Brian C. Rakitin

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.

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.

Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency- and time-dependent effects.

Although improvements in performance due to TMS have been demonstrated with some cognitive tasks, performance improvement has not previously been demonstrated with working memory tasks. In the present study, a delayed match-to-sample task was used in which repetitive TMS (rTMS) at 1, 5, or 20 Hz was applied to either left dorsolateral prefrontal or midline parietal cortex during the retention (delay) phase of the task. Only 5 Hz stimulation to the parietal site resulted in a significant decrease in reaction time (RT) without a corresponding decrease in accuracy. This finding was replicated in a second experiment, in which 5 Hz rTMS at the parietal site was applied during the retention phase or during presentation of the recognition probe. Significant speeding of RT occurred in the retention phase but not the probe phase. This finding suggests that TMS may improve working memory performance, in a manner that is specific to the timing of stimulation relative to performance of the task, and to stimulation frequency.

Predicting Age-Related Dual-Task Effects With Individual Differences on Neuropsychological Tests.

This study examined the relation of dual-task performance to individual differences on neuropsychological tests. Neuropsychological test scores from 16 young and 16 older participants were simultaneously submitted to a factor analysis that yielded 2 factors (Attention/Executive and Memory) that differed by age and 2 (Motor Speed and Cognitive Status) that did not. Regression analyses revealed that these factors were significant predictors of performance on a delayed visual recognition task, but the relationship varied as a function of task condition. The Memory and Motor Speed factors were the strongest predictors of single-task performance, but the Attention/Executive factor was the most important predictor of dual-task performance. The authors conclude that compromised central executive may underlie age-related decline in dual-task performance.

Age-related differences in executive control of working memory

In two experiments, we used dual-task methodology to assess the effect of aging on executive control of working memory. We hypothesized that (1) age-related dual-task costs would be observed even when individual tasks represent different perceptual modalities; (2) age would modulate the effect of increased temporal overlap on dual-task performance; and (3) the vulnerability of specific memory mechanisms to interference would be age related. We found that aging was associated with disproportionate dual-task costs that increased when extending the overlap between individual tasks. The effect of interference with encoding, and arguably output, was disproportionately larger in old than in young individuals. Ensuring that individual tasks represent different perceptual modalities is important but insufficient when using dual-task methodology to assess the effect of aging on executive function. The degree of temporal overlap between individual tasks and the sensitivity of specific memory operations to interference should be considered, as well.

Remediation of Sleep-Deprivation–Induced Working Memory Impairment with fMRI-Guided Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) was applied to test the role of selected cortical regions in remediating sleep-deprivation-induced deficits in visual working memory (WM) performance. Three rTMS targets were chosen using a functional magnetic resonance imaging (fMRI)-identified network associated with sleep-deprivation-induced WM performance impairment: 2 regions from the network (upper left middle occipital gyrus and midline parietal cortex) and 1 nonnetwork region (lower left middle occipital gyrus). Fifteen participants underwent total sleep deprivation for 48 h. rTMS was applied at 5 Hz during a WM task in a within-subject sham-controlled design. The rTMS to the upper-middle occipital site resulted in a reduction of the sleep-induced reaction time deficit without a corresponding decrease in accuracy, whereas stimulation at the other sites did not. Each subject had undergone fMRI scanning while performing the task both pre- and postsleep deprivation, and the degree to which each individual activated the fMRI network was measured. The degree of performance enhancement with upper-middle occipital rTMS correlated with the degree to which each individual failed to sustain network activation. No effects were found in a subset of participants who performed the same rTMS procedure after recovering from sleep deprivation, suggesting that the performance enhancements seen following sleep deprivation were state dependent.

Supporting performance in the face of age-related neural changes: testing mechanistic roles of cognitive reserve

Age impacts multiple neural measures and these changes do not always directly translate into alterations in clinical and cognitive measures. This partial protection from the deleterious effects of age in some individuals is referred to as cognitive reserve (CR) and although linked to variations in intelligence and life experiences, its mechanism is still unclear. Within the framework of a theoretical model we tested two potential mechanistic roles of CR to maintain task performance, neural reserve and neural compensation, in young and older adults using functional and structural MRI. Neural reserve refers to increased efficiency and/or capacity of existing functional neural resources. Neural compensation refers to the increased ability to recruit new, additional functional resources. Using structural and functional measures and task performance, the roles of CR were tested using path analysis. Results supported both mechanistic theories of CR and the use of our general theoretical model.

Self-report of cognitive impairment and Mini-Mental State Examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.

The impact of age-related changes on working memory functional activity.

This work investigated associations of age-related brain atrophy and functional neural networks identified using multivariate analyses of BOLD fMRI data in young and elder participants (young, N = 37; mean age = 25; elders, N = 15; mean age = 74). Two networks were involved in retaining increasing loads of verbal information in working memory. Network utilizations were used to test associations between function and indices of grey matter volume changes using voxel based morphometry. Global changes in brain volume were not associated with the secondary network. Lower regional grey matter volume in the left pre-central gyrus within the primary network was associated with increased secondary network utilization independent of age group. Decreased regional grey matter volume was associated with increased age only in the elders. Increased secondary network expression was associated with increased slope of reaction times across memory load, in the elders. These results support the theory of neural compensation, that elder participants recruit additional neural resources to maintain task performance in the face of age-related decreases in regional grey matter volume.

Task difficulty modulates young - old differences in network expression

The extent of task-related fMRI activation can vary as a function of task difficulty. Also the efficiency or capacity of the brain networks underlying task performance can change with aging. We asked whether the expression of a network underlying task performance would differ as a function of task demand in old and young individuals. 26 younger and 23 older healthy adults performed a delayed item recognition task that used the response signal method to parametrically manipulate the extrinsic difficulty of the task by imposing five different deadlines for recognition response. Both age groups showed a speed-accuracy trade-off, but the younger group achieved greater discriminability at the longer deadlines. We identified a spatial pattern of fMRI activation during the probe phase whose expression increased as the response deadline shortened and the task became more difficult. This pattern was expressed to a greater degree by the old group at the long deadlines, when the task was easiest. By contrast, this pattern was expressed to a greater degree by the younger group at the short deadlines, when the task was hardest. This suggests reduced efficiency and capacity of this network in older subjects. These findings suggest that neuroimaging studies comparing task-related activation across groups with different cognitive abilities must be interpreted in light of the relative difficulty of the task for each group.