Biomedical subjects

Joseph Flynn

Publications and source records attributed to Joseph Flynn.

12 recordsLinked to original sources

PubMed2006

Distinct spatial patterns of brain activity associated with memory storage and search.

The time it takes for a human participant to decide whether a given stimulus is an element of a remembered set increases approximately linearly with the number of elements in the set. Here we tested for and detected a spatial pattern of brain activity whose magnitude of expression during this memory search process correlates with set size. We then tested the idea that memory search simply involves a re-activation of neurons involved in remembering the set by statistically comparing the patterns of brain activity corresponding to memory search and set size dependent working memory maintenance. These patterns were significantly different, suggesting that memory search and working memory maintenance are mediated by distinct neural mechanisms.

Adult↗

PubMed2006

Age-related changes in brain activation during a delayed item recognition task.

To test competing models of age-related changes in brain functioning (capacity limitation, neural efficiency, compensatory reorganization, and dedifferentiation), young (n=40; mean age=25.1 years) and elderly (n=18; mean age=74.4 years) subjects performed a delayed item recognition task for visually presented letters with three set sizes (1, 3, or 6 letters) while being scanned with BOLD fMRI. Spatial patterns of brain activity corresponding to either the slope or y-intercept of fMRI signal with respect to set size during memory set encoding, retention delay, or probe stimulus presentation trial phases were compared between elder and young populations. Age effects on fMRI slope during encoding and on fMRI y-intercept during retention delay were consistent with neural inefficiency; age effects on fMRI slope during retention delay were consistent with dedifferentiation. None of the other fMRI signal components showed any detectable age effects. These results suggest that, even within the same task, the nature of brain activation changes with aging can vary based on cognitive process engaged.

Adult↗

PubMed2006

Structural MRI covariance patterns associated with normal aging and neuropsychological functioning.

Structural magnetic resonance imaging (MRI) studies have shown dramatic age-associated changes in grey and white matter volume, but typically use univariate analyses that do not explicitly test the interrelationship among brain regions. The current study used a multivariate approach to identify covariance patterns of grey and white matter tissue density to distinguish older from younger adults. A second aim was to examine whether the expression of the age-associated covariance topographies is related to performance on cognitive tests affected by normal aging. Eighty-four young (mean age=24.0) and 29 older (mean age=73.1) participants were scanned with a 1.5T MRI machine and assessed with a cognitive battery. Images were spatially normalized and segmented to produce grey and white matter density maps. A multivariate technique, based on the subprofile scaling model, was used to capture sources of between- and within-group variation to produce a linear combination of principal components that represented a "pattern" or "network" that best discriminated between the two age groups. Univariate analyses were also conducted with statistical parametric maps. Grey and white matter covariance patterns were identified that reliably discriminated between the groups with greater than 0.90 sensitivity and specificity. The identified patterns were similar for the univariate and multivariate techniques, and involved widespread regions of the cortex and subcortex. Age and the expression of both patterns were significantly associated with performance on tests of attention, language, memory, and executive functioning. The results suggest that identifiable networks of grey and white matter regions systematically decline with age and that pattern expression is linked to age-related cognitive decline.

Adult↗

PubMed2005

Brain networks associated with cognitive reserve in healthy young and old adults.

In order to understand the brain networks that mediate cognitive reserve, we explored the relationship between subjects' network expression during the performance of a memory test and an index of cognitive reserve. Using H2(15)O positron emission tomography, we imaged 17 healthy older subjects and 20 young adults while they performed a serial recognition memory task for nonsense shapes under two conditions: low demand, with a unique shape presented in each study trial; and titrated demand, with a study list size adjusted so that each subject recognized shapes at 75% accuracy. A factor score that summarized years of education, and scores on the NART and the WAIS-R Vocabulary subtest was used as an index of cognitive reserve. The scaled subprofile model was used to identify a set of functionally connected regions (or topography) that changed in expression across the two task conditions and was differentially expressed by the young and elderly subjects. The regions most active in this topography consisted of right hippocampus, posterior insula, thalamus, and right and left operculum; we found concomitant deactivation in right lingual gyrus, inferior parietal lobe and association cortex, left posterior cingulate, and right and left calcarine cortex. Young subjects with higher cognitive reserve showed increased expression of the topography across the two task conditions. Because this topography, which is responsive to increased task demands, was differentially expressed as a function of reserve level, it may represent a neural manifestation of innate or acquired reserve. In contrast, older subjects with higher cognitive reserve showed decreased expression of the topography across tasks. This suggests some functional reorganization of the network used by the young subjects. Thus, for the old subjects this topography may represent an altered, compensatory network that is used to maintain function in the face of age-related physiological changes.

Adult↗

PubMed2004

Positive evidence against human hippocampal involvement in working memory maintenance of familiar stimuli.

Subjects (n = 40) performed a delayed item recognition task for visually presented letters with three set sizes (1, 3 or 6 letters). Accuracy was close to ceiling at all set sizes, so we took set size as a proxy for WM load (i.e. the amount of information being maintained in WM). Functional magnetic resonance imaging (fMRI) signal associated with the delay period increased in a nearly linear fashion with WM load in the left inferior frontal gyrus/anterior insula (possibly Broca's area, BA 44/45), right anterior insula, bilateral caudate, bilateral precentral gyrus (BA 6), bilateral middle frontal gyrus (BA 9/46), bilateral inferior parietal lobule (with foci in both BA 39 and 40), left superior parietal lobule (BA 7), medial frontal gyrus (BA 6), anterior cingulate gyrus (BA 32) and bilateral superior frontal gyrus (BA 8). These results lend support to the idea that at least some of the cortical mechanisms of WM maintenance, potentially rehearsal, exhibit a scaling with WM load. In contrast, the delay-related fMRI signal in hippocampus followed an inverted U-shape, being greatest during the intermediate level of WM load, with relatively lower values at the lowest and highest levels of WM load. This pattern of delay-related fMRI activity, orthogonal to WM load, is seemingly not consonant with a role for hippocampus in WM maintenance of phonologically codable stimuli. This finding could possibly be related more to the general familiarity of the letter stimuli than their phonological codability per se.

Adult↗

PubMed2004

Identification and differential vulnerability of a neural network in sleep deprivation.

The study aimed to identify task-related brain activation networks whose change in expression exhibits subject differences as a function of differential susceptibility to sleep deprivation. Brain activity during a non-verbal recognition memory task was investigated in an event-related functional MRI paradigm both prior to and after 48 h of sleep deprivation. Nineteen healthy subjects participated. Regional covariance analysis was applied to data. An activation network pattern was identified whose expression decreased from pre- to post-sleep deprivation in 15 out 19 subjects (P < 0.05). Differential decrease in expression correlated with worsening performance in recognition accuracy (P < 0.05). Sites of de-activation were found in the posterior cerebellum, right fusiform gyrus and precuneus, and left lingual and inferior temporal gyri; increased activation was found in the bilateral insula, claustrum and right putamen. A network whose expression decreased after sleep deprivation and correlated with memory performance was identified. We conclude that this activation network plays a role in cognitive function during sleep deprivation.

Adaptation, Physiological↗

PubMed2004

Cognitive reserve-mediated modulation of positron emission tomographic activations during memory tasks in Alzheimer disease.

BACKGROUND: Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathological abnormalities so that he or she remains free of symptoms. Epidemiological data and evidence from positron emission tomography suggest that it may be mediated through education or IQ. OBJECTIVE: To investigate CR-mediated differential brain activation in Alzheimer disease (AD) subjects compared with healthy elderly persons. PARTICIPANTS: Using radioactive water positron emission tomography, we scanned 12 AD patients and 17 healthy elderly persons while performing a serial recognition memory task for nonverbalizable shapes under 2 conditions: low demand, in which one shape was presented in each study trial, and titrated demand, in which the study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. Positron emission tomographic scan acquisition included the encoding and recognition phases. A CR factor score that summarized years of education, National Adult Reading Test estimated IQ, and Wechsler Adult Intelligence Scale-Revised vocabulary subtest score (explaining 71% of the total variance) was used as an index of CR. Voxel-wise, multiple regression analyses were performed with the "activation" difference (titrated demand-low demand) as the dependent variables and the CR factor score as the independent one. Brain regions where regression slopes differed between the 2 groups were identified. RESULTS: The slopes were significantly more positive for the AD patients in the left precentral gyrus and in the left hippocampus and significantly more negative in the right fusiform, right middle occipital, left superior occipital, and left middle temporal gyri. CONCLUSION: Brain regions where systematic relationships (slopes) between subjects' education-IQ and brain activation differ as a function of disease status may mediate the differential ability to cope with (ie, delay or modify) clinical manifestations of AD.

Aged↗

PubMed2003

Association of life activities with cerebral blood flow in Alzheimer disease: implications for the cognitive reserve hypothesis.

BACKGROUND: Regional cerebral blood flow (CBF), a good indirect index of cerebral pathologic changes in Alzheimer disease (AD), is more severely reduced in patients with higher educational attainment and IQ when controlling for clinical severity. This has been interpreted as suggesting that cognitive reserve allows these patients to cope better with the pathologic changes in AD. OBJECTIVE: To evaluate whether premorbid engagement in various activities may also provide cognitive reserve. DESIGN: We evaluated intellectual, social, and physical activities in 9 patients with early AD and 16 healthy elderly controls who underwent brain H(2)(15)O positron emission tomography. In voxelwise multiple regression analyses that controlled for age and clinical severity, we investigated the association between education, estimated premorbid IQ, and activities, and CBF. RESULTS: In accordance with previous findings, we replicated an inverse association between education and CBF and IQ and CBF in patients with AD. In addition, there was a negative correlation between previous reported activity score and CBF in patients with AD. When both education and IQ were added as covariates in the same model, a higher activity score was still associated with more prominent CBF deficits. No significant associations were detected in the controls. CONCLUSIONS: At any given level of clinical disease severity, there is a greater degree of brain pathologic involvement in patients with AD who have more engagement in activities, even when education and IQ are taken into account. This may suggest that interindividual differences in lifestyle may affect cognitive reserve by partially mediating the relationship between brain damage and the clinical manifestation of AD.

Aged↗

PubMed2003

Relation of cognitive reserve and task performance to expression of regional covariance networks in an event-related fMRI study of nonverbal memory.

Cognitive reserve (CR) has been established as a mechanism that can explain individual differences in the clinical manifestation of neural changes associated with aging or neurodegenerative diseases. CR may represent individual differences in how tasks are processed (i.e., differences in the component processes), or in the underlying neural circuitry (of the component processes). CR may be a function of innate differences or differential life experiences. To investigate to what extent CR can account for individual differences in brain activation and task performance, we used fMRI to image healthy young individuals while performing a nonverbal memory task. We used IQ estimates as a proxy for CR. During both study and test phase of the task, we identified regional covariance patterns whose change in subject expression across two task conditions correlated with performance and CR. Common brain regions in both activation patterns were suggestive of a brain network previously found to underlie overt and covert shifts of spatial attention. After partialing out the influence of task performance variables, this network still showed an association with the CR, i.e., there were reserve-related physiological differences that presumably would persist were there no subject differences in task performance. This suggests that this network may represent a neural correlate of CR.

Adult↗

PubMed2003

Cognitive reserve modulates functional brain responses during memory tasks: a PET study in healthy young and elderly subjects.

Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathology so that he remains free of symptomatology. Epidemiological evidence and in vivo neurometabolic data suggest that CR may be mediated through education or IQ. The goal of this study was to investigate CR-mediated differential brain activation in 17 healthy young adults and 19 healthy elders. Using nonquantitative H(2)(15)O PET scanning, we assessed relative regional cerebral blood flow while subjects performed a serial recognition memory task under two conditions: nonmemory control (NMC), in which one shape was presented in each study trial; and titrated demand (TD), in which study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. A factor score that summarized years of education and scores on two IQ indices was used as an index of CR. Voxel-wise, multiple regression analyses were performed with TD minus NMC difference PET counts as the dependent variable and the CR variable as the independent variable of interest. We identified brain regions where regression slopes were different from zero in each separate group, and also those where regression slopes differed between the two age groups. The slopes were significantly more positive in the young in the right inferior temporal gyrus, right postcentral gyrus, and cingulate, while the elderly had a significantly more positive slope in left cuneus. Brain regions where systematic relationships between CR and brain activation differ as a function of aging are loci where compensation for aging has occurred. They may mediate differential ability to cope with brain changes in aging.

Adult↗

PubMed2003

Exploring the neural basis of cognitive reserve.

There is epidemiologic and imaging evidence for the presence of cognitive reserve, but the neurophysiologic substrate of CR has not been established. In order to test the hypothesis that CR is related to aspects of neural processing, we used fMRI to image 19 healthy young adults while they performed a nonverbal recognition test. There were two task conditions. A low demand condition required encoding and recognition of single items and a titrated demand condition required the subject to encode and then recognize a larger list of items, with the study list size for each subject adjusted prior to scanning such that recognition accuracy was 75%. We hypothesized that individual differences in cognitive reserve are related to changes in neural activity as subjects moved from the low to the titrated demand task. To test this, we examined the correlation between subjects' fMRI activation and NART scores. This analysis was implemented voxel-wise in a whole brain fMRI dataset. During both the study and test phases of the recognition memory task we noted areas where, across subjects, there were significant positive and negative correlations between change in activation from low to titrated demand and the NART score. These correlations support our hypothesis that neural processing differs across individuals as a function of CR. This differential processing may help explain individual differences in capacity, and may underlie reserve against age-related or other pathologic changes.

Adaptation, Physiological↗

PubMedDate not supplied

Altered PET functional brain responses in cognitively intact elderly persons at risk for Alzheimer disease (carriers of the epsilon4 allele).

OBJECTIVE: Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. METHODS: Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. RESULTS: Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. CONCLUSION: Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

Aged↗