Spindle-slow oscillation coupling correlates with memory performance and connectivity changes in a hippocampal network after sleep.

After experiences are encoded, post-encoding reactivations during sleep have been proposed to mediate long-term memory consolidation. Spindle-slow oscillation coupling during NREM sleep is a candidate mechanism through which a hippocampal-cortical dialogue may strengthen a newly formed memory engram. Here, we investigated the role of fast spindle- and slow spindle-slow oscillation coupling in the consolidation of spatial memory in humans with a virtual watermaze task involving allocentric and egocentric learning strategies. Furthermore, we analyzed how resting-state functional connectivity evolved across learning, consolidation, and retrieval of this task using a data-driven approach. Our results show task-related connectivity changes in the executive control network, the default mode network, and the hippocampal network at post-task rest. The hippocampal network could further be divided into two subnetworks of which only one showed modulation by sleep. Decreased functional connectivity in this subnetwork was associated with higher spindle-slow oscillation coupling power, which was also related to better memory performance at test. Overall, this study contributes to a more holistic understanding of the functional resting-state networks and the mechanisms during sleep associated to spatial memory consolidation.

Sleep Leads to Brain-Wide Neural Changes Independent of Allocentric and Egocentric Spatial Training in Humans and Rats.

Sleep is important for memory consolidation and systems consolidation in particular, which is thought to occur during sleep. While there has been a significant amount of research regarding the effect of sleep on behavior and certain mechanisms during sleep, evidence that sleep leads to consolidation across the system has been lacking until now. We investigated the role of sleep in the consolidation of spatial memory in both rats and humans using a watermaze task involving allocentric- and egocentric-based training. Analysis of immediate early gene expression in rodents, combined with functional magnetic resonance imaging in humans, elucidated similar behavioral and neural effects in both species. Sleep had a beneficial effect on behavior in rats and a marginally significant effect in humans. Interestingly, sleep led to changes across multiple brain regions at the time of retrieval in both species and in both training conditions. In rats, sleep led to increased gene expression in the hippocampus, striatum, and prefrontal cortex. In the humans, sleep led to an activity increase in brain regions belonging to the executive control network and a decrease in activity in regions belonging to the default mode network. Thus, we provide cross-species evidence for system-level memory consolidation occurring during sleep.

Variants of the Morris water maze task to comparatively assess human and rodent place navigation.

Performance in the Morris water maze has been widely used in routine behavioural studies of rodents. Since the advent of computer-based virtual environments, adaptations of the water maze have become available for human research. Despite decades of comparative neuroscience, formal comparisons of human and animal place navigation performance are rare. We studied 36 subjects, 18 young male mice in a Morris water maze and 18 male students in a virtual version. Quantitative measures (escape latencies, distances and platform crossings) indicated no discernable differences between human and rodent performance, reinforcing the task's general validity and its implied cross-species comparability. However, we extracted, using an a priori free classification method, qualitatively different movement patterns for mice and humans, patterns that reflect the probable strategy that individuals might have been using to solve the task. Our results indicated young male students to have most likely solved the maze by means of spatial strategies whereas mice were observed more often to have adopted non-spatial strategies. These differences could be attributed to differences in our maze setups (spatial cues, task instruction, training protocol, motivation) and gave further hints that maze learning depends on many factors. In summary performance on both spatial tasks was equivalent in humans and mice but the kind of maze learning that was used to achieve maximum performance was different.

Memory and Spatial Cognition in Breast Cancer Patients Undergoing Adjuvant Endocrine Therapy.

INTRODUCTION: It is generally accepted that estrogens play a protective role in cognitive function. Therefore, it can be expected that subtotal estrogen deprivation following aromatase inhibition will alter cognitive performance. METHODS: In a cross-sectional study we investigated 80 postmenopausal women with breast cancer. Memory and spatial cognition were compared across 4 treatment groups: tamoxifen only (TAM, n = 22), aromatase inhibitor only (AI, n = 22), TAM followed by AI ('SWITCH group', n = 15), and patients with local therapy (LT) only (surgery and radiation, n = 21). Duration of the 2 endocrine monotherapy arms prior to the assessment ranged from 1 to 3 years. The 'SWITCH group' received 2-3 years TAM followed by at least 1 year and at most 3 years of AI. Memory and spatial cognition were investigated as planned comparisons. Investigations of processing speed, attention, executive function, visuoconstruction and self-perception of memory were exploratory. RESULTS: With regard to general memory, AI patients performed significantly worse than the LT group (p = 0.013). Significant differences in verbal memory did not remain significant after p-value correction for multiple testing. We found no significant differences concerning spatial cognition between the groups. CONCLUSION: AI treatment alone significantly impairs general memory compared to the LT group.

Characterizing Aging, Mild Cognitive Impairment, and Dementia with Blood-Based Biomarkers and Neuropsychology.

BACKGROUND: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. OBJECTIVE: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. METHODS: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-ß (Aß) species, pro-inflammatory markers, anti-Aß autoantibodies, and ApoE allele status, respectively. RESULTS: Plasma Aß1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aß1-40 did not differ, but increases with age in healthy controls. The Aß1-42 to Aß1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aß1-42 and Aß1-42 to Aß1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aß, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aß did not differ. CONCLUSION: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aß for diagnosis of MCI and AD. Anti-pGlu-Aß autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aß analysis with additional and independent information.

Search strategies in a human water maze analogue analyzed with automatic classification methods.

Although human spatial cognition is at the focus of intense research efforts, experimental evidence on how search strategies differ among age and gender groups remains elusive. To address this problem, we investigated the interaction between age, sex, and strategy usage within a novel virtual water maze-like procedure (VWM). We studied 28 young adults 20-29 years (14 males) and 30 middle-aged adults 50-59 years (15 males). Younger age groups outperformed older groups with respect to place learning. We also observed a moderate sex effect, with males outperforming females. Unbiased classification of human search behavior within this paradigm was done by means of an exploratory method using sparse non-negative matrix factorization (SNMF) and a parameter-based algorithm as an a priori classifier. Analyses of search behavior with the SNMF and the parameter-based method showed that the older group relied on less efficient search strategies, but females did not drop so dramatically. Place learning was related to the adaptation of elaborated search strategies. Participants using place-directed strategies obtained the highest score on place learning, and deterioration of place learning in the elderly was due to the use of less efficient non-specific strategies. A high convergence of the SNMF and the parameter-based classifications could be shown. Furthermore, the SNMF classification was cross validated with the traditional eyeballing method. As a result of this analysis, we conclude that SNMF is a robust exploratory method for the classification of search behavior in water maze procedures.