Charles Nicholson

Professor, Department of Neuroscience & Physiology

550 First Avenue
Room 460, Lab 496 and 4100A Medical Science Building
New York, NY 10016
Tel: 212 263 5421; Lab: 212 263 0920
Email: or

Research Summary:

Diffusion of Substances in the Brain

The extracellular space (ECS) is comprised of the narrow spaces (20 – 60 nm) that separate each cell from its neighbor and collectively form a connected volume that occupies some 20% of the brain. My laboratory has studied diffusion of substances in brain ECS for 30 years using two methods that we originated based on a ‘point source paradigm’.  The first technique is the real time iontophoresis (RTI) method using iontophoresis of tetramethylammonium (TMA) in conjunction with an ion-selective microelectrode and the second method is the integrative optical imaging (IOI) method based on quantifying the images of diffusing fluorescent molecules.  These methods enable diffusion to be characterized in a very small volume of brain tissue in real time.

The goal of our work has been to use experimental analysis of diffusion in parallel with appropriate theoretical modeling to reveal the structural and functional properties of the ECS.  We have determined how a wide variety of molecules are hindered in their diffusion and begun to account for the origins of this reduced diffusion.  We have also made extensive measurements of the amount of ECS in the brain.  At present we are focused on improving our experimental techniques and using the MCell Monte Carlo modeling software to understand diffusion anisotropy and the interaction of diffusing molecules with the extracellular matrix.

Earlier work included comparative cerebellar electrophysiology, the analysis of extracellular field potentials and current source density, stimulation of cells by applied electric fields, spreading depression, recording of rapid extracellular ionic transients and dopamine kinetics.

Selected Publications:

  • Thorne, R. G., Lakkaraju, A., Rodriguez-Boulan, E. and Nicholson, C. (2008) In vivo diffusion of lactoferrin in brain extracellular space is regulated by interactions with heparan sulfate. Proc Natl Acad Sci U S A 105: 8416-8421.

  • Sykova, E. and Nicholson, C. (2008) Diffusion in brain extracellular space. Physiol Rev 88: 1277-1340.

  • Hrabetova, S., Masri, D., Tao, L., Xiao, F. and Nicholson, C. (2009) Calcium diffusion enhanced after cleavage of negatively charged components of brain extracellular matrix by chondroitinase ABC. J Physiol. 587: 4029-4049.

  • Li, X., Patel, J.C., Wang, J., Avshalumov, M. V., Nicholson, C., Buxbaum, J. D., Elder, G. A., Rice, M. E. and Yue, Z. (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. J Neurosci 30: 1788-1797.

  • Nicholson, C., Kamali-Zare, P. and Tao, L. Brain extracellular space as a diffusion barrier. Comput Visual Sci (in press).

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