Research Part 1: Introduction Research Part 2: Paleocortical precursors Research Part 3: Synaptic long term potentiation (LTP) Research Part 4: Neocortex Research Part 5: Applications     1. Introduction and Timeline Executive Summary Analysis of a number of important human brain circuits has led to specific and distinct hypotheses of their functions. Simulations at various levels of simplification and abstraction have demonstrated substantial computational power and efficiency of the hypothesized operations. Extensive mathematical characterization of these functions, and comparison with related algorithms have been performed and published in scientific journals. Many of the resulting derived algorithmic methods have led to applications in military, commercial, and medical domains. Specific anatomical, physiological, and behavioral predictions have been tested in animal and human experiments, with results that support the growing body of hypotheses. Further construction of computational simulation systems, more extensive mathematical analyses, and continued empirical testing of biological and behavioral predictions, are ongoing in our laboratory.   Timeline of selected research highlights 1990 - 1991 » Simulations of olfactory bulb and paleocortex identify novel hypothesis of olfactory perceptual function Ambros-Ingerson, J., Granger, R., and Lynch, G. (1990). Simulation of paleocortex performs hierarchical clustering. Science, 247: 1344-1348. Granger, R., and Lynch, G. (1991). Higher olfactory processes: Perceptual learning and memory. Current Opin. Neurosci., 1: 209-214. » Behavioral and electrophysiological predictions tested in freely moving animals Granger, R., Staubli, U., Powers, H., Otto, T., Ambros-Ingerson, J., and Lynch, G. (1991). Behavioral tests of a prediction from a cortical network simulation. Psychol. Sci., 2: 116-118. McCollum, J., Larson, J., Otto, T., Schottler, F. Granger, R., and Lynch, G. (1991). Short-latency single-unit processing in olfactory cortex. J. Cognitive Neurosci., 3: 293-299.   1992 - 1994 » Network modeling of excitatory-inhibitory physiological interaction in cortex Coultrip, R., Granger, R., and Lynch, G. (1992). A cortical model of winner-take-all competition via lateral inhibition. Neural Networks, 5: 47-54. Anton, P., Granger, R., and Lynch, G. (1993). Simulated dendritic spines influence reciprocal synaptic strengths and lateral inhibition in the olfactory bulb. Brain Res., 628: 157-165. » Identifcation of 'ampakines': a novel class of centrally-active compounds that act at ampa-type glutamate receptors, which are the most numerous neurotransmitter receptor type in the human brain Granger, R., Staubli, U., Davis, M., Perez, Y., Nilsson, L., Rogers, G., and Lynch, G. (1993). A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning-dependent task. Synapse, 15: 326-329.   1994 - 1996 » derivation of advanced temporal sequence algorithms, and Bayes classification methods, from brain circuits Granger R, Whitson J, Larson J, Lynch G (1994) Non-Hebbian properties of LTP enable high-capacity encoding of temporal sequences. Proc. Nat'l. Acad. Sci., 91: 10104-10108. Coultrip, R. and Granger, R. (1994). LTP learning rules in sparse networks approximate Bayes classifiers via Parzen's method. Neural Networks, 7: 463-476. » Modeling of hippocampal fields CA1, CA3, dentate, and entorhinal cortex Granger R, Wiebe S, Taketani M, Ambros-Ingerson J, Lynch G. (1996). Distinct memory circuits comprising the hippocampal region. Hippocampus, 6: 567-578. Kilborn, K., Lynch, G., and Granger, R. (1996). Effects of LTP on response selectivity of simulated cortical neurons. J. Cognitive Neurosci., 8: 328-343.   1996 - 1998 » Human and animal studies demonstrating amelioration of age-related deficits via glutamatergic receptor modulation Granger, R., Deadwyler, S., Davis, M., Moskowitz, B., Kessler, M., Rogers, G., and Lynch, G. (1996). Facilitation of glutamate receptors reverses an age-associated memory impairment in rats. Synapse, 22: 332-337. Lynch, G., Granger, R., Davis, M., Ambros-Ingerson, J., Kessler, M., Schehr, R. (1997). Evidence that a positive modulator of glutamate receptors improves recall in elderly human subjects. Experimental Neurology, 145: 89-92 Ingvar M, Ambros J, Davis M, Granger R, Kessler M, Rogers G, Schehr R, Lynch G. (1997). Enhancement by an ampakine of memory encoding in humans. Exper Neurol, 146: 553-559.   1999 - 2001 » Novel brain activity assay based on in-situ hybridization of immediate-early genes (IEGs) Lynch, G., Granger, R., Gall, C., Palmer, L. (2000). Assay for determination of neuronal activity in brain tissue. U.S. Patent # 5,998,139 (6 claims). Hess U, Granger R, Lynch G, Gall C (1997) Differential patterns of c-fos mRNA expression in amygdala during successive stages of odor discrimination learning. Learning & Memory 4: 262-283. » Novel method for 2-D current source density analysis for localization of electrophysiological activity Shimono K, Brucher F, Granger R, Lynch G, Taketani M (2000) Origins and distribution of cholinergically induced beta rhythms in hippocampal slices. J. Neuroscience 20: 8462-8473. Shimono, K., Taketani, M., Brucher, F., Kubota, D., Colgin, L., Robertson, S., Granger R., Lynch, G. (2001). Continuous two-dimensional current-source density analyses of electrophysiological activity in hippocampal slices. Neurocomputing 38: 899-905. » Novel methods for EEG-based neurological diagnostics Granger R (2001) Method and computer program product for assessing neurological conditions and treatments using evoked response potentials. U.S. Patent # 6,223,074 (54 claims). Granger, R., and Lynch, G. (2001). Method and apparatus for assessing susceptibility to stroke. U.S. Patent # 6,280,393 (17 claims).   2002 - 2003 » Benzothiadiazides: A new family of glutamate receptor compounds Phillips, D, Sonnenberg, J, Arai, A, Vaswani, R, Krutzik, P, Kleisli, T, Kessler, M, Granger, R, Lynch, G, Chamberlin, R (2002). 5'-Alkyl-benzothiadiazides: A new subgroup of AMPA receptor modulators with improved affinity. Bioorganic & Medicinal Chem. 10: 1229-1248. Arai, A, Yan-Fang, X, Kessler, M, Phillips, D, Chamberlin, R, Granger, R, Lynch, G. (2002). Effects of 5'-Alklyl-Benzothiadiazides on AMPA receptor biophysics and synaptic responses. Molecular Pharmacology, 62: 566-577. » Clinical demonstration of EEG-based diagnostic in Alzheimer's patients Granger, R. (2001). NeuroGraph Evoked Potential System. Food and Drug Administration (FDA) 510(k) clearance #K010669. Benvenuto J, Jin Y, Casale M, Lynch G, Granger R (2002) Identification of diagnostic evoked response potential segments in Alzheimer¹s Disease. Exper. Neurology, 176: 269-276.   2004-2005 » Integrative modeling of thalamo-cortico-striatal processing Rodriguez A, Whitson J, Granger R (2004) Derivation and analysis of basic computational operations of thalamocortical circuits. J. Cognitive Neurosci, 16: 856-877. Granger R, Petrovic S, Felch A, Kerr J, Johnson M, Wuerth C, Benvenuto J. (2004) Engines of the brain: The computational instruction set of perception and cognition. MIT AAAI Symposium (P.Winston, Ed). CA: AAAI Press. Granger R. (2004) Brain circuit implementation: High-precision computation from low-precision components. In:Replacement Parts for the Brain (T.Berger,Ed) MA: MIT Press.