*******This webpage is no longer current *******
To visit the new Yassalab page please go to http://yassalab.org

Research Areas:

• Information Processing in the Hippocampus
• Modulatory influences on hippocampal learning: attention, emotion, and reward
• Domain specificity and associative processing medial temporal lobe cortices
• Memory dysfunction in psychiatric disorders (depression, anxiety, obsessive-compulsive disorder)
• Studies of amnestic patients
• Neurocognitive Aging as a Model of Hippocampal Impairment
• High-Resolution Diffusion Tensor Imaging of the Hippocampus and the Perforant Path
• Differentiating Healthy Aging from Alzheimer's dementia
• Neuroimaging Methods Development

Information Processing in the Hippocampus

Virtually every computational model of the hippocampus includes a description of two key processes: (1) pattern separation, i.e., the process of disambiguating similar representations to minimize interference, and (2) pattern completion, i.e., the process by which incomplete representations are filled in based on pre-existing knowledge. These processes allow us to flexibly encode new events as distinct from old (separation) and to generalize across contexts (completion). The CA3 region of the hippocampus is thought to maintain the dynamic balance between the two processes. This region's bias can be influenced by whether it is primarily driven by the dentate granule cells (where the separation signal originates) or by its recurrent collaterals that form an autoassociative network capable of completion. Evidence from rodent studies and human neuroimaging studies has strongly supported these models, observing separation signals in the dentate gyrus and CA3 when environments or stimuli were made similar. Our laboratory is involved in attempting to elucidate the particular roles of the CA3 and dentate gyrus regions in separation over multiple dimensions, e.g. spatial vs. temporal vs. object-based separation. We conduct these investigation using high-resolution (1.5 mm isotropic) fMRI and experimental psychological techniques. In addition, we are interested in how this circuitry can discriminate or generalize among similar inputs in the context of naturalistic tasks, such as face/name association and spatial navigation. Figure 1 is a "simplified" illustration of hippocampal circuitry. The hippocampus receives input from many cortical areas and is under the influence of many neuromodulators. We are additionally interested in examining the role of these neuromodulatory inputs in altering the separation/completion bias in the hippocampus.

Figure 1. Simplified view of the hippocampal network and its interactions with cortical areas

Further Reading:

Guzowski JF, Knierim JJ, Moser EI (2004) Ensemble dynamics of hippocampal regions CA3 and CA1. Neuron 44(4):581-4.
Leutgeb JK, Leutgeb S, Moser MB, Moser EI (2007) Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 315(5814):961-6.
Bakker A, Kirwan CB, Miller M, Stark CE (2008) Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 319(5870):1640-2.
Lacy JW, Yassa MA, Stark SM, Stark CEL. (2011) Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity. Learni

[Jump to Top]

Neurocognitive aging as a model of hippocampal impairment

Our laboratory is also involved in the application of rodent models of neurocognitive aging to healthy older adults and those with amnestic mild cognitive impairment (aMCI), a subset of cognitively impaired individuals that are likely to progress to Alzheimer's disease. Rodent work has strongly suggested that one of the hallmark features of neurocognitive aging is a partial knockdown of the dentate gyrus that results in a failure to represent similar environments as distinct from old (reduced pattern separation). In the absence of the dentate's separation signal, the CA3 could be driven by its recurrent collaterals, thus biasing it towards completion. We have tested this hypothesis in aged humans and in cognitively impaired individuals, finding strong support for the model's predictions. Figure 2 below is a working model of the key changes in hippocampal circuitry with age based on a combination of findings from animals and humans. This work is intimately related to some of the work conducted in the Gallagher laboratory with aged rodents.

Figure 2. A working model for hippocampal changes associated with neurocognitive aging

Further Reading:

Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE (2010) High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage 51(3):1242-52.
Yassa MA, Lacy JW, Stark SM, Albert MS, Gallagher M, Stark CE (2010) Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus (in press)
Stark SM, Yassa MA, Stark CE (2010) Individual differences in spatial pattern separation performance associated with healthy aging in humans. Learn Mem 17(6):284-8.
Gallagher M, Bakker A, Yassa MA, Stark CE. Bridging neurocognitive aging and disease modification: targeting functional mechanisms of memory impairment. Curr Alzheimer Res 7(3):197-9.
Wilson IA, Gallagher M, Eichenbaum H, Tanila H (2006) Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci 29(12):662-70.

[Jump to Top]

High-resolution diffusion tensor imaging of the hippocampus and the perforant path

Rodent work has shown that the perforant path (input to the hippocampus) is degraded with age. Perforant path degradation deprives the dentate and CA3 of cortical input, which may in turn contributing to the shift in bias from separation to completion. Although evidence for this degradation has been shown in animals, comparable evidence in humans is lacking. We sought to develop a new method to image the hippocampus at very high resolution in order to visualize and evaluate the integrity of the perforant path in young and aged humans to test the model's predictions. We chose diffusion tensor imaging (DTI) for this investigation, as it is best suited to address this question. DTI is typically used to investigate white matter microstructure and is based on the principle that water will diffuse more readily along the principal axis of an axon than perpendicular to it. This signal is enhanced in regions of high axonal integrity and decreased in areas where white matter is not as organized. Traditional DTI is incapable of detecting white matter signals within the hippocampus due to resolution limitations. However, recent advances in imaging techniques have allowed us to reach submillimeter resolution (0.6 mm), which is sufficient to resolve the perforant path and hippocampal subfields. Using this high-resolution DTI technique, we found evidence in older adults for a specific degradation in the perforant path. The extent of this degradation predicted both functional activity impairments in the CA3 and dentate gyrus in older adults, as well as pattern separation behavior. This method also shows clear microstructural details within hippocampal subfields (e.g. diffusion signals arising from apical dendrites). High-res DTI is an important future avenue of research and can make strong links between animal and human investigations of the hippocampus, as well as become a powerful biomarker for AD.

A sample high-res image showing the perforant path tensors (in vertical orange oval)

Further Reading:

Yassa MA, Muftuler LT, Stark CEL (2010). Ultrahigh-resolution microstructural diffusion tensor imaging (msDTI) elucidates perforant path degradation in aged humans in vivo. PNAS 107(28): 12687-12691.

[Jump to Top]

Dissociating healthy aging from Alzheimer's dementia

One critical advantage to the study of neurocognitive aging is that we additionally gain a more complete understanding of the processes that change with healthy aging and changes that could potentially lead to pathology.This can be done by studying individuals with mild cognitive impairment (MCI), a preclinical phase that is associated with a high risk of conversion to Alzheimer's disease. We have found that individuals with amnestic MCI (aMCI), a form of MCI where the hallmark cognitive features include memory loss, show a further degradation in pattern separation abilities, coupled with a decreased target recognition ability, suggesting that their memory system as a whole is compromised. In high-resolution fMRI studies, we observed that their CA3/dentate activity during a separation task is elevated beyond that of healthy aging. In addition, we found that activity in the entorhinal cortex was decreased compared to controls, also suggesting that this region, which is the first to suffer from cellular loss in the course of AD, may be functionally impaired earlier on in the disease process. Based on this work and work in the rodent, a clinical trial has started at JHU (led by Dr. Gallagher) to investigate the potential therapeutic effects of low-dose antiepileptic agents on reducing the hyperactivity in the CA3/dentate region and potentially reversing the deleterious effects of this imbalance.

Further Reading:

Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE (2010) High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage 51(3):1242-52.
Gallagher M, Bakker A, Yassa MA, Stark CE. Bridging neurocognitive aging and disease modification: targeting functional mechanisms of memory impairment. Curr Alzheimer Res 7(3):197-9.

[Jump to Top]

Neuroimaging Methods Development

In addition to the research areas above, my laboratory is also involved in developing new techniques for the acquisition and processing of high-resolution structural and functional neuroimaging data. We work with MRI physicists, computational anatomists, and computer engineers to push the limits on existing technology to provide new and enhanced platforms for investigations. Developing the high-resolution msDTI methods above is one of these endeavors. In addition, we collaborate with other laboratories (Center for Imaging Science at JHU, Stark Lab at UC Irvine, PICSL Lab at UPenn, MedIC Lab at JHU Radiology and many others) to develop new tools and techniques for image visualization and analysis. Some of our projects include techniques for regional alignment of fMRI data, volumetric analysis, analysis and tractography of diffusion imaging data and MRI image segmentation and atlas labeling.

Further Reading:

Yassa MA, Muftuler LT, Stark CEL (2010). Ultrahigh-resolution microstructural diffusion tensor imaging (msDTI) elucidates perforant path degradation in aged humans in vivo. PNAS 107(28): 12687-12691.
Yassa MA, Stark CEL (2009). A quantitative evaluation of cross-participant alignment techniques for MRI studies of the medial temporal lobe. Neuroimage 44(2) 319-327.
Bazin PL, Cuzzocreo JL, Yassa MA, Gandler W, McAuliffe MJ, Bassett, SS, Pham DL (2007) Volumetric neuroimage analysis extensions for the MIPAV software package. J Neurosci Methods 165(1):111-21.

[Jump to Top]

Copyright © 2011 Michael A. Yassa. All Rights Reserved.

Related Content Section 1

Related Content Section 2

Style DIV, please skip.