Nicole D. Anderson

Aging Gracefully: Compensatory Brain Activity in High-Performing Older Adults

Whereas some older adults show significant cognitive deficits, others perform as well as young adults. We investigated the neural basis of these different aging patterns using positron emission tomography (PET). In PET and functional MRI (fMRI) studies, prefrontal cortex (PFC) activity tends to be less asymmetric in older than in younger adults (Hemispheric Asymmetry Reduction in Old Adults or HAROLD). This change may help counteract age-related neurocognitive decline (compensation hypothesis) or it may reflect an age-related difficulty in recruiting specialized neural mechanisms (dedifferentiation hypothesis). To compare these two hypotheses, we measured PFC activity in younger adults, low-performing older adults, and high-performing older adults during recall and source memory of recently studied words. Compared to recall, source memory was associated with right PFC activations in younger adults. Low-performing older adults recruited similar right PFC regions as young adults, but high-performing older adults engaged PFC regions bilaterally. Thus, consistent with the compensation hypothesis and inconsistent with the dedifferentiation hypothesis, a hemispheric asymmetry reduction was found in high-performing but not in low-performing older adults. The results suggest that low-performing older adults recruited a similar network as young adults but used it inefficiently, whereas high-performing older adults counteracted age-related neural decline through a plastic reorganization of neurocognitive networks.

The effects of divided attention on encoding and retrieval processes in human memory.

The authors examined the effects of divided attention (DA) at encoding and retrieval in free recall, cued recall, and recognition memory in 4 experiments. Lists of words or word pairs were presented auditorily and recalled orally; the secondary task was a visual continuous reaction-time (RT) task with manual responses. At encoding, DA was associated with large reductions in memory performance, but small increases in RT; trade-offs between memory and RT were under conscious control. In contrast, DA at retrieval resulted in small or no reductions in memory, but in comparatively larger increases in RT, especially in free recall. Memory performance was sensitive to changes in task emphasis at encoding but not at retrieval. The results are discussed in terms of controlled and automatic processes and speculatively linked to underlying neuropsychological mechanisms.

The attentional demands of encoding and retrieval in younger and older adults: 1. Evidence from divided attention costs

Four studies examined the effects of divided attention in younger and older adults. Attention was divided at encoding or retrieval in free recall (Experiment 1), cued recall (Experiments 2 and 3), and recognition (Experiment 4). Dividing attention at encoding disrupted memory performance equally for the two age groups; by contrast, for both age groups, dividing attention at retrieval had little or no effect on memory performance. Secondary task reaction times (RTs) were slowed to a greater extent for the older adults than for the younger adults, especially at retrieval. Age-related differences in RT costs at retrieval were largest in free recall, smaller in cued recall, and smallest in recognition. These results provide evidence for an age-related increase in the attentional demands of encoding and retrieval.

Intensive Methotrexate and Cytarabine Followed by High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Patients With Newly Diagnosed Primary CNS Lymphoma: An Intent-to-Treat Analysis

PURPOSE To assess the safety and efficacy of intensive methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma (PCNSL). PATIENTS AND METHODS Twenty-eight patients received induction chemotherapy using high-dose systemic methotrexate (3.5 g/m2) and cytarabine (3 g/m2 daily for 2 days). Fourteen patients with chemosensitive disease evident on neuroimaging then received high-dose therapy using carmustine, etoposide, cytarabine, and melphalan with autologous stem-cell rescue. RESULTS The objective response rate to the induction-phase chemotherapy was 57%, and median overall survival is not yet assessable, with a median follow-up time of 28 months. The overall median event-free survival time is 5.6 months for all patients and 9.3 months for 14 patients who underwent transplantation. Six of these 14 patients (43%) remained disease-free at last follow-up. Treatment was well tolerated; there was one transplantation-related death. Prospective neuropsychologic evaluations have revealed no evidence of treatment-related neurotoxicity. CONCLUSION This treatment approach is feasible in patients with newly diagnosed PCNSL without evidence of significant related neurotoxicity. Although the transplantation results are similar to those achieved in patients with aggressive or poor-prognosis systemic lymphoma, the low response rate to induction chemotherapy and the significant number of patients who experienced relapse soon after HDT suggest that more aggressive induction chemotherapy may be warranted.

A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia.

Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an N-ethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.

Lateralization of Prefrontal Activity during Episodic Memory Retrieval: Evidence for the Production-Monitoring Hypothesis

We propose a new hypothesis concerning the lateralization of prefrontal cortex (PFC) activity during verbal episodic memory retrieval. The hypothesis states that the left PFC is differentially more involved in semantically guided information production than is the right PFC, and that the right PFC is differentially more involved in monitoring and verification than is the left PFC. This production-monitoring hypothesis differs from the existing systematic-heuristic hypothesis, which proposes that the left PFC is primarily involved in systematic retrieval operations, and the right PFC in heuristic retrieval operations. To compare the two hypotheses, we measured PFC activity using positron emission tomography (PET) during the performance of four episodic retrieval tasks: stem cued recall, associative cued recall, context recognition (source memory), and item recognition. Recall tasks emphasized production processes, whereas recognition tasks emphasized monitoring processes. Stem cued recall and context-recognition tasks underscored systematic operations, whereas associative cued recall and item-recognition tasks underscored heuristic operations. Consistent with the production-monitoring hypothesis, the left PFC was more activated for recall than for recognition tasks and the right PFC was more activated for recognition than for recall tasks. Inconsistent with the systematic-heuristic hypothesis, the left PFC was more activated for heuristic than for systematic tasks and the right PFC showed the converse result. Additionally, the study yielded activation differences outside the PFC. In agreement with a previous recall/recognition PET study, anterior cingulate, cerebellar, and striatal regions were more activated for recall than for recognition tasks, and the converse occurred for posterior parietal regions. A right medial temporal lobe region was more activated for stem cued recall and context recognition than for associative cued recall and item recognition, possibly reflecting perceptual integration. In sum, the results provide evidence for the production-monitoring hypothesis and clarify the role of different brain regions typically activated in PET and functional magnetic resonance imaging (fMRI) studies of episodic retrieval.

The Effect of Divided Attention on Encoding and Retrieval in Episodic Memory Revealed by Positron Emission Tomography

The effects of divided attention (DA) on episodic memory encoding and retrieval were investigated in 12 normal young subjects by positron emission tomography (PET). Cerebral blood flow was measured while subjects were concurrently performing a memory task (encoding and retrieval of visually presented word pairs) and an auditory tone-discrimination task. The PET data were analyzed using multivariate Partial Least Squares (PLS), and the results revealed three sets of neural correlates related to specific task contrasts. Brain activity, relatively greater under conditions of full attention (FA) than DA, was identified in the occipital-temporal, medial, and ventral-frontal areas, whereas areas showing relatively more activity under DA than FA were found in the cerebellum, temporo-parietal, left anterior-cingulate gyrus, and bilateral dorsolateral-prefrontal areas. Regions more active during encoding than during retrieval were located in the hippocampus, temporal and the prefrontal cortex of the left hemisphere, and regions more active during retrieval than during encoding included areas in the medial and right-prefrontal cortex, basal ganglia, thalamus, and cuneus. DA at encoding was associated with specific decreases in rCBF in the left-prefrontal areas, whereas DA at retrieval was associated with decreased rCBF in a relatively small region in the right-prefrontal cortex. These different patterns of activity are related to the behavioral results, which showed a substantial decrease in memory performance when the DA task was performed at encoding, but no change in memory levels when the DA task was performed at retrieval.

Changing everyday memory behaviour in amnestic mild cognitive impairment: A randomised controlled trial

One of the defining differences between mild cognitive impairment (MCI) and dementia is the degree of independence in everyday activities. Effecting memory-related behavioural change in MCI could help maintain daily function and prolong the time before onset of dependency. However, it is well known that changing previously well-established behaviours is difficult to achieve. We conducted a randomised controlled trial to evaluate the effectiveness of a multidisciplinary group-based intervention programme in changing everyday memory behaviour in individuals with amnestic MCI. The intervention provided evidenced-based memory training and lifestyle education to optimise memory behaviour. Fifty-four participants were randomly assigned to treatment or waitlist-control conditions. Consistent with our primary goal, treatment participants showed an increase in memory-strategy knowledge and use from pre-test to immediate post-test, and these gains were maintained at three-month post-test relative to waitlist controls. There were no group differences in memory beliefs or on laboratory tests of objective memory performance. The increase in memory-strategy knowledge and use was associated with the degree of participation in the programme. Individuals with MCI, therefore, can acquire and maintain knowledge about memory strategies and, importantly, can change their everyday memory behaviour by putting this knowledge into practice. This incorporation of practical memory strategies into daily routines could potentially provide the means for maintaining functional independence by individuals with MCI, an issue to be addressed in future research.

Recollection- and Familiarity-Based Memory in Healthy Aging and Amnestic Mild Cognitive Impairment

Little is known about the cognitive mechanisms of the memory impairment associated with amnestic mild cognitive impairment (aMCI). We explored recollection and familiarity in 27 healthy young adults, 45 healthy older adults, and 17 individuals with aMCI. Relative to the younger adults, recollection was reduced in the older adults, especially among those with aMCI. Familiarity did not differ among groups. In the healthy younger and older adults, better performance on a set of clinical memory measures that are sensitive to medial temporal lobe functioning was associated with greater recollection. In addition, among the healthy older adults better executive functioning was also associated with greater recollection. These results are consistent with the notion that recollection is a product of strategic processes mediated by the prefrontal cortex that suppport the retrieval of context-dependent memories from the hippocampus. Hippocampal atrophy associated with aMCI may disrupt this brain network, and thereby interfere with recollection.

Asymmetry between encoding and retrieval processes: Evidence from divided attention and a calibration analysis

Two experiments provide further information on the effects of divided attention (DA) on encoding and retrieval processes. The first experiment examined the effects of decision and motor difficulty of a concurrent reaction time task. A calibration analysis was used in the second experiment to test the hypothesis that shifting attentional emphasis away from encoding to the secondary task reduces the level of processing the to-be-remembered items receive. Overall, the results confirm and extend the conclusions of Craik, Govoni, Naveh-Benjamin, and Anderson (1996) and Naveh-Benjamin, Craik, Guez, and Dori (1998), by pointing to clear differences between encoding and retrieval processes: Encoding is affected by simultaneous task demands, especially those associated with “central” resources involved in conscious decision making, whereas retrieval is obligatory in that it is largely immune to the effects of simultaneous demands. The results of the calibration analysis suggest that one reason for the poorer memory performance as a result of DA at encoding is a qualitative shift to less deep, elaborative strategies.