Dopamine D1-Receptor Organization Contributes to Functional Brain Architecture.

Recent work has recognized a gradient-like organization in cortical function, spanning from primary sensory to transmodal cortices. It has been suggested that this axis is aligned with regional differences in neurotransmitter expression. Given the abundance of dopamine D1-receptors (D1DR), and its importance for modulation and neural gain, we tested the hypothesis that D1DR organization is aligned with functional architecture, and that inter-regional relationships in D1DR co-expression modulate functional cross talk. Using the world's largest dopamine D1DR-PET and MRI database (N = 180%, 50% female), we demonstrate that D1DR organization follows a unimodal-transmodal hierarchy, expressing a high spatial correspondence to the principal gradient of functional connectivity. We also demonstrate that individual differences in D1DR density between unimodal and transmodal regions are associated with functional differentiation of the apices in the cortical hierarchy. Finally, we show that spatial co-expression of D1DR primarily modulates couplings within, but not between, functional networks. Together, our results show that D1DR co-expression provides a biomolecular layer to the functional organization of the brain.

DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes: A new window into cognitive aging.

Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age-related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5-year longitudinal study spanning the adult human lifespan. DyNAMiC examines age-related changes in the brain's structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age-sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20-80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [11 C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [11 C]raclopride PET measuring D2DR. Age-related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u-shaped association between D1DR and resting-state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age-related cognitive decline.

Distinct and Common Large-Scale Networks of the Hippocampal Long Axis in Older Age: Links to Episodic Memory and Dopamine D2 Receptor Availability.

The hippocampal longitudinal axis has been linked to dissociated functional networks relevant to episodic memory. However, the organization of axis-dependent networks and their relation to episodic memory in aging remains less explored. Moreover, age-related deterioration of the dopamine (DA) system, affecting memory and functional network properties, might constitute a source of reduced specificity of hippocampal networks in aging. Here, we characterized axis-dependent large-scale hippocampal resting-state networks, their relevance to episodic memory, and links to DA in older individuals (n = 170, 64-68 years). Partial least squares identified 2 dissociated networks differentially connected to the anterior and posterior hippocampus. These overlapped with anterior-temporal/posterior-medial networks in young adults, indicating preserved organization of axis-dependent connectivity in old age. However, axis-specific networks were overall unrelated to memory and hippocampal DA D2 receptor availability (D2DR) measured with [11C]-raclopride positron emission tomography. Further analyses identified a memory-related network modulated by hippocampal D2DR, equally connected to anterior-posterior regions. This network included medial frontal, posterior parietal, and striatal areas. The results add to the current understanding of large-scale hippocampal connectivity in aging, demonstrating axis-dependent connectivity with dissociated anterior and posterior networks, as well as a primary role in episodic memory of connectivity shared by regions along the hippocampalaxis.

Predicting episodic and spatial memory performance from hippocampal resting-state functional connectivity: Evidence for an anterior-posterior division of function.

fMRI studies have identified distinct resting-state functional connectivity (RSFC) networks associated with the anterior and posterior hippocampus. However, the functional relevance of these two networks is still largely unknown. Hippocampal lesion studies and task-related fMRI point to a role for the anterior hippocampus in nonspatial episodic memory and the posterior hippocampus in spatial memory. We used Relevance Vector Regression (RVR), a machine-learning method that enables predictions of continuous outcome measures from multivariate patterns of brain imaging data, to test the hypothesis that patterns of whole-brain RSFC associated with the anterior hippocampus predict episodic memory performance, while patterns of whole-brain RSFC associated with the posterior hippocampus predict spatial memory performance. Magnetic resonance imaging and memory assessment took place at two separate occasions. The anterior and posterior RSFC largely corresponded with previous findings, and showed no effect of laterality. Supporting the hypothesis, RVR produced accurate predictions of episodic performance from anterior, but not posterior, RSFC, and accurate predictions of spatial performance from posterior, but not anterior, RSFC. In contrast, a univariate approach could not predict performance from resting-state connectivity. This supports a functional dissociation between the anterior and posterior hippocampus, and indicates a multivariate relationship between intrinsic functional networks and cognitive performance within specific domains, that is relatively stable over time.

Structural whole-brain covariance of the anterior and posterior hippocampus: Associations with age and memory.

The hippocampus (HC) interacts with distributed brain regions to support memory and shows significant volume reductions in aging, but little is known about age effects on hippocampal whole-brain structural covariance. It is also unclear whether the anterior and posterior HC show similar or distinct patterns of whole-brain covariance and to what extent these are related to memory functions organized along the hippocampal longitudinal axis. Using the multivariate approach partial least squares, we assessed structural whole-brain covariance of the HC in addition to regional volume, in young, middle-aged and older adults (n = 221), and assessed associations with episodic and spatial memory. Based on findings of sex differences in both memory and brain aging, we further considered sex as a potential modulating factor of age effects. There were two main covariance patterns: one capturing common anterior and posterior covariance, and one differentiating the two regions by capturing anterior-specific covariance only. These patterns were differentially related to associative memory while unrelated to measures of single-item memory and spatial memory. Although patterns were qualitatively comparable across age groups, participants' expression of both patterns decreased with age, independently of sex. The results suggest that the organization of hippocampal structural whole-brain covariance remains stable across age, but that the integrity of these networks decreases as the brain undergoes age-related alterations.

The inter-play between facilitation and context in the promoting action on research implementation in health services framework: A qualitative exploratory implementation study embedded in a cluster randomized controlled trial to reduce restraint in nursing homes.

AIM: To explore the inter-play between external facilitation and nursing home contexts relative to intervention outcomes. BACKGROUND: The Promoting Action on Research Implementation in Health Services framework is frequently used to theoretically inform implementation and research in nursing and recent reviews indicate high face validity for health services. However, the inter-play and relationship between framework sub-elements of evidence, context and facilitation and the prospective utility in non-English speaking contexts warrant further illumination. DESIGN: In an overarching single-blind cluster-randomized controlled trial, we applied participatory action research and ethnography from August 2011-June 2015 to evaluate a standardized education intervention to reduce restraint and agitation in nursing home residents living with dementia. The trial results are published elsewhere. METHODS: Prospectively informed by the PARIHS framework, a research team and eight facilitators participating in dual roles as action researchers designed, implemented, and evaluated the intervention. How contextual factors influenced the facilitation processes were explored in focus group interviews (1), reflection notes (84) written by the facilitators' after each education session, ethnographic field studies (6 homes), and co-analysis workshops (5). Directed content analysis was used to analyse data. RESULTS: Clinical leaders taking roles of internal facilitator influenced the success of implementation, while complex and fluctuating context elements determined whether restraint use was reduced- or not. The PARIHS framework was found to be relevant in a non-English nursing home setting, albeit some elements merit further conceptualization. CONCLUSIONS: Our findings confirm the prospective utility of the PARIHS framework for implementation in a non-English context, particularly the notion of implementation processes as dynamic and multifaceted.

Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan.

Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.

Overlapping effects of age on associative memory and the anterior hippocampus from middle to older age.

The anterior hippocampus has been implicated in associative memory, and along with hippocampal volume, this type of memory declines with age. However, few cross-sectional studies include middle-aged samples, making it unclear at what point these age-related changes occur. In addition, although men and women have been shown to differ in associative memory and rates of age-related hippocampal atrophy, sex-differences in aging are rarely studied. To address these issues, we assessed memory for word-pairs, hippocampal volume and activation during encoding and retrieval, across middle-aged (n=39) and older (n=44) participants, specifically in relation to sex. Older adults showed significantly poorer associative memory compared to middle-aged adults, paralleled by smaller anterior hippocampi and less activation during successful retrieval. The age-by-sex interaction observed in memory performance was also mirrored in the volume and activation of the hippocampus, indicating more pronounced age-effects in men as compared to women. These results indicate a specific role of the anterior hippocampus in verbal associative memory and suggest they both decline between middle-age and older age.