Neuroscience Graduate Program at UCSF
Neural Mechanisms of Attention and Memory
How we perceive stimuli in our environment involves an integration of two distinct influences: externally- and internally-driven attention. Sensory input from our surroundings often demand attention based on stimulus characteristics such as novelty or salience (Bottom-up processing), but we are also capable of directing attention toward encountered stimuli based on our goals (Top-down modulation). Top-down modulation is a bi-directional process in that it underlies our ability to both focus our attention on task-relevant stimuli and ignore irrelevant distractions by differentially enhancing or suppressing neural activity in sensory cortical regions depending on the relevance of the information to our goals. Thus, it serves as a neural basis for selective attention and a critical foundation for memory. We now know that top-down modulation is manifest via reciprocal, long-range connections between multiple, distributed brain regions - neural networks. However, crucial details concerning the nature of top-down modulation, as well as its underlying network interactions, remain poorly understood. Furthermore, alterations in top-down modulation may underlie the wide range of cognitive deficits associated with normal aging and neurological disease, and is thus fertile territory for clinically relevant research.
Research in our laboratory focuses on furthering our understanding of the neural mechanisms of top-down modulation (how it works), alterations that occur in aging and neurological disease (what goes wrong) and how we may intervene therapeutically when deficits are detected (how we can fix it). To accomplish this, we couple several human neurophysiologic techniques, including functional magnetic resonance imaging (fMRI), electroencephalography (EEG) and transcranial magnetic stimulation (TMS).
Neural mechanisms of top-down modulation. Our research into the neural basis of top-down modulation focuses on four aspects: 1) its dependence on neural network interactions, specifically between the prefrontal cortex and the visual association cortex 2) the complex relationship between enhancement and suppression, 3) its role at the junction of attention and memory, and 4) commonality between stimulus-present (e.g., selective attention, memory encoding) and stimulus-absent (e.g., mental imagery, working memory maintenance) modulation. This is addressed via aunique multi-methodological approach in which the tools of cognitive neuroscience are coupled within the same cognitive experiments, allowing us to capitalize on their respective strengths: the spatial resolution of fMRI to identify cortical network nodes, the ability of TMS to induce transient perturbations in identified cortical regions, and the time resolution of EEG to evaluate temporal dynamics of long range communication between regions.
Alterations in top-down modulation in normal aging and disease. Normal aging is characterized by deficits that cross multiple cognitive domains, including attention, working memory and episodic memory. Our primary objective is to generate parsimonious principles of cognitive aging by identifying common neural mechanisms whose impairments underlie a broad range of age-related cognitive deficits. The role of top-down modulation at the crossroads of attention and memory makes it an ideal system to study the aging brain. We recently discovered that healthy older adults exhibit a prominent deficit in the suppression of cortical activity associated with task-irrelevant representations, while enhancement of task-relevant activity is preserved (Gazzaley et al., Nature Neuroscience, 2005). Moreover, this suppression-specific attention deficit correlates with their impaired working memory performance. Research in our lab continues to investigate the underlying etiology and the generalizability of this deficit. New projects evaluate alterations in top-down modulation in individuals with mild cognitive impairment (MCI) and early dementia.
Therapeutic interventions. In addition to advancing our understanding of how the healthy brain functions and alterations that occur with normal aging and disease, an important goal of our lab is to use this information for the development of therapeutic interventions to alleviate cognitive impairments that diminish the quality of life for many individuals. Our efforts are currently focused on two projects: 1) A pharmacological fMRI study to evaluate the influence of cholinergic manipulation (donepezil treatment) on top-down modulation in older individuals with MCI, and 2) An EEG study to evaluate the role of intensive cognitive training in improving cognition and top-down modulation in healthy older adults.
Omar Al-Hashimi, Graduate Student
Joaquin Anguera, Postdoctoral Fellow
Lisa Bauer, Postdoctoral Fellow
Jacob Bollinger, Postdoctoral Fellow
Joey Ka-Yee Essoe, Research Associate
Jyoti Mishra, Postdoctoral Fellow
Michael Rubens, Research Associate
Peter Wais, Postdoctoral Fellow
Ted Zanto, Postdoctoral Fellow
David Ziegler, Postdoctoral Fellow
Clapp, W., Rubens, M. & Gazzaley, A. A deficit in switching between functional brain networks underlies the impact of multitasking on working memory in older adults. Proceedings of the National Academy of Science USA 108: 7212–7217(2011)
Chadick, J.Z. & Gazzaley, A. Differential coupling of visual cortical areas with the default network or frontal-parietal network based on task goals. Nature Neuroscience 14: 830-2 (2011) "PMC Journal - In Process"
Kalkstein, J., Checkersfield, K., Bollinger, J. & Gazzaley, A. Diminished top-down control underlies a visual imagery deficit in normal aging. Journal of Neuroscience (2011) - In press
Zanto, T.P, Pan, P., Liu, H., Bollinger, J., Nobre, K. & Gazzaley, A. Age-related changes in orienting attention in time. Journal of Neuroscience 31:12461–12470 (2011)
Zanto, T., Rubens, M., Thangavel, A. & Gazzaley, A. A causal role of the prefrontal cortex in top-down modulation of early visual processing and working memory. Nature Neuroscience 14: 656-661 (2011)
Bollinger, J. Rubens, M., Zanto, T.P. & Gazzaley, A. Expectation-driven changes in cortical functional connectivity influence working-memory and long-term memory performance. Journal of Neuroscience 30: 14399-14410 (2010)
Wais, P., Rubens, M., Boccanfuso, J. & Gazzaley, A. Neural Mechanisms Underlying the Impact of Visual Distraction on Long-Term Memory Retrieval. Journal of Neuroscience (2010)
Rutman, A.M., Clapp, W.C., Chadick, J.Z., Gazzaley, A. Early top-down control of visual processing predicts working memory performance. Journal of Cognitive Neuroscience (2009)
Zanto, T. & Gazzaley, A. Neural suppression of irrelevant information underlies optimal working memory performance. Journal of Neuroscience 29 (10): 3059-3066 (2009)
Gazzaley, A., Clapp, W., Kelley, J., McEvoy, K., Knight, R., D’Esposito, M. Age-related top-down suppression deficit in the early stages of cortical visual memory processing. Proceedings of the National Academy of Science USA 105(35): 13122-13126. (2008)
Gazzaley, A., Sheridan, M.A., Cooney, J and D’Esposito, M. Age-related deficits in component processes of working memory. Neuropsychology 21(5): 532-539(2007)
Gazzaley, A., Rissman, J Cooney, J.W.,Rutman, A., Seibert, T, Clapp, W, D’Esposito, M. Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing. Cerebral Cortex 17:i125-i135 (2007)
D’Esposito, M., Cooney, J.W., Postle, B.R., Gazzaley, A., Gibbs, S.E. The role of the prefrontal cortex on component processes of working memory: Evidence from lesion and fMRI data. Journal of the International Neuropsychological Society 12(2), 248-260 (2006)
Gazzaley, A., Cooney, J.W., Rissman, J., D’Esposito, M. Top-down suppression deficit underlies working memory impairment in normal aging. Nature Neuroscience 8(10), 1298-1300. (2005)
Gazzaley, A., Cooney, J.W., McEvoy, K., Knight, R. D’Esposito, M. Top-down enhancement and suppression of the magnitude and speed of neural activity. Journal of Cognitive Neuroscience. 17(3), 507-517. (2005)
Gazzaley, A., Rissman, J., D’Esposito, M. Functional Connectivity during working memory maintenance. Cognitive, Affective and Behavioral Neuroscience 4(4), 580-599. (2004)
Rissman, J., Gazzaley, A. and D’Esposito, M. Measuring functional connectivity during distinct stages of a cognitive task. Neuroimage 23(2), 752-763. (2004)
Gazzaley, A., Benson, D.L., Huntley, G.W. and Morrison, J.H. Differential subcellular regulation of NMDAR1 protein and mRNA in dendrites of dentate gyrus granule cells after perforant path transection. Journal of Neuroscience 17(6): 2006-17. (1997)
Gazzaley, A., Weiland, N.G., McEwen, B.S. and Morrison, J.H. Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus. Journal of Neuroscience 16(21): 6830-8. (1996)
Gazzaley, A., Siegel, S.J., Kordower, J.H., Mufson, E.J. and Morrison, J.H. Circuit-specific alterations of N-methyl-D-aspartate receptor subunit 1 in the dentate gyrus of aged monkeys. Proceedings of the National Academy of Science USA 93(7): 3121-5. (1996)
Adam Gazzaley, M.D. / Ph.D.
UCSF MC 0444
675 Nelson Rising Lane, Room 511C
San Francisco, CA. 94158