treatments for patients with SFT and metastasis to the brain.
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http://dx.doi.org/10.1155/2020/3938270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166291PMC
April 2020

Polysomy is associated with poor outcome in 1p/19q codeleted oligodendroglial tumors.

Neuro Oncol 2019 09;21(9):1164-1174

Department of Pathology, NYU Langone Health, New York, New York.

Background: Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p/19q status.

Methods: We analyzed 412 histologic oligodendroglial tumors with use of 1p/19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p/19q was performed. Polysomy was defined as more than two 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p/19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS).

Results: In our cohort, 333 tumors (81%) had 1p/19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p/19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p/19q loss had significantly better PFS and OS than did the group with 1p/19q maintenance (P < 0.0001 each). Patients with 1p/19q loss and polysomy showed significantly shorter PFS survival than patients with 1p/19q codeletion only (P < 0.0001), but longer PFS and OS than patients with 1p/19q maintenance (P < 0.01 and P < 0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% polysomic cells. Polysomy had no prognostic significance on PFS or OS in patients with 1p/19q maintenance.

Conclusions: The presence of polysomy in oligodendroglial tumors with codeletion of 1p/19q predicts early recurrence and short survival in patients with 1p/19q codeleted tumors.
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http://dx.doi.org/10.1093/neuonc/noz098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571489PMC
September 2019

Primary Epithelioid Sarcoma of Orbit: A Case Report and Review of the Literature.

Case Rep Oncol Med 2018 17;2018:3989716. Epub 2018 Dec 17.

Department of Radiation Oncology, Cancer Care Northwest, Spokane, WA, USA.

Epithelioid sarcoma is a rare high-grade malignancy identified by Enzinger in 1970. It accounts for 1% of all reported soft tissue sarcomas and presents most commonly in distal upper extremities in young adults with a male predominance. At this time, there are only 5 previously reported cases of primary epithelioid sarcoma of the orbit. We present a primary orbital epithelioid sarcoma case of a patient who underwent orbital exenteration followed by external beam radiation treatment. Because the literature is limited, this is to our knowledge the largest descriptive analysis of cases of orbital epithelioid sarcoma. We also provide a detailed review of all the previously reported primary orbital epithelioid sarcoma cases, as well as a discussion on the use of postoperative radiation therapy for patients with epithelioid sarcoma. Surgical resection followed by adjuvant radiation therapy appears to be a safe option for local treatment of this rare malignancy, but further future studies are needed of this rare clinical situation in order to better understand and optimize treatment for patients with orbital epithelioid sarcoma.
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http://dx.doi.org/10.1155/2018/3989716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311860PMC
December 2018

Cardiac arrhythmia and neuroexcitability gene variants in resected brain tissue from patients with sudden unexpected death in epilepsy (SUDEP).

NPJ Genom Med 2018 27;3. Epub 2018 Mar 27.

1Comprehensive Epilepsy Center, NYU Langone Medical Center, New York, NY USA.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction. Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including , , , , , , , and . In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including , , , , , and , which were not present in living epilepsy controls. Our data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.
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http://dx.doi.org/10.1038/s41525-018-0048-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869741PMC
March 2018

T2-FLAIR Mismatch, an Imaging Biomarker for IDH and 1p/19q Status in Lower-grade Gliomas: A TCGA/TCIA Project.

Clin Cancer Res 2017 Oct 27;23(20):6078-6085. Epub 2017 Jul 27.

Department of Radiology, NYU Langone Medical Center, New York, New York.

Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower-grade glioma molecular subtypes. MRI scans from the TCGA/TCIA lower grade glioma database ( = 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2-FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort ( = 82) was analyzed to validate the T2-FLAIR mismatch sign. Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity [ = 0.234 (0.111-0.358)], T2-FLAIR mismatch sign [ = 0.728 (0.538-0.918)], lesion margins [ = 0.292 (0.135-0.449)], and peritumoral edema [ = 0.173 (0.096-0.250)]. All 15 cases that were positive for the T2-FLAIR mismatch sign were -mutant, 1p/19q non-codeleted tumors ( < 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2-FLAIR mismatch sign [ = 0.747 (0.536-0.958)]; all 10 cases positive for the T2-FLAIR mismatch sign were -mutant, 1p/19q non-codeleted tumors ( < 0.00001; PPV = 100%, NPV = 76%). Among lower-grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the -mutant, 1p/19q non-codeleted molecular subtype. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0560DOI Listing
October 2017

Mutant IDH1 and seizures in patients with glioma.

Neurology 2017 May 12;88(19):1805-1813. Epub 2017 Apr 12.

From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.

Objective: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1 increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons.

Methods: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1 status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5.

Results: Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1) patients and in 59%-74% of IDH1 patients ( < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1 was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5.

Conclusions: The D2HG product of IDH1 may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1 gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1 inhibitors may improve antiepileptic therapy in patients with IDH1 gliomas.
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http://dx.doi.org/10.1212/WNL.0000000000003911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419985PMC
May 2017

Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-β Small Molecule Inhibitor.

Neoplasia 2016 Dec;18(12):795-805

Department of Neurosurgery, NYU School of Medicine; Kimmel Center for Stem Cell Biology, NYU School of Medicine; Perlmutter Cancer Center, NYU School of Medicine; Brain Tumor Center, NYU School of Medicine. Electronic address:

High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-β (TGF-β) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-β signaling, indicated variable levels of TGF-β pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-β during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-β type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of γ-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-β signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.
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http://dx.doi.org/10.1016/j.neo.2016.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156509PMC
December 2016

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway.

Acta Neuropathol 2017 03 3;133(3):417-429. Epub 2016 Nov 3.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 408 E 69th St. (Z564), New York, NY, 10065, USA.

Epileptogenic tumors affecting children and young adults are a morphologically diverse collection of neuroepithelial neoplasms that, as a group, exhibit varying levels of glial and/or neuronal differentiation. Recent advances in molecular profiling technology, including comprehensive DNA sequencing and methylation analysis, have enabled the application of more precise and biologically relevant classification schemes to these tumors. In this report, we describe a morphologically and molecularly distinct epileptogenic neoplasm, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY), which likely accounts for a sizable portion of oligodendroglioma-like tumors affecting the pediatric population. Characteristic microscopic findings most notably include infiltrative growth, the invariable presence of oligodendroglioma-like cellular components, and intense immunolabeling for cluster of differentiation 34 (CD34). Moreover, integrative molecular profiling reveals a distinct DNA methylation signature for PLNTYs, along with frequent genetic abnormalities involving either B-Raf proto-oncogene (BRAF) or fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3). These findings suggest that PLNTY represents a distinct biological entity within the larger spectrum of pediatric, low-grade neuroepithelial tumors.
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http://dx.doi.org/10.1007/s00401-016-1639-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325850PMC
March 2017

Mutant IDH1 and thrombosis in gliomas.

Acta Neuropathol 2016 12 23;132(6):917-930. Epub 2016 Sep 23.

Department of Neurosurgery, Northwestern University, Tarry 2-705, 300 East Superior Street, Chicago, IL, 60611, USA.

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.
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http://dx.doi.org/10.1007/s00401-016-1620-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640980PMC
December 2016

Adult Primary Spinal Epidural Extraosseous Ewing's Sarcoma: A Case Report and Review of the Literature.

Case Rep Neurol Med 2016 17;2016:1217428. Epub 2016 Aug 17.

Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY 10016, USA; Brain Tumor Center, NYU Langone Medical Center, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.

Background. Extraosseous Ewing's sarcoma in the spinal epidural space is a rare malignancy, especially in adults. Case Presentation. A 40-year-old male presented with back pain and urinary hesitancy. MRI revealed a thoracic extradural mass with no osseous involvement. He underwent surgery for gross total resection of the mass, which was diagnosed as Ewing's sarcoma. He was subsequently treated with chemoradiotherapy. He remains disease-free 1 year after surgery. Review of the literature indicated only 45 previously reported cases of spinal epidural extraosseous Ewing's sarcoma in adults. Conclusions. Extraosseous Ewing's sarcoma in the spinal epidural space is a rare clinical entity that should be included in the differential for spinal epidural masses. Its treatment is multidisciplinary but frequently requires surgical intervention due to compressive neurologic symptoms. Gross total resection appears to correlate with improved outcomes.
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http://dx.doi.org/10.1155/2016/1217428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005550PMC
September 2016

Posterior Spinal Artery Aneurysm Presenting with Leukocytoclastic Vasculitis.

J Cerebrovasc Endovasc Neurosurg 2016 Mar 31;18(1):42-7. Epub 2016 Mar 31.

Department of Neurosurgery, New York University School of Medicine, New York, NY, USA.

Rupture of isolated posterior spinal artery (PSA) aneurysms is a rare cause of subarachnoid hemorrhage (SAH) that presents unique diagnostic challenges owing to a nuanced clinical presentation. Here, we report on the diagnosis and management of the first known case of an isolated PSA aneurysm in the context of leukocytoclastic vasculitis. A 53-year-old male presented to an outside institution with acute bilateral lower extremity paralysis 9 days after admission for recurrent cellulitis. Early magnetic resonance imaging was read as negative and repeat imaging 15 days after presentation revealed SAH and a compressive spinal subdural hematoma. Angiography identified a PSA aneurysm at T9, as well as other areas suspicious for inflammatory or post-hemorrhagic reactive changes. The patient underwent a multilevel laminectomy for clot evacuation and aneurysm resection to prevent future hemorrhage and to establish a diagnosis. The postoperative course was complicated by medical issues and led to the diagnosis of leukocytoclastic vasculitis that may have predisposed the patient to aneurysm development. Literature review reveals greater mortality for cervical lesions than thoracolumbar lesions and that the presence of meningitic symptoms portents better functional outcome than symptoms of cord compression. The outcome obtained in this case is consistent with outcomes reported in the literature.
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http://dx.doi.org/10.7461/jcen.2016.18.1.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842908PMC
March 2016

ERG is a novel and reliable marker for endothelial cells in central nervous system tumors.

Clin Neuropathol 2015 May-Jun;34(3):117-27

ETS-related gene (ERG) is a transcription factor that has been linked to angiogenesis. Very little research has been done to assess ERG expression in central nervous system (CNS) tumors. We evaluated 57 CNS tumors, including glioblastomas (GBMs) and hemangioblastomas (HBs), as well as two arteriovenous malformations and four samples of normal brain tissue with immunohistochemistry using a specific ERG rabbit monoclonal antibody. In addition, immunostains for CD31, CD34, and α-smooth muscle actin (α-SMA) were performed on all samples. CD31 demonstrated variable and sometimes weak immunoreactivity for endothelial cells. Furthermore, in 1 case of a GBM, CD34 stained not only endothelial cells, but also tumor cells. In contrast, we observed that ERG was only expressed in the nuclei of endothelial cells, for example, in the hyperplastic vascular complexes that comprise the glomeruloid microvascular proliferation seen in GBMs. Conversely, α-SMA immunoreactivity was identified in the abluminal cells of these hyperplastic vessels. Quantitative evaluation with automated methodology and custom Matlab 2008b software was used to calculate percent staining of ERG in each case. We observed significantly higher quantitative expression of ERG in HBs than in other CNS tumors. Our results show that ERG is a novel, reliable, and specific marker for endothelial cells within CNS tumors that can be used to better study the process of neovascularization.
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http://dx.doi.org/10.5414/NP300817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542182PMC
August 2015