To Örebro University

Aging is typically accompanied by a decline in working memory (WM) capacity, even in the absence of pathology. Proficient WM requires cognitive control processes that can retain goal-relevant information for easy retrieval and resolve interference from irrelevant information. Aging has been associated with a reduced ability to resolve proactive interference (PI) in WM, leading to impaired retrieval of goal-relevant information. It remains unclear how age-related differences in the ability to resolve PI in WM are related to patterns of resting-state functional connectivity (rsFC) in the brain. Here, we investigated the association between PI in WM and rsFC cross-sectionally (n = 237) and 5 years longitudinally (n = 134) across the adult life span by employing both seed-based and data-driven approaches. Results revealed that the ability to resolve PI was associated with differential patterns of inferior frontal gyrus (IFG) rsFC in younger/middle-aged adults (25-60 years) and older adults (65-80 years) in two clusters centered in the vermis and caudate. Specifically, more PI was associated with stronger inferior frontal gyrus-vermis connectivity and weaker inferior frontal gyrus-caudate connectivity in older adults, while younger/middle-aged adults showed associations in the opposite directions with the identified clusters. Longitudinal analyses revealed that a reduced ability to control PI was associated with reduced inferior frontal gyrus-insula and inferior frontal gyrus-anterior cingulate cortex connectivity in older adults, while younger/middle-aged adults showed associations in the opposite direction with these clusters. Whole brain multivariate pattern analyses showed age-differential patterns of rsFC indicative of age-related structural decline and age-related compensation. The current results show that rsFC is associated with the ability to control PI in WM and that these associations are modulated by age.

Both animal and human studies indicate that individual variation in the neurometabolites gamma-aminobutyric acid and glutamate is linked to cognitive function. Age-related differences in these neurometabolites could potentially explain lower cognitive ability in older age. Working memory-the capacity to hold a limited amount of information online for a short period-has a central role in cognition, and this ability is also impaired in older individuals. Here, we investigated the relationship between gamma-aminobutyric acid (GABA+) levels and a composite measure of glutamate/glutamine (Glx) in the hippocampus and inferior frontal gyrus (IFG) and how these neurochemical markers relate to working memory in younger and older adults. Across age groups, we found a significant positive association between working memory accuracy and Glx in the IFG, as well as a significant negative association between GABA+ in this region and proactive interference. Age-stratified analyses demonstrated significant positive associations between components of working memory and hippocampal/IFG Glx, as well as a significant negative association between IFG GABA+ and proactive interference in older adults only. These results provide novel evidence for a specific involvement of excitatory Glx and working memory accuracy as well as inhibitory GABA+ for control of proactive interference in working memory, and how these effects are differentially affected by age.

Prior research has established that insomnia is predctive of pain in adolescents and that psychological mechanisms have a crucial role in this relationship. Adolescent girls report more insomnia and pain than boys, yet little is known of gender differences in how insomnia influences pain. This study assessed gender differences in levels and trajectories of insomnia and pain during adolescence, and whether rumination and negative mood mediated the effect of insomnia on pain. Longitudinal survey data measured on 5 annual occasions (Nbaseline = 2,767) were analyzed in a multigroup longitudinal serial mediation model. A final model was generated with insomnia as the predictor, rumination and depressed mood as mediators, pain as the outcome, and gender the grouping variable. The results showed that insomnia predicted pain in adolescents, with an effect 3.5 times larger in girls than boys. Depressed mood was the main mediator in boys. In girls, rumination was the only significant mediator. There were significant gender differences in the effects of insomnia on rumination and pain, and in the effects of rumination on depressed mood and pain, with stronger effects in girls. These results highlight that girls and boys should be considered separately when studying the relationship between insomnia and pain. PERSPECTIVE: Levels of insomnia and pain are progressively higher in adolescent girls than boys, across adolescence. The predictive strength of insomnia symptoms for future pain is 3.5 times greater in girls, with distinct gender-specific underlying pathways: rumination partially mediates this effect in girls, while depressed mood does so in boys.

Proactive interference (PI) appears when familiar information interferes with newly acquired information and is a major cause of forgetting in working memory. It has been proposed that encoding of item-context associations might help mitigate familiarity-based PI. Here, we investigate whether encoding-related brain activation could predict subsequent level of PI at retrieval using trial-specific parametric modulation. Participants were scanned with event-related fMRI while performing a 2-back working memory task with embedded 3-back lures designed to induce PI. We found that the ability to control interference in working memory was modulated by level of activation in the left inferior frontal gyrus, left hippocampus, and bilateral caudate nucleus during encoding. These results provide insight to the processes underlying control of PI in working memory and suggests that encoding of temporal context details support subsequent interference control.

Developmental dyslexia (DD) is defined as difficulties in learning to read even with normal intelligence and adequate educational guidance. Deficits in implicit sequence learning (ISL) abilities have been reported in children with DD. We investigated brain plasticity in a group of 17 children with DD, compared with 18 typically developing (TD) children, after two sessions of training on a serial reaction time (SRT) task with a 24-h interval. Our outcome measures for the task were: a sequence-specific implicit learning measure (ISL), entailing implicit recognition and learning of sequential associations; and a general visuomotor skill learning measure (GSL). Gray matter volume (GMV) increased, and white matter volume (WMV) decreased from day 1 to day 2 in cerebellar areas regardless of group. A moderating effect of group was found on the correlation between WMV underlying the left precentral gyrus at day 2 and the change in ISL performance, suggesting the use of different underlying learning mechanisms in DD and TD children during the ISL task. Moreover, DD had larger WMV in the posterior thalamic radiation compared with TD, supporting previous reports of atypical development of this structure in DD. Further studies with larger sample sizes are warranted to validate these results.

Semantic judgements involve the use of general knowledge about the world in specific situations. Such judgements are typically associated with activity in a number of brain regions that include the left inferior frontal gyrus (IFG). However, previous studies showed activity in brain regions associated with mentalizing, including the right temporoparietal junction (TPJ), in semantic judgements that involved social knowledge. The aim of the present study was to investigate if social and non-social semantic judgements are dissociated using a combination of fMRI and repetitive TMS. To study this, we asked participants to estimate the percentage of exemplars in a given category that shared a specified attribute. Categories could be either social (i.e., stereotypes) or non-social (i.e., object categories). As expected, fMRI results (n = 26) showed enhanced activity in the left IFG that was specific to non-social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation (n = 19) to this brain region specifically disrupted non-social semantic judgements. Also as expected, the right TPJ showed enhanced activity to social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation to this brain region specifically disrupted social semantic judgements. It is possible that the causal networks involved in social and non-social semantic judgements may be more complex than expected.

The human brain is organized as a hierarchical global network. Functional connectivity research reveals that sensory cortices are connected to corresponding association cortices via a series of intermediate nodes linked by synchronous neural activity. These sensory pathways and relay stations converge onto central cortical hubs such as the default-mode network (DMN). The DMN regions are believed to be critical for representing concepts and, hence, language acquisition and use. Although prior research has established that major senses are placed at a similar distance from the DMN-five to six connective steps-it is still unknown how the olfactory system functionally connects to the large-scale cortical hubs of the human brain. In this study, we investigated the connective distance from olfactory seed areas to the DMN. The connective distance involves a series of three to four intermediate steps. Furthermore, we parcellated the olfactory cortical subregions and found evidence of two distinct olfactory pathways. One emerges from the anterior olfactory nucleus and olfactory tubercle; it involves early access to the orbitofrontal cortex, known for processing reward and multisensory signals. The other emerges from the frontal and temporal regions of the piriform cortex, involving the anterior insula, intermediate frontal sulcus, and parietal operculum. The results were confirmed in a replication cohort. Our results provide evidence that olfaction has unique early access to the central cortical networks via dual pathways.

The patterns of brain activation and functional connectivity, task-related and task-free, as a function of age have been well documented over the past 30 years. However, the aging brain undergoes structural changes that are likely to affect the functional properties of the brain. The relationship between brain structure and function started to be investigated more recently. Brain structure and brain function can influence behavioral outcomes independently, and several studies highlight independent contribution of structure and function on cognition. Here, a central assumption is that brain structure also affects behavior indirectly through its influence on brain function. In such a model, structure supports function. Although findings generally suggest that structure may indeed influence function, the direction of the associations, the variability in terms of regional effects and age windows when associations are observed vary greatly. Also, a certain number of studies highlight the independent contribution of structure and function on cognition. A critical aspect of studying aging is the necessity of longitudinal designs, allowing to observe true aging effects - as compared with age differences in cross-sectional designs. This review aims to give an updated account on research dealing with multimodal neuroimaging in aging, and more specifically on the links between structure and function and associated cognitive outcomes, putting in parallel findings from cross-sectional and longitudinal studies. Additionally, we discuss potential mechanisms by which age-related changes in structure may affect function, but also factors (sample characteristics, methodology) that may contribute to the heterogeneity of the findings and the lack of consensus on the associations between structure, function, cognition and aging.

BACKGROUND: An increasing number of cross-sectional studies suggests that diet may impact memory and cognition in healthy older adults. However, randomized, controlled trials investigating the effects of whole-diet interventions on memory and cognition in healthy older adults are rather rare and conflicting results are often reported.

OBJECTIVE: Therefore, a systematic review was conducted to compile the current evidence regarding the potential effects of whole-diet interventions on 1) memory and, 2) other cognitive outcomes in older adults.

METHODS: Studies that reported on randomized, controlled trials with dietary interventions in healthy older adults (60 yrs. and older) were included. Studies utilizing supplements, single food items or trials in specific patient groups (ie neurodegenerative diagnoses) were excluded.

RESULTS: For the 23 included articles, the main outcomes examined fell into one or more of the following categories: cognitive task-based outcomes related to memory, other cognitive task-based outcomes, and additional outcomes related to cognitive function or disease risk. Three of the studies that investigated dietary interventions alone and two multi-domain study showed positive effects on memory function, whereas five multi-domain interventions and one intervention that focused on diet alone showed positive effects on other cognitive outcomes.

CONCLUSIONS: The effect of randomized, controlled whole-diet interventions on memory and cognitive function in healthy older adults is modest and inconclusive, highlighting the need for more well-designed, sufficiently powered studies. Furthermore, the potential mechanisms by which diet impacts cognition in healthy aging need to be elucidated.

REGISTRY AND REGISTRY NUMBER FOR SYSTEMATIC REVIEWS OR META-ANALYSES: This systematic review is registered in PROSPERO under ID CRD42022329759.

BACKGROUND AND OBJECTIVES: We examined the extent to which externalizing behaviors such as violent and nonviolent criminal behavior, and substance use disorders (SUD) are associate with the onset of Alzheimer's disease (AD) and any dementia in prior generations.

RESEARCH DESIGN AND METHODS: A nationwide cohort of 2,463,033 individuals born between 1973 and 1997 (index persons) were linked to their biological relatives (parents, grandparents, and uncles/aunts) using Swedish national registers. Cox regression models were used to examine the association between each measure of externalizing behaviors with AD and any dementia in each of the relative cohorts.

RESULTS: Parents of index persons with externalizing behaviors had an increased risk for AD compared with parents of index persons without externalizing behaviors-nonviolent criminal behavior: Hazard Ratio (HR) = 1.16, 95% Confidence Intervals (CI) 1.10-1.22; violent criminal behavior: HR = 1.32 (95% CI: 1.19-1.45); SUD: HR = 1.28 (95% CI: 1.17, 1.40). The associations attenuated with decreasing familial relatedness. Relatives of individuals with externalizing behaviors compared with relatives of individuals without, showed an increased risk of having both early-onset and late-onset AD but the strength of the associations was higher for early-onset AD than for late-onset AD. A similar pattern of results was observed for the association with any dementia.

DISCUSSION AND IMPLICATIONS: Externalizing behaviors are associated with AD and any dementia in prior generations. The associations were stronger for parents in comparison with grandparents and uncles/aunts, suggesting shared familial risks between conditions. This warrants further studies examining common genetic and family-wide environmental factors that may contribute to identifying common underlying mechanisms to the development of externalizing behaviors, AD, and any dementia.