Craig E.L. Stark

When zero is not zero: The problem of ambiguous baseline conditions in fMRI

By using blocked and rapid event-related functional MRI studies of memory, we explored the implications of using rest periods as a baseline condition in functional MRI studies. Activity in the medial temporal lobe (as well as in other brain regions) was substantially higher during rest than during several alternative baseline conditions. The effect of this elevated activity during rest was to reduce, eliminate, or even reverse the sign of the activity during task conditions relevant to memory functions. The results demonstrate that periods of rest are associated with significant cognitive activity and, therefore, provide a nonoptimal baseline for memory tasks. These results were observed not only when relatively long blocks of rest were used (experiment 1), but also when rest consisted of the short null trials typically used in rapid event-related designs (experiment 2). The findings have important implications for the design and interpretation of a wide range of fMRI studies of cognition.

Pattern Separation in the Human Hippocampal CA3 and Dentate Gyrus

Pattern separation, the process of transforming similar representations or memories into highly dissimilar, nonoverlapping representations, is a key component of many functions ascribed to the hippocampus. Computational models have stressed the role of the hippocampus and, in particular, the dentate gyrus and its projections into the CA3 subregion in pattern separation. We used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding. Although activity consistent with a bias toward pattern completion was observed in CA1, the subiculum, and the entorhinal and parahippocampal cortices, activity consistent with a strong bias toward pattern separation was observed in, and limited to, the CA3/dentate gyrus. These results provide compelling evidence of a key role of the human CA3/dentate gyrus in pattern separation.

Pattern separation in the hippocampus

The ability to discriminate among similar experiences is a crucial feature of episodic memory. This ability has long been hypothesized to require the hippocampus, and computational models suggest that it is dependent on pattern separation. However, empirical data for the role of the hippocampus in pattern separation have not been available until recently. This review summarizes data from electrophysiological recordings, lesion studies, immediate-early gene imaging, transgenic mouse models, as well as human functional neuroimaging, that provide convergent evidence for the involvement of particular hippocampal subfields in this key process. We discuss the impact of aging and adult neurogenesis on pattern separation, and also highlight several challenges to linking across species and approaches, and suggest future directions for investigation.

Medial temporal lobe activation during encoding and retrieval of novel face-name pairs

The human medial temporal lobe (MTL) is known to be involved in declarative memory, yet the exact contributions of the various MTL structures are not well understood. In particular, the data as to whether the hippocampal region is preferentially involved in the encoding and/or retrieval of associative memory have not allowed for a consensus concerning its specific role. To investigate the role of the hippocampal region and the nearby MTL cortical areas in encoding and retrieval of associative versus non‐associative memories, we used functional magnetic resonance imaging (fMRI) to measure brain activity during learning and later recognition testing of novel face‐name pairs. We show that there is greater activity for successful encoding of associative information than for non‐associative information in the right hippocampal region, as well as in the left amygdala and right parahippocampal cortex. Activity for retrieval of associative information was greater than for non‐associative information in the right hippocampal region also, as well as in the left perirhinal cortex, right entorhinal cortex, and right parahippocampal cortex. The implications of these data for a clear functional distinction between the hippocampal region and the MTL cortical structures are discussed.

Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults.

There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age‐related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age‐related neural changes in the human hippocampus using high‐resolution (1.5 mm isotropic) blood‐oxygenation level‐dependent fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared with young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging.

High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic mild cognitive impairment

Functional magnetic resonance imaging (fMRI) studies have observed hyperactivity in the hippocampal region in individuals with Mild Cognitive Impairment (MCI). However, the actual source of such hyperactivity is not well understood. Studies of aged rats observed similar hyperactive signals in the CA3 region of the hippocampus that correlated with spatial memory deficits and, in particular, with their ability to represent novel environments as being distinct from familiar ones (pattern separation). In this study, we tested the hypothesis that patients with amnestic MCI (aMCI) have deficits in pattern separation, along with hyperactive fMRI BOLD activity in the CA3 region of the hippocampus. We used high-resolution fMRI during a continuous recognition task designed to emphasize pattern separation. We conducted hippocampal subfield-level region of interest analyses to test for dysfunctional activity in aMCI patients. We found that patients showed impaired performance on trials that taxed their pattern separation abilities. We also observed hyperactive BOLD signals in the CA3/dentate and hypoactive signals in the entorhinal cortex during the separation condition. In a high-resolution morphometric analysis of hippocampal subfields, aMCI patients also had smaller CA3/dentate and CA1 volumes (no difference in the subiculum). The CA3/dentate region bilaterally also exhibited the largest shape deformations in aMCI patients, suggesting that this locus is affected early in the course of the disease. These findings suggest that structural and functional changes in the CA3/dentate region of the hippocampus contribute to the deficits in episodic memory that are observed in patients with aMCI. The functional hyperactivity may be evidence for a dysfunctional encoding mechanism, consistent with the predictions of computational models of hippocampal learning.

A quantitative evaluation of cross-participant registration techniques for MRI studies of the medial temporal lobe.

Accurate cross-participant alignment within the medial temporal lobe (MTL) region is critical for fMRI studies of memory. However, traditional alignment approaches have been exceptionally poor at registering structures in this area due to significant inter-individual anatomic variability. In this study, we evaluated the performance of twelve registration approaches. Specifically, we extended several traditional approaches such as SPMs normalization and AFNIs 3dWarpDrive to improve the quality of alignment in the MTL region by using weighting masks or applying the transformations directly to ROI segmentations. In addition, we evaluated the performance of three fully deformable methods, DARTEL, Diffeomorphic Demons, and LDDMM that are effectively unconstrained by number of degrees of freedom. For each, we first assessed the methods ability to achieve optimal overlap between segmentations of subregions of the MTL across participants. Then we evaluated the smoothness of group average structural images aligned using each method to assess the blur that results when voxels of different tissue types are averaged together. In general, we found that when anatomical segmentation is possible, substantial improvement in registration accuracy can be gained in the MTL even with a small number of deformations. When segmentation is not possible, the fully deformable models provide some improvement over more traditional approaches and in a few cases even approach the performance of the ROI-based approaches. The best performance is achieved when both methods are combined. We note that these conclusions are not limited to the MTL and are easily extendable to other areas of the brain.

Age-related memory deficits linked to circuit-specific disruptions in the hippocampus

Converging data from rodents and humans have demonstrated an age-related decline in pattern separation abilities (the ability to discriminate among similar experiences). Several studies have proposed the dentate and CA3 subfields of the hippocampus as the potential locus of this change. Specifically, these studies identified rigidity in place cell remapping in similar environments in the CA3. We used high-resolution fMRI to examine activity profiles in the dentate gyrus and CA3 in young and older adults as stimulus similarity was incrementally varied. We report evidence for “representational rigidity” in older adults’ dentate/CA3 that is linked to behavioral discrimination deficits. Using ultrahigh-resolution diffusion imaging, we quantified both the integrity of the perforant path as well as dentate/CA3 dendritic changes and found that both were correlated with dentate/CA3 functional rigidity. These results highlight structural and functional alterations in the hippocampal network that predict age-related changes in memory function and present potential targets for intervention.

Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity

Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while monitoring CA1 and CA3/dentate for separation and completion-like signals using high-resolution fMRI. In the CA1, activity varied in a graded fashion in response to increases in the change in input. In contrast, the CA3/dentate showed a stepwise transfer function that was highly sensitive to small changes in input.

A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment

Changes in memory performance are one of the hallmark symptoms of mild cognitive impairment and are affected by healthy aging as well. Pattern separation, which refers to the process of orthogonalizing overlapping inputs into distinct memory representations, may be a sensitive marker of these memory changes. Here, we describe a paradigm, the Behavioral Pattern Separation Task-Object Version (BPS-O task), which reveals age-related changes in pattern separation performance. Specifically, we report an age-related decline in pattern separation in healthy adults, ranging from ages 20 to 89. When we classify those individuals aged 60 and older into two groups, Aged Unimpaired (AU) and Aged Impaired (AI) based on their delayed word recall performance, we observe impairments in pattern separation performance in the Impaired group, but no overall impairment in recognition performance. In contrast, those individuals diagnosed with mild cognitive impairment demonstrate worse performance than age-matched controls in both pattern separation and recognition memory performance. Therefore, the BPS-O task provides a sensitive measure for observing changes in memory performance across the lifespan and may be useful for the early detection of memory impairments that may provide an early signal of later development to mild cognitive impairment.