Publications by authors named "Ilana J Bennett"

30 Publications

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Neuroimaging measures of iron and gliosis explain memory performance in aging.

Hum Brain Mapp 2021 Sep 14. Epub 2021 Sep 14.

Department of Neuroscience, University of California Riverside, Riverside, California, USA.

Evidence from animal and histological studies has indicated that accumulation of iron in the brain results in reactive gliosis that contributes to cognitive deficits. The current study extends these findings to human cognitive aging and suggests that magnetic resonance imaging (MRI) techniques like quantitative relaxometry can be used to study iron and its effects in vivo. The effects of iron on microstructure and memory performance were examined using a combination of quantitative relaxometry and multicompartment diffusion imaging in 35 young (21.06 ± 2.18 years) and 28 older (72.58 ± 6.47 years) adults, who also completed a memory task. Replicating past work, results revealed age-related increases in iron content (R2*) and diffusion, and decreases in memory performance. Independent of age group, iron content was significantly related to restricted (intracellular) diffusion in regions with low-moderate iron (hippocampus, caudate) and to all diffusion metrics in regions with moderate-high iron (putamen, globus pallidus). This pattern is consistent with different stages of iron-related gliosis, ranging from astrogliosis that may influence intracellular diffusion to microglial proliferation and increased vascular permeability that may influence all sources of diffusion. Further, hippocampal restricted diffusion was significantly related to memory performance, with a third of this effect related to iron content; consistent with the hypothesis that higher iron-related astrogliosis in the hippocampus is associated with poorer memory performance. These results demonstrate the sensitivity of MRI to iron-related gliosis and extend our understanding of its impact on cognition by showing that this relationship also explains individual differences in memory performance.
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http://dx.doi.org/10.1002/hbm.25652DOI Listing
September 2021

Age group differences in learning-related activity reflect task stage, not learning stage.

Behav Brain Res 2021 Sep 7;416:113570. Epub 2021 Sep 7.

Department of Psychology, University of California, Riverside, 900 University Avenue, Riverside, CA 92521 United States of America. Electronic address:

Healthy aging is accompanied by declines in the ability to learn associations between events, even when their relationship cannot be described. Previous functional magnetic resonance imaging (fMRI) studies have attributed these implicit associative learning (IAL) deficits to differential engagement of the hippocampus and basal ganglia in older relative to younger adults in early and late stages of the task, respectively. However, these task stages have been confounded with age group differences in learning performance that emerge later and to a lesser degree in older adults. To disentangle the effects of task stage from learning stage (i.e., when there is significant evidence of learning) on age group differences in the neural substrates of IAL, we acquired fMRI data while 28 younger (20.8 ± 2.3 years) and 22 older (73.6 ± 6.8 years) healthy adults completed the Triplets Learning Task, in which the location of two cues predicted the location of a target with high (HF) or low (LF) frequency. When matched for task stage, results revealed worse learning performance and increased IAL-related activity in the hippocampus during the early stage and in the globus pallidum during the late stage in older relative to younger adults. However, when matched for learning stage, there were no significant age group differences in learning performance or IAL-related activity. Thus, although learning emerges later for older adults, they are engaging similar brain regions as younger adults when learning the associations, suggesting that previous reports of age group differences reflect effects of age on task stage, but not learning stage.
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http://dx.doi.org/10.1016/j.bbr.2021.113570DOI Listing
September 2021

Age affects white matter microstructure and episodic memory across the older adult lifespan.

Neurobiol Aging 2021 10 4;106:282-291. Epub 2021 Jul 4.

Department of Psychology, University of California, Riverside, CA, USA.

Diffusion imaging studies have observed age-related degradation of white matter that contributes to cognitive deficits separately in younger-old (ages 65-89) and oldest-old (ages 90+) adults. But it remains unclear whether these age effects are magnified in advanced age groups, which may reflect disease-related pathology. Here, we tested whether age-related differences in white matter microstructure followed linear or nonlinear patterns across the entire older adult lifespan (65-98 years), these patterns were influenced by oldest-old adults at increased risk of dementia (cognitive impairment no dementia, CIND), and they explained age effects on episodic memory. Results revealed nonlinear microstructure declines across fiber classes (medial temporal, callosal, association, projection and/or thalamic) that were largest for medial temporal fibers. These patterns remained after excluding oldest-old participants with CIND, indicating that aging of white matter microstructure cannot solely be explained by pathology associated with early cognitive impairment. Moreover, finding that the effect of age on episodic memory was mediated by medial temporal fiber microstructure suggests it is essential for facilitating memory-related neural signals across the older adult lifespan.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.021DOI Listing
October 2021

Impact of Locus Coeruleus and Its Projections on Memory and Aging.

Brain Connect 2021 Sep 3. Epub 2021 Sep 3.

Center for Advanced Neuroimaging and University of California Riverside, Riverside, California, USA.

Locus coeruleus (LC) is the primary source of norepinephrine to the brain and its efferent projections innervate many brain regions, including the thalamus. The LC degrades with normal aging, but not much is known regarding whether its structural connectivity evolves with age or predicts aspects of cognition. Here, we use high-resolution diffusion tensor imaging-based tractography to examine structural connectivity between LC and the thalamus in younger and older adults. We found LC projections to be bundled in a fiber tract anatomically consistent with the central tegmental tract (CTT) and branched from this tract into the thalamus. The older cohort exhibited a significant reduction in mean and radial diffusivity within CTT, as compared with the young cohort. We also observed a significant correlation between CTT mean, axial, and radial diffusivities and memory performance (delayed recall) in the older adult cohort. These observations suggest that although LC projections degrade with age, the degree of degradation is associated with cognitive abilities in older adults.
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http://dx.doi.org/10.1089/brain.2020.0947DOI Listing
September 2021

Estimates of brain age for gray matter and white matter in younger and older adults: Insights into human intelligence.

Brain Res 2021 07 15;1763:147431. Epub 2021 Mar 15.

Center for BrainHealth®, School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas, TX, USA; Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.

Aging entails a multifaceted complex of changes in macro- and micro-structural properties of human brain gray matter (GM) and white matter (WM) tissues, as well as in intellectual abilities. To better capture tissue-specific brain aging, we combined volume and distribution properties of diffusivity indices to derive subject-specific age scores for each tissue. We compared age-related variance between younger and older adults for GM and WM age scores, and tested whether tissue-specific age scores could explain different effects of aging on fluid (Gf) and crystalized (Gc) intelligence in younger and older adults. Chronological age was strongly associated with GM (R = 0.73) and WM (R = 0.57) age scores. The GM age score accounted for significantly more variance in chronological age in younger relative to older adults (p < 0.001), whereas the WM age score accounted for significantly more variance in chronological age in older compared to younger adults (p < 0.025). Consistent with existing literature, younger adults outperformed older adults in Gf while older adults outperformed younger adults in Gc. The GM age score was negatively associated with Gf in younger adults (p < 0.02), whereas the WM age score was negatively associated with Gc in older adults (p < 0.02). Our results provide evidence for differences in the effects of age on GM and WM in younger versus older adults that may contribute to age-related differences in Gf and Gc.
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http://dx.doi.org/10.1016/j.brainres.2021.147431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428193PMC
July 2021

Implicit associative learning relates to basal ganglia gray matter microstructure in young and older adults.

Behav Brain Res 2021 01 2;397:112950. Epub 2020 Oct 2.

Department of Psychology, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA.

Older adults are impaired at implicit associative learning (IAL), or the learning of relationships between stimuli in the environment without conscious awareness. These age effects have been attributed to differential engagement of the basal ganglia (e.g. caudate, globus pallidus) and hippocampus throughout learning. However, no studies have examined gray matter diffusion relations with IAL, which can reveal microstructural properties that vary with age and contribute to learning. In this study, young (18-29 years) and older (65-87 years) adults completed the Triplet Learning Task, in which participants implicitly learn that the location of cues predict the target location on some trials (high frequency triplets). Diffusion imaging was also acquired and multicompartment diffusion metrics were calculated using neurite orientation dispersion and density imaging (NODDI). As expected, results revealed age deficits in IAL (smaller differences in performance to high versus low frequency triplets in the late learning stage) and age-related differences in basal ganglia and hippocampus free, hindered, and restricted diffusion. Significant correlations were seen between restricted caudate diffusion and early IAL and between hindered globus pallidus diffusion and late IAL, which were not moderated by age group. These findings indicate that individual differences in basal ganglia, but not hippocampal, gray matter microstructure contribute to learning, independent of age, further supporting basal ganglia involvement in IAL.
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http://dx.doi.org/10.1016/j.bbr.2020.112950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661017PMC
January 2021

Age- and memory- related differences in hippocampal gray matter integrity are better captured by NODDI compared to single-tensor diffusion imaging.

Neurobiol Aging 2020 12 12;96:12-21. Epub 2020 Aug 12.

Department of Neuroscience, University of California Riverside, Riverside, CA, USA; Department of Psychology, University of California Riverside, Riverside, CA, USA.

Single-tensor diffusion imaging (DTI) has traditionally been used to assess integrity of white matter. For example, we previously showed that integrity of limbic white matter tracts declines in healthy aging and relates to episodic memory performance. However, multi-compartment diffusion models may be more informative about microstructural properties of gray matter. The current study examined hippocampal gray matter integrity using both single-tensor and multi-compartment (neurite orientation dispersion and density imaging, NODDI) diffusion imaging. Younger (20-38 years) and older (59-84 years) adults also completed the Mnemonic Similarity Task to measure mnemonic discrimination performance. Results revealed age-related declines in both single-tensor (lower fractional anisotropy, higher mean diffusivity) and multi-compartment (higher restricted, hindered and free diffusion) measures of hippocampal gray matter integrity. As expected, NODDI measures (hindered and free diffusion) captured more age-related variance than DTI measures. Moreover, mnemonic discrimination of highly similar lure items in memory was related to hippocampal gray matter integrity in younger but not older adults. These findings support the notion that age-related differences in gray matter integrity are better captured by multi-compartment versus single-tensor diffusion models and show that the relationship between mnemonic discrimination and hippocampal gray matter integrity is moderated by age.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722017PMC
December 2020

Evidence of Neural Microstructure Abnormalities in Type I Chiari Malformation: Associations Among Fiber Tract Integrity, Pain, and Cognitive Dysfunction.

Pain Med 2020 10;21(10):2323-2335

Department of Neurosurgery, Johns Hopkins Medical Center, Baltimore, Maryland, USA.

Background: Previous case-control investigations of type I Chiari malformation (CMI) have reported cognitive deficits and microstructural white matter abnormalities, as measured by diffusion tensor imaging (DTI). CMI is also typically associated with pain, including occipital headache, but the relationship between pain symptoms and microstructure is not known.

Methods: Eighteen CMI patients and 18 adult age- and education-matched control participants underwent DTI, were tested using digit symbol coding and digit span tasks, and completed a self-report measure of chronic pain. Tissue microstructure indices were used to examine microstructural abnormalities in CMI as compared with healthy controls. Group differences in DTI parameters were then reassessed after controlling for self-reported pain. Finally, DTI parameters were correlated with performance on the digit symbol coding and digit span tasks within each group.

Results: CMI patients exhibited greater fractional anisotropy (FA), lower radial diffusivity, and lower mean diffusivity in multiple brain regions compared with controls in diffuse white matter regions. Group differences no longer existed after controlling for self-reported pain. A significant correlation between FA and the Repeatable Battery for the Assessment of Neuropsychological Status coding performance was observed for controls but not for the CMI group.

Conclusions: Diffuse microstructural abnormalities appear to be a feature of CMI, manifesting predominantly as greater FA and less diffusivity on DTI sequences. These white matter changes are associated with the subjective pain experience of CMI patients and may reflect reactivity to neuroinflammatory responses. However, this hypothesis will require further deliberate testing in future studies.
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http://dx.doi.org/10.1093/pm/pnaa094DOI Listing
October 2020

Neural substrates of mnemonic discrimination: A whole-brain fMRI investigation.

Brain Behav 2020 03 3;10(3):e01560. Epub 2020 Feb 3.

Department of Psychology, University of California, Riverside, California.

Introduction: A fundamental component of episodic memory is the ability to differentiate new and highly similar events from previously encountered events. Numerous functional magnetic resonance imaging (fMRI) studies have identified hippocampal involvement in this type of mnemonic discrimination (MD), but few studies have assessed MD-related activity in regions beyond the hippocampus. Therefore, the current fMRI study examined whole-brain activity in healthy young adults during successful discrimination of the test phase of the Mnemonic Similarity Task.

Method: In the study phase, participants made "indoor"/"outdoor" judgments to a series of objects. In the test phase, they made "old"/"new" judgments to a series of probe objects that were either repetitions from the memory set (targets), similar to objects in the memory set (lures), or novel. We assessed hippocampal and whole-brain activity consistent with MD using a step function to identify where activity to targets differed from activity to lures with varying degrees of similarity to targets (high, low), responding to them as if they were novel.

Results: Results revealed that the hippocampus and occipital cortex exhibited differential activity to repeated stimuli relative to even highly similar stimuli, but only hippocampal activity predicted discrimination performance.

Conclusions: These findings are consistent with the notion that successful MD is supported by the hippocampus, with auxiliary processes supported by cortex (e.g., perceptual discrimination).
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http://dx.doi.org/10.1002/brb3.1560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066353PMC
March 2020

Characterization of age-related microstructural changes in locus coeruleus and substantia nigra pars compacta.

Neurobiol Aging 2020 03 29;87:89-97. Epub 2019 Nov 29.

Center for Advanced Neuroimaging, University of California Riverside, Riverside, CA, USA; Department of Bioengineering, University of California Riverside, Riverside, CA, USA. Electronic address:

Locus coeruleus (LC) and substantia nigra pars compacta (SNpc) degrade with normal aging, but not much is known regarding how these changes manifest in MRI images, or whether these markers predict aspects of cognition. Here, we use high-resolution diffusion-weighted MRI to investigate microstructural and compositional changes in LC and SNpc in young and older adult cohorts, as well as their relationship with cognition. In LC, the older cohort exhibited a significant reduction in mean and radial diffusivity, but a significant increase in fractional anisotropy compared with the young cohort. We observed a significant correlation between the decrease in LC mean, axial, and radial diffusivities and measures examining cognition (Rey Auditory Verbal Learning Test delayed recall) in the older adult cohort. This observation suggests that LC is involved in retaining cognitive abilities. In addition, we observed that iron deposition in SNpc occurs early in life and continues during normal aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064384PMC
March 2020

Recognition Memory Dysfunction Relates to Hippocampal Subfield Volume: A Study of Cognitively Normal and Mildly Impaired Older Adults.

J Gerontol B Psychol Sci Soc Sci 2019 09;74(7):1132-1141

Department of Neurobiology and Behavior, University of California, Irvine.

Objectives: The current study examined recognition memory dysfunction and its neuroanatomical substrates in cognitively normal older adults and those diagnosed with mild cognitive impairment (MCI).

Methods: Participants completed the Mnemonic Similarity Task, which provides simultaneous measures of recognition memory and mnemonic discrimination. They also underwent structural neuroimaging to assess volume of medial temporal cortex and hippocampal subfields.

Results: As expected, individuals diagnosed with MCI had significantly worse recognition memory performance and reduced volume across medial temporal cortex and hippocampal subfields relative to cognitively normal older adults. After controlling for diagnostic group differences, however, recognition memory was significantly related to whole hippocampus volume, and to volume of the dentate gyrus/CA3 subfield in particular. Recognition memory was also related to mnemonic discrimination, a fundamental component of episodic memory that has previously been linked to dentate gyrus/CA3 structure and function.

Discussion: Results reveal that hippocampal subfield volume is sensitive to individual differences in recognition memory in older adults independent of clinical diagnosis. This supports the notion that episodic memory declines along a continuum within this age group, not just between diagnostic groups.
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http://dx.doi.org/10.1093/geronb/gbx181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748802PMC
September 2019

Age-related white matter integrity differences in oldest-old without dementia.

Neurobiol Aging 2017 08 26;56:108-114. Epub 2017 Apr 26.

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA; Department of Neurology, University of California, Irvine, CA, USA; Department of Epidemiology, University of California, Irvine, CA, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.

Aging is known to have deleterious effects on cerebral white matter, yet little is known about these white matter alterations in advanced age. In this study, 94 oldest-old adults without dementia (90-103 years) underwent diffusion tensor imaging to assess relationships between chronological age and multiple measures of integrity in 18 white matter regions across the brain. Results revealed significant age-related declines in integrity in regions previously identified as being sensitive to aging in younger-old adults (corpus callosum, fornix, cingulum, external capsule). For the corpus callosum, the effect of age on genu fractional anisotropy was significantly weaker than the relationship between age and splenium fractional anisotropy. Importantly, age-related declines in white matter integrity did not differ in cognitively normal and cognitively impaired not demented oldest-old, suggesting that they were not solely driven by cognitive dysfunction or preclinical dementia in this advanced age group. Instead, white matter in these regions appears to remain vulnerable to normal aging processes through the 10th decade of life.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647141PMC
August 2017

Cognitive Slowing in Gulf War Illness Predicts Executive Network Hyperconnectivity: Study in a Population-Representative Sample.

Neuroimage Clin 2016;12:535-541. Epub 2016 Aug 26.

School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.
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http://dx.doi.org/10.1016/j.nicl.2016.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030369PMC
August 2016

Visual Acuity does not Moderate Effect Sizes of Higher-Level Cognitive Tasks.

Exp Aging Res 2016 ;42(3):221-63

c Brain Imaging and Analysis Center , Duke University Medical Center , Durham , North Carolina , USA.

Background/study Context: Declining visual capacities in older adults have been posited as a driving force behind adult age differences in higher-order cognitive functions (e.g., the "common cause" hypothesis of Lindenberger & Baltes, 1994, Psychology and Aging, 9, 339-355). McGowan, Patterson, and Jordan (2013, Experimental Aging Research, 39, 70-79) also found that a surprisingly large number of published cognitive aging studies failed to include adequate measures of visual acuity. However, a recent meta-analysis of three studies (La Fleur and Salthouse, 2014, Psychonomic Bulletin & Review, 21, 1202-1208) failed to find evidence that visual acuity moderated or mediated age differences in higher-level cognitive processes. In order to provide a more extensive test of whether visual acuity moderates age differences in higher-level cognitive processes, we conducted a more extensive meta-analysis of topic.

Methods: Using results from 456 studies, we calculated effect sizes for the main effect of age across four cognitive domains (attention, executive function, memory, and perception/language) separately for five levels of visual acuity criteria (no criteria, undisclosed criteria, self-reported acuity, 20/80-20/31, and 20/30 or better).

Results: As expected, age had a significant effect on each cognitive domain. However, these age effects did not further differ as a function of visual acuity criteria.

Conclusion: The current meta-analytic, cross-sectional results suggest that visual acuity is not significantly related to age group differences in higher-level cognitive performance-thereby replicating La Fleur and Salthouse (2014). Further efforts are needed to determine whether other measures of visual functioning (e.g., contrast sensitivity, luminance) affect age differences in cognitive functioning.
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http://dx.doi.org/10.1080/0361073X.2016.1156964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902024PMC
January 2017

Mnemonic discrimination relates to perforant path integrity: An ultra-high resolution diffusion tensor imaging study.

Neurobiol Learn Mem 2016 Mar 4;129:107-12. Epub 2015 Jul 4.

Center for the Neurobiology of Learning and Memory and Department of Neurobiology and Behavior, University of California, Irvine, United States.

Pattern separation describes the orthogonalization of similar inputs into unique, non-overlapping representations. This computational process is thought to serve memory by reducing interference and to be mediated by the dentate gyrus of the hippocampus. Using ultra-high in-plane resolution diffusion tensor imaging (hrDTI) in older adults, we previously demonstrated that integrity of the perforant path, which provides input to the dentate gyrus from entorhinal cortex, was associated with mnemonic discrimination, a behavioral outcome designed to load on pattern separation. The current hrDTI study assessed the specificity of this perforant path integrity-mnemonic discrimination relationship relative to other cognitive constructs (identified using a factor analysis) and white matter tracts (hippocampal cingulum, fornix, corpus callosum) in 112 healthy adults (20-87 years). Results revealed age-related declines in integrity of the perforant path and other medial temporal lobe (MTL) tracts (hippocampal cingulum, fornix). Controlling for global effects of brain aging, perforant path integrity related only to the factor that captured mnemonic discrimination performance. Comparable integrity-mnemonic discrimination relationships were also observed for the hippocampal cingulum and fornix. Thus, whereas perforant path integrity specifically relates to mnemonic discrimination, mnemonic discrimination may be mediated by a broader MTL network.
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http://dx.doi.org/10.1016/j.nlm.2015.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699874PMC
March 2016

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness.

Clin Psychol Sci 2014 May;2(3):319-327

School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA ; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM.
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http://dx.doi.org/10.1177/2167702613506580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352953PMC
May 2014

Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan.

Cereb Cortex 2015 Sep 13;25(9):2988-99. Epub 2014 May 13.

Center for the Neurobiology of Learning and Memory, Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.

Accurate memory for discrete events is thought to rely on pattern separation to orthogonalize the representations of similar events. Previously, we reported that a behavioral index of pattern separation was correlated with activity in the hippocampus (dentate gyrus, CA3) and with integrity of the perforant path, which provides input to the hippocampus. If the hippocampus operates as part of a broader neural network, however, pattern separation would likely also relate to integrity of limbic tracts (fornix, cingulum bundle, and uncinate fasciculus) that connect the hippocampus to distributed brain regions. In this study, healthy adults (20-89 years) underwent diffusion tensor imaging and completed the Behavioral Pattern Separation Task-Object Version (BPS-O) and Rey Auditory Verbal Learning Test (RAVLT). After controlling for global effects of brain aging, exploratory skeleton-wise and targeted tractography analyses revealed that fornix integrity (fractional anisotropy, mean diffusivity, and radial diffusivity; but not mode) was significantly related to pattern separation (measured using BPS-O and RAVLT tasks), but not to recognition memory. These data suggest that hippocampal disconnection, via individual- and age-related differences in limbic tract integrity, contributes to pattern separation performance. Extending our earlier work, these results also support the notion that pattern separation relies on broad neural networks interconnecting the hippocampus.
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http://dx.doi.org/10.1093/cercor/bhu093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553719PMC
September 2015

Advances in functional neuroanatomy: a review of combined DTI and fMRI studies in healthy younger and older adults.

Neurosci Biobehav Rev 2013 Aug 26;37(7):1201-10. Epub 2013 Apr 26.

School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX 75235, USA.

Structural connections between brain regions are thought to influence neural processing within those regions. It follows that alterations to the quality of structural connections should influence the magnitude of neural activity. The quality of structural connections may also be expected to differentially influence activity in directly versus indirectly connected brain regions. To test these predictions, we reviewed studies that combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) in younger and older adults. By surveying studies that examined relationships between DTI measures of white matter integrity and fMRI measures of neural activity, we identified variables that accounted for variability in these relationships. Results revealed that relationships between white matter integrity and neural activity varied with (1) aging (i.e., positive and negative DTI-fMRI relationships in younger and older adults, respectively) and (2) spatial proximity of the neural measures (i.e., positive and negative DTI-fMRI relationships when neural measures were extracted from adjacent and non-adjacent brain regions, respectively). Together, the studies reviewed here provided support for both of our predictions.
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http://dx.doi.org/10.1016/j.neubiorev.2013.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691337PMC
August 2013

Isolating age-group differences in working memory load-related neural activity: assessing the contribution of working memory capacity using a partial-trial fMRI method.

Neuroimage 2013 May 26;72:20-32. Epub 2013 Jan 26.

School of Behavioral and Brain Sciences, University of Texas at Dallas, TX 75235, USA.

Previous studies examining age-group differences in working memory load-related neural activity have yielded mixed results. When present, age-group differences in working memory capacity are frequently proposed to underlie these neural effects. However, direct relationships between working memory capacity and working memory load-related activity have only been observed in younger adults. These relationships remain untested in healthy aging. Therefore, the present study examined patterns of working memory load-related activity in 22 younger and 20 older adults and assessed the contribution of working memory capacity to these load-related effects. Participants performed a partial-trial delayed response item recognition task during functional magnetic resonance imaging. In this task, participants encoded either 2 or 6 letters, maintained them during a delay, and then indicated whether a probe was present in the memory set. Behavioral results revealed faster and more accurate responses to load 2 versus 6, with age-group differences in this load condition effect for the accuracy measure. Neuroimaging results revealed one region (medial superior frontal gyrus) that showed age-group differences in load-related activity during the retrieval period, with less (greater) neural activity for the low versus high load condition in younger (older) adults. Furthermore, for older adults, load-related activity did not vary as a function of working memory capacity. Thus, working memory-related activity varies with healthy aging, but these patterns are not due solely to working memory capacity. Neurocognitive aging theories that feature capacity will need to account for these results.
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http://dx.doi.org/10.1016/j.neuroimage.2013.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602125PMC
May 2013

Diffusion tensor imaging of cerebral white matter integrity in cognitive aging.

Biochim Biophys Acta 2012 Mar 16;1822(3):386-400. Epub 2011 Aug 16.

Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, USA.

In this article we review recent research on diffusion tensor imaging (DTI) of white matter (WM) integrity and the implications for age-related differences in cognition. Neurobiological mechanisms defined from DTI analyses suggest that a primary dimension of age-related decline in WM is a decline in the structural integrity of myelin, particularly in brain regions that myelinate later developmentally. Research integrating behavioral measures with DTI indicates that WM integrity supports the communication among cortical networks, particularly those involving executive function, perceptual speed, and memory (i.e., fluid cognition). In the absence of significant disease, age shares a substantial portion of the variance associated with the relation between WM integrity and fluid cognition. Current data are consistent with one model in which age-related decline in WM integrity contributes to a decreased efficiency of communication among networks for fluid cognitive abilities. Neurocognitive disorders for which older adults are at risk, such as depression, further modulate the relation between WM and cognition, in ways that are not as yet entirely clear. Developments in DTI technology are providing a new insight into both the neurobiological mechanisms of aging WM and the potential contribution of DTI to understanding functional measures of brain activity. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
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http://dx.doi.org/10.1016/j.bbadis.2011.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241892PMC
March 2012

White matter tract integrity predicts visual search performance in young and older adults.

Neurobiol Aging 2012 Feb 12;33(2):433.e21-31. Epub 2011 Mar 12.

Center for Brain Health and School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX 75235, USA.

Functional imaging research has identified frontoparietal attention networks involved in visual search, with mixed evidence regarding whether different networks are engaged when the search target differs from distracters by a single (elementary) versus multiple (conjunction) features. Neural correlates of visual search, and their potential dissociation, were examined here using integrity of white matter connecting the frontoparietal networks. The effect of aging on these brain-behavior relationships was also of interest. Younger and older adults performed a visual search task and underwent diffusion tensor imaging (DTI) to reconstruct 2 frontoparietal (superior and inferior longitudinal fasciculus; SLF and ILF) and 2 midline (genu, splenium) white matter tracts. As expected, results revealed age-related declines in conjunction, but not elementary, search performance; and in ILF and genu tract integrity. Importantly, integrity of the superior longitudinal fasciculus, ILF, and genu tracts predicted search performance (conjunction and elementary), with no significant age group differences in these relationships. Thus, integrity of white matter tracts connecting frontoparietal attention networks contributes to search performance in younger and older adults.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117024PMC
February 2012

White matter integrity correlates of implicit sequence learning in healthy aging.

Neurobiol Aging 2011 Dec 7;32(12):2317.e1-12. Epub 2010 May 7.

Department of Psychology, Georgetown University, Washington, DC 20057, USA.

Previous research has identified subcortical (caudate, putamen, hippocampus) and cortical (dorsolateral prefrontal cortex, DLPFC; frontal motor areas) regions involved in implicit sequence learning, with mixed findings for whether these neural substrates differ with aging. The present study used diffusion tensor imaging (DTI) tractography to reconstruct white matter connections between the known gray matter substrates, and integrity of these tracts was related to learning in the alternating serial reaction time task (ASRT) in younger and healthy older adults. Both age groups showed significant sequence learning (better performance to predictable, frequently occurring vs. less frequent events), with an age-related difference in the late learning stage. Caudate-DLPFC and hippocampus-DLPFC tract integrity were related to ASRT sequence learning, and these brain-behavior relationships did not differ significantly between age groups. Additionally, age-related decreases in caudate-DLPFC tract integrity mediated age-related differences in late stage sequence learning. Together, these findings complement studies of gray matter substrates underlying implicit sequence learning, and provide evidence for similar white matter integrity-sequence learning relationships in younger and healthy older adults.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920348PMC
December 2011

Cerebral white matter integrity and cognitive aging: contributions from diffusion tensor imaging.

Neuropsychol Rev 2009 Dec 25;19(4):415-35. Epub 2009 Aug 25.

Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC 27710, USA.

The integrity of cerebral white matter is critical for efficient cognitive functioning, but little is known regarding the role of white matter integrity in age-related differences in cognition. Diffusion tensor imaging (DTI) measures the directional displacement of molecular water and as a result can characterize the properties of white matter that combine to restrict diffusivity in a spatially coherent manner. This review considers DTI studies of aging and their implications for understanding adult age differences in cognitive performance. Decline in white matter integrity contributes to a disconnection among distributed neural systems, with a consistent effect on perceptual speed and executive functioning. The relation between white matter integrity and cognition varies across brain regions, with some evidence suggesting that age-related effects exhibit an anterior-posterior gradient. With continued improvements in spatial resolution and integration with functional brain imaging, DTI holds considerable promise, both for theories of cognitive aging and for translational application.
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http://dx.doi.org/10.1007/s11065-009-9113-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787975PMC
December 2009

Age-related differences in multiple measures of white matter integrity: A diffusion tensor imaging study of healthy aging.

Hum Brain Mapp 2010 Mar;31(3):378-90

Department of Psychology, Georgetown University, Washington, District of Columbia 20057, USA.

Diffusion tensor imaging (DTI) measures diffusion of molecular water, which can be used to calculate indices of white matter integrity. Early DTI studies of aging primarily focused on two global measures of integrity; the average rate (mean diffusivity, MD) and orientation coherence (fractional anisotropy, FA) of diffusion. More recent studies have added measures of water movement parallel (axial diffusivity, AD) and perpendicular (radial diffusivity, RD) to the primary diffusion direction, which are thought to reflect the neural bases of age differences in diffusion (i.e., axonal shrinkage and demyelination, respectively). In this study, patterns of age differences in white matter integrity were assessed by comparing younger and healthy older adults on multiple measures of integrity (FA, AD, and RD). Results revealed two commonly reported patterns (Radial Increase Only and Radial/Axial Increase), and one relatively novel pattern (Radial Increase/Axial Decrease) that varied by brain region and may reflect differential aging of microstructural (e.g., degree of myelination) and macrostructural (e.g., coherence of fiber orientation) properties of white matter. In addition, larger age differences in FA in frontal white matter were consistent with the anterior-posterior gradient of age differences in white matter integrity. Together, these findings complement other recent studies in providing information about patterns of diffusivity that are characteristic of healthy aging.
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http://dx.doi.org/10.1002/hbm.20872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826569PMC
March 2010

An abbreviated implicit spatial context learning task that yields greater learning.

Behav Res Methods 2009 May;41(2):391-5

Georgetown University, Washington, DC 20057, USA.

The spatial contextual cuing task (SCCT) (Chun & Jiang, 1998) is an implicit learning task that appears to depend on the medial temporal lobes. This unusual combination has been of interest in functional imaging studies and research with clinical populations, where testing time is at a premium. However, the original version of the SCCT is time-consuming. In this study, 29 young adults (age range, 18-22 years) completed the SCCT, in which participants respond to the orientation of a target in arrays containing 11 distractors. Either 12 (original version) or 6 (abbreviated version) arrays repeated across the experiment, with the remaining novel arrays being generated randomly. Results revealed that the magnitude of learning (faster responses to repeated versus novel arrays) was larger when there were fewer repeated arrays, with no explicit awareness in most participants. Thus, the abbreviated version remained implicit, with the additional benefit of increasing the magnitude of learning.
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http://dx.doi.org/10.3758/BRM.41.2.391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669684PMC
May 2009

Two forms of implicit learning in young adults with dyslexia.

Ann N Y Acad Sci 2008 Dec;1145:184-98

Department of Psychology, Georgetown University, Washington, DC 20057, USA.

Implicit learning is thought to underlie the acquisition of many skills including reading. Previous research has shown that some forms of implicit learning are reduced in individuals with dyslexia (e.g., sequence learning), whereas other forms are spared (e.g., spatial context learning). However, it has been proposed that dyslexia-related motor dysfunction may have contributed to the implicit sequence learning deficits reported earlier. To assess implicit sequence learning in the absence of a motor sequence, 16 young adults diagnosed with dyslexia (20.6 +/- 1.5 years) and 18 healthy controls (20.8 +/- 2.0 years) completed a triplet frequency learning task (TRIP) that involved learning a sequential regularity in which the location of certain events followed a repeating pattern, but motor responses did not. Participants also completed the spatial contextual cueing task (SCCT), which involved learning a spatial regularity in which the location of distractors in some visual arrays predicted the target location. In addition, neuropsychological tests of real-word and pseudo-word reading were administered. TRIP task analyses revealed no between-group differences in pattern learning, but a positive correlation between individual learning scores and reading ability indicated that poor readers learned less well than did good readers. Thus, earlier reports of reduced implicit sequence learning in dyslexics cannot be entirely accounted for by motor sequencing deficits. No significant correlations or group differences in learning were found for SCCT. These findings offer additional evidence for a link between poor reading and impaired implicit sequence learning.
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http://dx.doi.org/10.1196/annals.1416.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691650PMC
December 2008

Age-related differences in implicit learning of subtle third-order sequential structure.

J Gerontol B Psychol Sci Soc Sci 2007 Mar;62(2):P98-103

Department of Psychology, Georgetown University, 301 N. White Gravenor Building, Washington, DC 20057, USA.

Age-related implicit learning deficits increase with sequence complexity, suggesting there might be limits to the level of structure that older adults can learn implicitly. To test for such limits, we had 12 younger and 12 older adults complete an alternating serial reaction time task containing subtle structure in which every third trial follows a repeating sequence and intervening trials are determined randomly. Results revealed significant age deficits in learning. However, both groups did learn the subtle regularity without explicit awareness, indicating that older adults remain sensitive to highly complex sequential regularities in their environment, albeit to a lesser degree than younger adults.
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http://dx.doi.org/10.1093/geronb/62.2.p98DOI Listing
March 2007

Memory evaluation in mild cognitive impairment using recall and recognition tests.

J Clin Exp Neuropsychol 2006 Nov;28(8):1408-22

Department of Neurology, University of California, Irvine, USA.

Amnestic mild cognitive impairment (MCI) is a selective episodic memory deficit that often indicates early Alzheimer's disease. Episodic memory function in MCI is typically defined by deficits in free recall, but can also be tested using recognition procedures. To assess both recall and recognition in MCI, MCI (n = 21) and older comparison (n = 30) groups completed the USC-Repeatable Episodic Memory Test. Subjects memorized two verbally presented 15-item lists. One list was used for three free recall trials, immediately followed by yes/no recognition. The second list was used for three-alternative forced-choice recognition. Relative to the comparison group, MCI had significantly fewer hits and more false alarms in yes/no recognition, and were less accurate in forced-choice recognition. Signal detection analysis showed that group differences were not due to response bias. Discriminant function analysis showed that yes/no recognition was a better predictor of group membership than free recall or forced-choice measures. MCI subjects recalled fewer items than comparison subjects, with no group differences in repetitions, intrusions, serial position effects, or measures of recall strategy (subjective organization, recall consistency). Performance deficits on free recall and recognition in MCI suggest a combination of both tests may be useful for defining episodic memory impairment associated with MCI and early Alzheimer's disease.
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http://dx.doi.org/10.1080/13803390500409583DOI Listing
November 2006

Age-related differences in auditory event-related potentials during a cued attention task.

Clin Neurophysiol 2004 Nov;115(11):2602-15

Department of Neurology, Institute for Brain Aging and Dementia, University of California, 154 Med Surge I, Irvine, CA 92697, USA.

Objective: To determine if aging is associated with differences in attentional regulation using behavioral and event-related potential (ERP) measures.

Methods: Younger (n=13;M=20 years) and older (n=12;M=76 years) subjects performed an auditory cued attention task. Verbal cues correctly (valid) or incorrectly (invalid) predicted the ear receiving a target tone 1.5 s later, or were uninformative (neutral). Targets were either 'high' (2000 Hz) or 'low' (1000 Hz) pitch monaural tones. Subjects pressed one of 4 buttons to indicate target ear and pitch. ERPs following cues and targets (P50, N100, P200, slow waves), and negative slow potentials (CNV) between cues and targets were assessed.

Results: Cue information had significant effects on reaction time for both groups (validvalid) but not older subjects. Target slow waves were also affected by cue information (invalid>valid), and the difference was larger and lasted longer in older subjects. Slow waves following cues were significantly larger in older subjects, but the subsequent CNV amplitudes were comparable among groups.

Conclusions: When performing a cued attention task, age differences are present in transient ERPs following cues and targets.

Significance: Age differences in ERPs associated with attentional regulation support the hypothesis that attentional changes contribute to cognitive aging.
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http://dx.doi.org/10.1016/j.clinph.2004.06.011DOI Listing
November 2004
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