Shu-Chen Li

Aging cognition: from neuromodulation to representation

Basic cognitive functions, such as the abilities to activate, represent, maintain, focus and process information, decline with age. A paradigm shift towards cross-level conceptions is needed in order to obtain an integrative understanding of cognitive aging phenomena that cuts across neural, information-processing, and behavioral levels. We review empirical data at these different levels, and computational theories proposed to enable their integration. A theoretical link is highlighted, relating deficient neuromodulation with noisy information processing, which might result in less distinctive cortical representations. These less distinctive representations might be implicated in working memory and attentional functions that underlie the behavioral manifestations of cognitive aging deficits.

The correlative triad among aging, dopamine, and cognition: Current status and future prospects

The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA is critically implicated also in higher-order cognitive functioning. Many cognitive functions and multiple markers of striatal and extrastriatal DA systems decline across adulthood and aging. Research examining the correlative triad among adult age, DA, and cognition has found strong support for the view that age-related DA losses are associated with age-related cognitive deficits. Future research strategies for examining the DA-cognitive aging link include assessing (a) the generality/specificity of the effects; (b) the relationship between neuromodulation and functional brain activation; and (c) the release of DA during actual task performance.

Transformations in the Couplings Among Intellectual Abilities and Constituent Cognitive Processes Across the Life Span

Two-component theories of intellectual development over the life span postulate that fluid abilities develop earlier during child development and decline earlier during aging than crystallized abilities do, and that fluid abilities support or constrain the acquisition and expression of crystallized abilities. Thus, maturation and senescence compress the structure of intelligence by imposing age-specific constraints upon its constituent processes. Hence, the couplings among different intellectual abilities and cognitive processes are expected to be strong in childhood and old age. Findings from a population-based study of 291 individuals aged 6 to 89 years support these predictions. Furthermore, processing robustness, a frequently overlooked aspect of processing, predicted fluid intelligence beyond processing speed in old age but not in childhood, suggesting that the causes of more compressed functional organization of intelligence differ between maturation and senescence. Research on developmental changes in functional brain circuitry may profit from explicitly recognizing transformations in the organization of intellectual abilities and their underlying cognitive processes across the life span.

Dual-tasking postural control: Aging and the effects of cognitive demand in conjunction with focus of attention

Postural control in everyday life is generally accompanied by posture-unrelated cognitive activity. Thus, mild forms of dual-tasking postural control are the norm rather than the exception. Based on this consideration and available evidence, we propose and empirically examined, in young and old adults, a non-monotonic, U-shaped relation between the efficacy of postural control and concurrent cognitive demands that reflect opposing trends of the effects of attention focus and attentional resource competition. When instructed to perform an easy cognitive task that presumably shifted the focus of attention away from posture control, the center of body pressure (COP) excursions decreased both in young and older adults relative to a single-task baseline where the focus of attention was explicitly directed towards the postural control task itself. However, when performing more demanding cognitive tasks, older adults showed increased COP displacements, in line with the predicted U-shape function, whereas young adults did not. We outline mechanisms linking postural control to cognitive demand and suggest routes for future investigation.

Human aging magnifies genetic effects on executive functioning and working memory

We demonstrate that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. We assess two common Val/Met polymorphisms, one affecting the Catechol-O-Methyltransferase (COMT) enzyme, which degrades dopamine (DA) in prefrontal cortex (PFC), and the other influencing the brain-derived neurotrophic factor (BDNF) protein. In two tasks (Wisconsin Card Sorting and spatial working memory), we find that effects of COMT genotype on cognitive performance are magnified in old age and modulated by BDNF genotype. Older COMT Val homozygotes showed particularly low levels of performance if they were also BDNF Met carriers. The age-associated magnification of COMT gene effects provides novel information on the inverted U-shaped relation linking dopaminergic neuromodulation in PFC to cognitive performance. The modulation of COMT effects by BDNF extends recent evidence of close interactions between frontal and medial-temporal circuitries in executive functioning and working memory.

Working memory plasticity in old age: practice gain, transfer, and maintenance.

Adult age differences in cognitive plasticity have been studied less often in working memory than in episodic memory. The authors investigated the effects of extensive working memory practice on performance improvement, transfer, and short-term maintenance of practice gains and transfer effects. Adults age 20-30 years and 70-80 years practiced a spatial working memory task with 2 levels of processing demands across 45 days for about 15 min per day. In both age groups and relative to age-matched, no-contact control groups, we found (a) substantial performance gains on the practiced task, (b) near transfer to a more demanding spatial n-back task and to numerical n-back tasks, and (c) 3-month maintenance of practice gains and near transfer effects, with decrements relative to postpractice performance among older but not younger adults. No evidence was found for far transfer to complex span tasks. The authors discuss neuronal mechanisms underlying adult age differences and similarities in patterns of plasticity and conclude that the potential of deliberate working memory practice as a tool for improving cognition in old age merits further exploration.

Age-related differences in white matter microstructure: Region-specific patterns of diffusivity

We collected MRI diffusion tensor imaging data from 80 younger (20-32 years) and 63 older (60-71 years) healthy adults. Tract-based spatial statistics (TBSS) analysis revealed that white matter integrity, as indicated by decreased fractional anisotropy (FA), was disrupted in numerous structures in older compared to younger adults. These regions displayed five distinct region-specific patterns of age-related differences in other diffusivity properties: (1) increases in both radial and mean diffusivity; (2) increases in radial diffusivity; (3) no differences in parameters other than FA; (4) a decrease in axial and an increase in radial diffusivity; and (5) a decrease in axial and mean diffusivity. These patterns suggest different biological underpinnings of age-related decline in FA, such as demyelination, Wallerian degeneration, gliosis, and severe fiber loss, and may represent stages in a cascade of age-related degeneration in white matter microstructure. This first simultaneous description of age-related differences in FA, mean, axial, and radial diffusivity requires histological and functional validation as well as analyses of intermediate age groups and longitudinal samples.

Linking cognitive aging to alterations in dopamine neurotransmitter functioning : Recent data and future avenues

Molecular-imaging studies of dopaminergic neurotransmission measure biomarkers of dopamine (DA), such as the DA transporter and D(1) and D(2) receptor densities in the living brain. These studies indicate that individual differences in DA functions are linked to cognitive performance irrespective of age, and serve as powerful mediators of age-related decline in executive functioning, episodic memory, and perceptual speed. This focused review targets several recent findings pertaining to these relationships. Specifically, we discuss novel evidence concerning (a) the role of DA in within-person cognitive variability; (b) age-related differences in DA release during cognitive processing; (c) DA release following cognitive training in younger and older adults; and (d) the relationship between DA and task-induced functional brain activity. Based on these lines of empirical inquiry, we outline a series of avenues for future research on aging, DA, and cognition.

Age-related decline in brain resources modulates genetic effects on cognitive functioning

Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words)

Genetic variation in dopaminergic neuromodulation influences the ability to rapidly and flexibly adapt decisions

The ability to rapidly and flexibly adapt decisions to available rewards is crucial for survival in dynamic environments. Reward-based decisions are guided by reward expectations that are updated based on prediction errors, and processing of these errors involves dopaminergic neuromodulation in the striatum. To test the hypothesis that the COMT gene Val158Met polymorphism leads to interindividual differences in reward-based learning, we used the neuromodulatory role of dopamine in signaling prediction errors. We show a behavioral advantage for the phylogenetically ancestral Val/Val genotype in an instrumental reversal learning task that requires rapid and flexible adaptation of decisions to changing reward contingencies in a dynamic environment. Implementing a reinforcement learning model with a dynamic learning rate to estimate prediction error and learning rate for each trial, we discovered that a higher and more flexible learning rate underlies the advantage of the Val/Val genotype. Model-based fMRI analysis revealed that greater and more differentiated striatal fMRI responses to prediction errors reflect this advantage on the neurobiological level. Learning rate-dependent changes in effective connectivity between the striatum and prefrontal cortex were greater in the Val/Val than Met/Met genotype, suggesting that the advantage results from a downstream effect of the prefrontal cortex that is presumably mediated by differences in dopamine metabolism. These results show a critical role of dopamine in processing the weight a particular prediction error has on the expectation updating for the next decision, thereby providing important insights into neurobiological mechanisms underlying the ability to rapidly and flexibly adapt decisions to changing reward contingencies.