Gaute Einevoll, Ph.D.
Professor of Physics, Department of Mathematical Sciences & Technology, Norwegian University of Life Sciences (UMB)
Multiscale modeling of cortical network activity: Key challenges
Gaute T. Einevoll Computational Neuroscience Group, Norwegian University of Life Sciences, 1432 Ås, Norway; Norwegian National Node of the International Neuroinformatics Coordinating Facility (INCF)
Several challenges must be met in the development of multiscale models of cortical network activity. In the presentation I will, based on ongoing work in our group (http://compneuro.umb.no/ ) on multiscale modeling of cortical columns, outline some of them. In particular,
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Combined modeling schemes for neuronal, glial and vascular dynamics [1,2],
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Development of sets of interconnected models describing system at different levels of biophysical detail [3-5],
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Multimodal modeling, i.e., how to model what you can measure [6-12],
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How to model when you don’t know all the parameters, and
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Development of neuroinformatics tools and routines to do simulations efficiently and accurately [13,14].
References:
- L. Øyehaug, I. Østby, C. Lloyd, S.W. Omholt, and G.T. Einevoll: Dependence of spontaneous neuronal firing and depolarisation block on astroglial membrane transport mechanisms, J Comput Neurosci 32, 147-165 (2012)
- I. Østby, L. Øyehaug, G.T. Einevoll, E. Nagelhus, E. Plahte, T. Zeuthen, C. Lloyd, O.P. Ottersen, and S.W. Omholt: Astrocytic mechanisms explaining neural-activity-induced shrinkage of extraneuronal space, PLoS Comp Biol 5, e1000272 (2009)
- T. Heiberg, B. Kriener, T. Tetzlaff, A. Casti, G.T. Einevoll, and H.E. Plesser: Firing-rate models can describe the dynamics of the retina-LGN connection, J Comput Neurosci (2013)
- T. Tetzlaff, M. Helias, G.T. Einevoll, and M. Diesmann: Decorrelation of neural-network activity by inhibitory feedback, PLoS Comp Biol 8, e10002596 (2012).
- E. Nordlie, T. Tetzlaff, and G.T. Einevoll: Rate dynamics of leaky integrate-and-fire neurons with strong synapses, Frontiers in Comput Neurosci 4, 149 (2010)
- G.T. Einevoll, F. Franke, E. Hagen, C. Pouzat, K.D. Harris: Towards reliable spike-train recording from thousands of neurons with multielectrodes, Current Opinion in Neurobiology 22, 11-17 (2012)
- H. Linden, T Tetzlaff, TC Potjans, KH Pettersen, S Grun, M Diesmann, GT Einevoll: Modeling the spatial reach of LFP, Neuron 72, 859-872 (2011).
- H. Linden, K.H. Pettersen, and G.T. Einevoll: Intrinsic dendritic filtering gives low-pass power spectra of local field potentials, J Computational Neurosci 29, 423-444 (2010)
- K.H. Pettersen and G.T. Einevoll: Amplitude variability and extracellular low-pass filtering of neuronal spikes, Biophysical Journal 94, 784-802 (2008).
- K.H. Pettersen, E. Hagen, and G.T. Einevoll: Estimation of population firing rates and current source densities from laminar electrode recordings, J Comput Neurosci 24, 291-313 (2008).
- K. Pettersen, A. Devor, I. Ulbert, A.M. Dale and G.T. Einevoll. Current-source density estimation based on inversion of electrostatic forward solution: Effects of finite extent of neuronal activity and conductivity discontinuities, Journal of Neuroscience Methods 154, 116-133 (2006).
- G.T. Einevoll, K. Pettersen, A. Devor, I. Ulbert, E. Halgren and A.M. Dale: Laminar Population Analysis: Estimating firing rates and evoked synaptic activity from multielectrode recordings in rat barrel cortex, Journal of Neurophysiology 97, 2174-2190 (2007).
- LFPy: A tool for simulation of extracellular potentials (http://compneuro.umb.no)
- E. Nordlie, M.-O. Gewaltig, H. E. Plesser: Towards reproducible descriptions of neuronal network models, PLoS Comp Biol 5, e1000456 (2009).
Claudia AM Wheeler-Kingshott, Ph.D.
University Reader in Magnetic Resonance Physics, Department of Neuroinflammation, UCL Institute of Neurology, London, UK
Abstract
Detecting neuronal activity in vivo non-invasively is possible with a number of techniques. Amongst these, in 1990 functional magnetic resonance imaging (fMRI) was proposed as a technique that has a great ability to spatially map brain activity by exploiting the blood oxygenation level dependent (BOLD) contrast mechanism [1, 2]. In fact, neuronal activation triggers a demand for oxygen and induces a localised increase in blood flow and blood volume, which actually exceeds the metabolic needs. This in turns causes an increase of oxyhaemoglobin in the venous compartment, which is a transient phenomenon and is accompanied by a transient change (decrease) in the concentration of deoxyhaemoglobin. Due to its paramagnetic properties, the amount of deoxyhaemoglobin present in the venous blood affects the local magnetic field seen by the spins (protons) and determines the local properties of the MR signal. A decrease in deoxyhaemoglobin during neuronal activity, therefore, induces local variations of this magnetic field that increases the average transverse relaxation time of tissue, measured via the T2* parameter [3]. This means that there is an increase of the MR signal (of the order of a few %, typically <5%) linked to metabolic changes happening during brain function. Activation can be inferred at different brain locations by performing tasks while acquiring the MR signal and comparing periods of rest to periods of activity.
The macroscopic changes of the BOLD signal are well characterised, while the reason for the increased blood supply, exceeding demands, needs further thoughts. Here we will discuss two approaches for explaining the BOLD phenomenon, one that links it to adenosine triphosphate production [4] and enzyme saturation, the other that relates it to the very slow diffusion of oxygen through the blood-brain-barrier with a consequent compensatory high demand of oxygen [5]. Some evidence of restricted oxygen diffusion has been shown by means of hypercapnia [6], although it is not excluded that both mechanisms may be present.
Overall, the BOLD signal changes theory and its physiological basis will be presented and discussed.
References
- Ogawa, S., et al., Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A, 1990. 87(24): p. 9868-72.
- Kwong, K.K., et al., Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci U S A, 1992. 89(12): p. 5675-9.
- Bandettini PA, et al. Spin-echo and gradient-echo EPI of human brain activation using BOLD contrast: a comparative study at 1.5 T. NMR Biomed. 1994 Mar;7(1-2):12-20
- Fox, P.T., et al., Nonoxidative glucose consumption during focal physiologic neural activity. Science, 1988. 241(4864): p. 462-4.
- Gjedde, A., et al. Reduction of functional capillary density in human brain after stroke. J Cereb Blood Flow Metab, 1990. 10(3): p. 317-26.
- Hoge, R.D., et al., Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex. Proc Natl Acad Sci U S A, 1999. 96(16): p. 9403-8.
Colin Barrow, Ph.D.
Chair in Biotechnology, School of Life & Environmental Sciences, Deakin University, Australia
Nano-biotechnology: Omega-3 Oils and Nanofibres
The health benefits of long-chain omega-3 fatty acids are well established, especially for eicosapentaenoic acid (EPA) and docosapentaenoic acid (DHA) from fish and microbial sources. In fact, a billion dollar market exists for these compounds as nutritional supplements, functional foods and pharmaceuticals. This presentation will describe some aspects of our omega-3 biotechnology research that are at the intersection of Nano-biotechnology and oil chemistry. These include the use of lipases for the concentration of omega-3 fats, through immobilization of these lipases on nanoparticles, and the microencapsulation and stabilization of omega-3 oils for functional foods. I will also describe some of our work on the enzymatic production of resolvins using lipoxygenases, and the fermentation of omega-3 oils from marine micro-organisms. Finally, I will describe some of our work on the formation of amyloid fibrils and graphene for various applications in nano-biotechnology.
Sanjeeva Srivastava, Ph.D.
Assistant Professor, Proteomics Lab, IIT-Bombay, India
Identification of Potential Early Diagnostic Biomarkers for Gliomas and Various Infectious Diseases using Proteomic Technologies
The spectacular advancements achieved in the field of proteomics research during the last decade have propelled the growth of proteomics for clinical research. Recently, comprehensive proteomic analyses of different biological samples such as serum or plasma, tissue, CSF, urine, saliva etc. have attracted considerable attention for the identification of protein biomarkers as early detection surrogates for diseases (Ray et al., 2011). Biomarkers are biomolecules that can be used for early disease detection, differentiation between closely related diseases with similar clinical manifestations as well as aid in scrutinizing disease progression. Our research group is performing in-depth analysis of alteration in human proteome in different types of brain tumors and various pathogenic infections to obtain mechanistic insight about the disease pathogenesis and host immune responses, and identification of surrogate protein markers for these fatal human diseases.
Applying 2D-DIGE in combination with MALDI-TOF/TOF MS we have analyzed the serum and tissue proteome profiles of glioblastoma multiforme; the most common and lethal adult malignant brain tumor (Gollapalli et al., 2012) (Figure 1). Results obtained were validated by employing different immunoassay-based approaches. In serum proteomic analysis we have identified some interesting proteins like haptoglobin, ceruloplasmin, vitamin-D binding protein etc. Moreover, proteomic analysis of different grades (grade-I to IV) of gliomas and normal brain tissue was performed and differential expressions of quite a few proteins such as SIRT2, GFAP, SOD, CDC42 have been identified, which have significant correlation with the tumor growth. While proteomic analysis of cerebrospinal fluid from low grade (grade I & II) vs. high grade (grade III & IV) gliomas revealed modulation of CSF levels of apolipoprotein E, dickkopf related protein 3, vitamin D binding protein and albumin in high grade gliomas. The prospective candidates identified in our studies provide a mechanistic insight of glioma pathogenesis and identification of potential biomarkers. We are also studying the role of JAK/STAT interactome and therapeutic potential of STAT3 inhibitors in gliomas using proteomics approach. Several candidates of the JAK/STAT interactome were identified with altered expression and a significant correlation was observed between STAT3 and PDK1 transcript expression level.
We have also investigated the changes in human serum proteome in different infectious diseases including falciparum and vivax malaria (Ray et al., 2012a; Ray et al., 2012b), dengue (Ray et al., 2012c) and leptospirosis (Srivastava et al., 2012). Although, quite a few serum proteins were found to be commonly altered in different infectious diseases and might be a consequence of inflammation mediated acute phase response signaling, uniquely modulated candidates were identified in each pathogenic infection indicating the some inimitable responses. Further, a panel of identified proteins consists of six candidates; serum amyloid A, hemopexin, apolipoprotein E, haptoglobin, retinol-binding protein and apolipoprotein A-I was used to build statistical sample class prediction models employing PLSDA and other classification methods to predict the clinical phenotypic classes and 91.37% overall prediction accuracy was achieved (Figure 2). ROC curve analysis was carried out to evaluate the individual performance of classifier proteins. The excellent discrimination among the different disease groups on the basis of differentially expressed proteins demonstrates the potential diagnostic implications of this analytical approach.
Keywords: Diagnostic biomarkers, Gliomas, Infectious Diseases, Proteomics, Serum proteome
Acknowledgments: This disease biomarker discovery research was supported by Department of Biotechnology, India grant (No. BT/PR14359/MED/30/916/2010), Board of Research in Nuclear Sciences (BRNS) DAE young scientist award (2009/20/37/4/BRNS) and a startup grant 09IRCC007 from the IIT Bombay. The active support from Advanced Center for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Hospital (TMH), and Seth GS Medical College and KEM Hospital Mumbai, India in clinical sample collection process is gratefully acknowledged.
References :
- Ray S, Reddy PJ, Jain R, Gollapalli K. Moiyadi A, Srivastava S. Proteomic technologies for the identification of disease biomarkers in serum: advances and challenges ahead. Proteomics 11: 2139-61, 2011.
- Gollapalli K, Ray S, Srivastava R, Renu D, Singh P, Dhali S, Dikshit JB, Srikanth R, Moiyadi A, Srivastava S. Investigation of serum proteome alterations in human glioblastoma multiforme. Proteomics 12(14): 2378-90, 2012.
- Ray S, Renu D, Srivastava R, Gollapalli K, Taur S, Jhaveri T, Dhali S, Chennareddy S, Potla A, Dikshit JB, Srikanth R, Gogtay N, Thatte U, Patankar S, Srivastava S. Proteomic investigation of falciparum and vivax malaria for identification of surrogate protein markers. PLoS One 7(8): e41751, 2012a.
- Ray S, Kamath KS, Srivastava R, Raghu D, Gollapalli K, Jain R, Gupta SV, Ray S, Taur S, Dhali S, Gogtay N, Thatte U, Srikanth R, Patankar S, Srivastava S. Serum proteome analysis of vivax malaria: An insight into the disease pathogenesis and host immune response. J Proteomics 75(10): 3063-80, 2012b.
- Srivastava R, Ray S, Vaibhav V, Gollapalli K, Jhaveri T, Taur S, Dhali S, Gogtay N, Thatte U, Srikanth R, Srivastava S. Serum profiling of leptospirosis patients to investigate proteomic alterations. J Proteomics 76: 56-68, 2012.
- Ray S, Srivastava R, Tripathi K, Vaibhav V, Srivastava S. Serum proteome changes in dengue virus-infected patients from a dengue-endemic area of India: towards new molecular targets? OMICS 16(10): 527-36, 2012c.
* Correspondence: Dr. Sanjeeva Srivastava, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai 400 076, India: E-mail: sanjeeva@iitb.ac.in; Phone: +91-22-2576-7779, Fax: +91-22-2572-3480
Michelle Hermiston, MD, Ph.D.
Assistant Professor, Department of Pediatrics University of California San Francisco, USA
Interrogating Signaling Networks at the Single Cell Level In Primary Human Patient Samples
Multiparameter phosphoflow cytometry is a highly sensitive proteomic approach that enables monitoring of biochemical perturbations at the single cell level. By combining antisera to cell surface markers and key intracellular proteins, perturbations in signaling networks, cell survival and apoptosis mediators, cell cycle regulators, and/or modulators of other cellular processes can be analyzed in a highly reproducible and sensitive manner in the basal state and in response to stimulation or drug treatment. Advantages of this approach include the ability to identify the biochemical consequences of genetic and/or epigenetic changes in small numbers of cells, to map potential interplay between various signaling networks simultaneously in a single cell, and to interrogate potential mechanisms of drug resistance or response in a primary patient sample. Application of this technology to patients with acute lymphoblastic leukemia or the autoimmune disease systemic lupus erythematosus (SLE) will be discussed.
Arathy R and Binoy B Nair
PC based heart sound monitoring system
Heart diseases caused by disorders of the heart and blood vessels, are world’s largest killers. Early detection and monitoring of heart abnormalities is essential for diagnosis and effective treatment of heart diseases. Severalmethodologies are used for screening and diagnosing heart diseases. They are auscultation, electrocardiogram (ECG), echo-cardiogram, ultrasound etc. The effectiveness and applicability of all these diagnostic methods are highly dependent on the equipment cost and size as well as skill of the physician. This paper presents the design and development of a low cost portable wireless/tubeless digital stethoscope which can be used by the physician for monitoring the patient from a distance. The stethoscope system interfaces to a PC and is also capable of analyzing the heart sounds and identifying abnormalities in the heart sound and its classification. Storage of heart sound for later analysis is also possible.This advanced functionality increases the physician’s diagnostic capability, and such a PCG is not still available in most hospitals. Acoustic stethoscope can be changed into a digital stethoscope by inserting an electric capacity microphone into its diaphragm (Wang, Chen and Samjin, 2009).
John Stanley, Satheesh Babu, Ramacahandran T and Bipin Nair
Pt-Pd decorated TiO2 nanotube array for the non-enzymatic determination of glucose in neutral medium
Rapidly expanding diabetic population and the complications associated with elevated glycemic levels necessitates the need for a highly sensitive, selective and stable blood glucose measurement strategy. The high sensitivity and selectivity of enzymatic sensors together with viable manufacturing technologies such as screen-printing have made a great social and economic impact. However, the intrinsic nature of the enzymes leads to lack of stability and consequently reduces shelf life and imposes the need for stringent storage conditions. As a result much effort has been directed towards the development of ‘enzyme-free’ glucose sensors (Park et al. 2006). In this paper, a non-enzymatic amperometric sensor for selective and sensitive direct electrooxidation of glucose in neutral medium was fabricated based on Platinum-Palladium (Pt–Pd) nanoparticle decorated titanium dioxide (TiO2) nanotube arrays. Highly ordered TiO2 nanotube arrays were obtained using a single step anodization process (Grimes C A and Mor G K 2009) over which Pt–Pd nanoparticles where electrochemically deposited. Scanning Electron Microscopy (SEM) analysis revealed the diameter of the TiO2 nanotubes to be approximately 40 nm. Elemental analysis after electrochemical deposition confirms the presence of Pt–Pd. Electrochemical characterization of the sensor was carried out using cyclic voltammetry technique (−1.0 to +1.0V) in phosphate buffer saline (PBS) pH 7.4. All further glucose oxidation studies were performed in PBS (pH 7.4). The sensor exhibited good linear response towards glucose for a concentration range of 1 μM to 20mM with a linear regression coefficient of R = 0.998. The electrodes are found to be selective in the presence of other commonly interfering molecules such as ascorbic acid, uric acid, dopamine and acetamidophenol. Thus a nonenzymatic sensor with good selectivity and sensitivity towards glucose in neutral medium has been developed.