Amphetamine modulates brain signal variability and working memory in younger and older adults.

Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SD(BOLD)) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SD(BOLD) levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SD(BOLD) and reaction time means (RT(mean)) and SDs (RT(SD)). Older adults who received AMPH in the first session tended to improve in RT(mean) and RT(SD) when SD(BOLD) was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD(BOLD) decreased (for RT(mean)) or no effect at all (for RT(SD)). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state- and practice-dependent neurochemical basis of human brain dynamics.

A scaffold for efficiency in the human brain.

The comprehensive relations between healthy adult human brain white matter (WM) microstructure and gray matter (GM) function, and their joint relations to cognitive performance, remain poorly understood. We investigated these associations in 27 younger and 28 older healthy adults by linking diffusion tensor imaging (DTI) with functional magnetic resonance imaging (fMRI) data collected during an n-back working memory task. We present a novel application of multivariate Partial Least Squares (PLS) analysis that permitted the simultaneous modeling of relations between WM integrity values from all major WM tracts and patterns of condition-related BOLD signal across all GM regions. Our results indicate that greater microstructural integrity of the major WM tracts was negatively related to condition-related blood oxygenation level-dependent (BOLD) signal in task-positive GM regions. This negative relationship suggests that better quality of structural connections allows for more efficient use of task-related GM processing resources. Individuals with more intact WM further showed greater BOLD signal increases in typical "task-negative" regions during fixation, and notably exhibited a balanced magnitude of BOLD response across task-positive and -negative states. Structure-function relations also predicted task performance, including accuracy and speed of responding. Finally, structure-function-behavior relations reflected individual differences over and above chronological age. Our findings provide evidence for the role of WM microstructure as a scaffold for the context-relevant utilization of GM regions.

Dopaminergic gene polymorphisms affect long-term forgetting in old age: further support for the magnification hypothesis.

Emerging evidence from animal studies suggests that suboptimal dopamine (DA) modulation may be associated with increased forgetting of episodic information. Extending these observations, we investigated the influence of DA-relevant genes on forgetting in samples of younger (n = 433, 20-31 years) and older (n = 690, 59-71 years) adults. The effects of single nucleotide polymorphisms of the DA D2 (DRD2) and D3 (DRD3) receptor genes as well as the DA transporter gene (DAT1; SLC6A3) were examined. Over the course of one week, older adults carrying two or three genotypes associated with higher DA signaling (i.e., higher availability of DA and DA receptors) forgot less pictorial information than older individuals carrying only one or no beneficial genotype. No such genetic effects were found in younger adults. The results are consistent with the view that genetic effects on cognition are magnified in old age. To the best of our knowledge, this is the first report to relate genotypes associated with suboptimal DA modulation to more long-term forgetting in humans. Independent replication studies in other populations are needed to confirm the observed association.

Cortical thickness is linked to executive functioning in adulthood and aging.

Executive functions that are dependent upon the frontal-parietal network decline considerably during the course of normal aging. To delineate neuroanatomical correlates of age-related executive impairment, we investigated the relation between cortical thickness and executive functioning in 73 younger (20-32 years) and 56 older (60-71 years) healthy adults. Executive functioning was assessed using the Wisconsin Card Sorting Test (WCST). Cortical thickness was measured at each location of the cortical mantle using surface-based segmentation procedures on high-resolution T1-weighted magnetic resonance images. For regions involved in WCST performance, such as the lateral prefrontal and parietal cortices, we found that thicker cortex was related to higher accuracy. Follow-up ROI-based analyses revealed that these associations were stronger in older than in younger adults. Moreover, among older adults, high and low performers differed in cortical thickness within regions generally linked to WCST performance. Our results indicate that the structural cortical correlates of executive functioning largely overlap with previously identified functional patterns. We conclude that structural preservation of relevant brain regions is associated with higher levels of executive performance in old age, and underscore the need to consider the heterogeneity of brain aging in relation to cognitive functioning.

Performance level modulates adult age differences in brain activation during spatial working memory.

Working memory (WM) shows pronounced age-related decline. Functional magnetic resonance imaging (fMRI) studies have revealed age differences in task-related brain activation. Evidence based primarily on episodic memory studies suggests that brain activation patterns can be modulated by task difficulty in both younger and older adults. In most fMRI aging studies on WM, however, performance level has not been considered, so that age differences in activation patterns are confounded with age differences in performance level. Here, we address this issue by comparing younger and older low and high performers in an event-related fMRI study. Thirty younger (20-30 years) and 30 older (60-70 years) healthy adults were tested with a spatial WM task with three load levels. A region-of-interest analysis revealed marked differences in the activation patterns between high and low performers in both age groups. Critically, among the older adults, a more "youth-like" load-dependent modulation of the blood oxygen level-dependent signal was associated with higher levels of spatial WM performance. These findings underscore the need of taking performance level into account when studying changes in functional brain activation patterns from early to late adulthood.

Load modulation of BOLD response and connectivity predicts working memory performance in younger and older adults.

Individual differences in working memory (WM) performance have rarely been related to individual differences in the functional responsivity of the WM brain network. By neglecting person-to-person variation, comparisons of network activity between younger and older adults using functional imaging techniques often confound differences in activity with age trends in WM performance. Using functional magnetic resonance imaging, we investigated the relations among WM performance, neural activity in the WM network, and adult age using a parametric letter n-back task in 30 younger adults (21-31 years) and 30 older adults (60-71 years). Individual differences in the WM network's responsivity to increasing task difficulty were related to WM performance, with a more responsive BOLD signal predicting greater WM proficiency. Furthermore, individuals with higher WM performance showed greater change in connectivity between left dorsolateral prefrontal cortex and left premotor cortex across load. We conclude that a more responsive WM network contributes to higher WM performance, regardless of adult age. Our results support the notion that individual differences in WM performance are important to consider when studying the WM network, particularly in age-comparative studies.

Ebbinghaus revisited: influences of the BDNF Val66Met polymorphism on backward serial recall are modulated by human aging.

The brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity, which underlies learning and memory. In a sample of 948 younger and older adults, we investigated whether a common Val66Met missense polymorphism (rs6265) in the BDNF gene affects the serial position curve--a fundamental phenomenon of associative memory identified by Hermann Ebbinghaus more than a century ago. We found a BDNF polymorphism effect for backward recall in older adults only, with Met-allele carriers (i.e., individuals with reduced BDNF signaling) recalling fewer items than Val homozygotes. This effect was specific to the primacy and middle portions of the serial position curve, where intralist interference and associative demands are especially high. The poorer performance of older Met-allele carriers reflected transposition errors, whereas no genetic effect was found for omissions. These findings indicate that effects of the BDNF polymorphism on episodic memory are most likely to be observed when the associative and executive demands are high. Furthermore, the findings are in line with the hypothesis that the magnitude of genetic effects on cognition is greater when brain resources are reduced, as is the case in old age.

[Structured Career Pathways in the University Medicine - From Promotion to Clinician Scientist Programs]. / Strukturierte Karrierewege in der Universitätsmedizin.

Scientifically active medical doctors are required for successful translation of novel basic findings into the clinic. However, there is an increasing tendency of young medical doctors to primarily follow a more clinically and not scientifically orientated career pathway. Therefore, the establishment of novel career education structures and career perspectives in university medicine are important to stop this development. Here, we will discuss the current situation and ongoing attempts to design novel structural programs that allow a better combination of clinical and scientific work by highlighting also current developments at the Faculty of Medicine at the University of Freiburg.

Functional MRI investigation of verbal selection mechanisms in lateral prefrontal cortex.

Response selection activates appropriate response representations to task-relevant environmental stimuli. Research implicates dorsolateral prefrontal cortex (dlPFC) for this process. On the other hand, studies of semantic selection, which activates verbal responses based on the semantic requirements of a task, implicate ventrolateral PFC (vlPFC). Despite this apparent dissociation, the neurocognitive distinction between response and semantic selection is controversial. The current functional MRI study attempts to resolve this controversy by investigating verbal response and semantic selection in the same participants. Participants responded vocally with a word to a visually presented noun, either from a memorized list of paired associates (response selection task), or by generating a semantically related verb (semantic selection task). We found a dissociation in left lateral PFC. Activation increased significantly in dlPFC with response selection difficulty, but not semantic selection difficulty. Conversely, semantic, but not response, selection difficulty increased activity significantly in vlPFC. Activity in left parietal cortex, on the other hand, was affected by difficulty increases in both selection tasks. These results suggest that response and semantic selection may be distinct cognitive processes mediated by different regions of lateral PFC; but both of these selection processes rely on cognitive mechanisms mediated by parietal cortex.

Dopamine and glutamate receptor genes interactively influence episodic memory in old age.

Both the dopaminergic and glutamatergic systems modulate episodic memory consolidation. Evidence from animal studies suggests that these two neurotransmitters may interact in influencing memory performance. Given that individual differences in episodic memory are heritable, we investigated whether variations of the dopamine D2 receptor gene (rs6277, C957T) and the N-methyl-D-aspartate 3A (NR3A) gene, coding for the N-methyl-D-aspartate 3A subunit of the glutamate N-methyl-D-aspartate receptor (rs10989591, Val362Met), interactively modulate episodic memory in large samples of younger (20-31 years; n = 670) and older (59-71 years; n = 832) adults. We found a reliable gene-gene interaction, which was observed in older adults only: older individuals carrying genotypes associated with greater D2 and N-methyl-D-aspartate receptor efficacy showed better episodic performance. These results are in line with findings showing magnification of genetic effects on memory in old age, presumably as a consequence of reduced brain resources. Our findings underscore the need for investigating interactive effects of multiple genes to understand individual difference in episodic memory.

COMT polymorphism and memory dedifferentiation in old age.

According to a neurocomputational theory of cognitive aging, senescent changes in dopaminergic modulation lead to noisier and less differentiated processing. The authors tested a corollary hypothesis of this theory, according to which genetic predispositions of individual differences in prefrontal dopamine (DA) signaling may affect associations between memory functions, particularly in old age. Latent correlations between factors of verbal episodic memory and spatial working memory were compared between individuals carrying different allelic variants of the Catechol-O-Methyltransferase (COMT) Val158Met polymorphism, which influences DA availability in prefrontal cortex. In younger adults (n = 973), correlations between memory functions did not differ significantly among the 3 COMT genotypes (r = .35); in older adults (n = 1333), however, the correlation was significantly higher in Val homozygotes (r = .70), whose prefrontal DA availability is supposedly the lowest of all groups examined, than in heterozygotes and Met homozygotes (both rs = .29). Latent means of the episodic memory and working memory factors did not differ by COMT status within age groups. However, when restricting the analysis to the low-performing tertile of older adults (n = 443), we found that Val homozygotes showed lower levels of performance in both episodic memory and working memory than heterozygotes and Met homozygotes. In line with the neurocomputational theory, the observed dedifferentiation of memory functions in older Val homozygotes suggests that suboptimal dopaminergic modulation may underlie multiple facets of memory declines during aging. Future longitudinal work needs to test this conjecture more directly.

Aging magnifies the effects of dopamine transporter and D2 receptor genes on backward serial memory.

Aging compromises dopamine transporter (DAT) and receptor mechanisms in the frontostriatal circuitry. In a sample of 1288 younger and older adults, we investigated (i) whether individual differences in genotypes of the DAT gene (i.e., SLC6A3, the DAT variable number of tandem repeat 9/9, 9/10, and 10/10) and in the D2 receptor (DRD2) gene (i.e., the C957T [rs6277] CC and any T) interactively contribute to phenotype variations in episodic memory performance; and (ii) whether these genetic effects are magnified in older adults, because of considerable declines in the dopamine functions. Our results showed that carrying genotypes associated with higher levels of striatal synaptic dopamine (DAT 9/9) and higher density of extrastriatal D2 receptors (C957T CC) were associated with better backward serial recall, an episodic memory task with high encoding and retrieval demands. Critically, the gene-gene interaction effect was reliably stronger in older than in younger adults. In line with the resource modulation hypothesis, our findings suggest that aging-related decline in brain phenotypes (e.g., dopamine functions) could alter the relations between genotypes and behavioral phenotypes (e.g., episodic memory).

Higher intraindividual variability is associated with more forgetting and dedifferentiated memory functions in old age.

Intraindividual trial-to-trial reaction time (RT) variability is commonly found to be higher in clinical populations or life periods that are associated with impaired cognition. In the present study, higher within-person trial-to-trial RT variability in a perceptual speed task is related to more forgetting and dedifferentiation of memory functions in older adults (aged 60-71 years). More specifically, our study showed that individuals in a high-variability group (n=175) forgot more memory scenes over a 1-week retention interval than individuals in the low-variability group (n=174). In contrast, slower RT speed was associated with poorer episodic memory in general, but unrelated to the amount of forgetting. Moreover, results from multiple group latent factor analyses showed that episodic memory and working memory functions were more highly correlated in the high-variability (r=.63) than in the low-variability (r=.25) group. Given that deficits in dopamine (DA) modulation may underlie increases in RT variability, the present findings are in line with (i) recent animal studies implicating DA in long-term episodic memory consolidation and (ii) neurocomputational work linking DA modulation of performance variability to dedifferentiation of cognitive functions in old age.

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).

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.