Despite the necessity to understand how the brain endures the initial stages of age-associated cognitive decline, no brain mechanism has been quantitatively specified to date. The brain may withstand ...the effects of cognitive aging through redundancy, a design feature in engineered and biological systems, which entails the presence of substitute elements to protect it against failure. Here, we investigated the relationship between functional network redundancy and age over the human lifespan and their interaction with cognition, analyzing resting-state functional MRI images and cognitive measures from 579 subjects. Network-wide redundancy was significantly associated with age, showing a stronger link with age than other major topological measures, presenting a pattern of accumulation followed by old-age decline. Critically, redundancy significantly mediated the association between age and executive function, with lower anti-correlation between age and cognition in subjects with high redundancy. The results suggest that functional redundancy accrues throughout the lifespan, mitigating the effects of age on cognition.
The hippocampus is critical for learning and memory and may be separated into anatomically-defined hippocampal subfields (aHPSFs). Hippocampal functional networks, particularly during resting state, ...are generally analyzed using aHPSFs as seed regions, with the underlying assumption that the function within a subfield is homogeneous, yet heterogeneous between subfields. However, several prior studies have observed similar resting-state functional connectivity (FC) profiles between aHPSFs. Alternatively, data-driven approaches investigate hippocampal functional organization without a priori assumptions. However, insufficient spatial resolution may result in a number of caveats concerning the reliability of the results. Hence, we developed a functional Magnetic Resonance Imaging (fMRI) sequence on a 7 T MR scanner achieving 0.94 mm isotropic resolution with a TR of 2 s and brain-wide coverage to (1) investigate the functional organization within hippocampus at rest, and (2) compare the brain-wide FC associated with fine-grained aHPSFs and functionally-defined hippocampal subfields (fHPSFs). This study showed that fHPSFs were arranged along the longitudinal axis that were not comparable to the lamellar structures of aHPSFs. For brain-wide FC, the fHPSFs rather than aHPSFs revealed that a number of fHPSFs connected specifically with some of the functional networks. Different functional networks also showed preferential connections with different portions of hippocampal subfields.
With an increasing prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) in response to an aging population, it is critical to identify and understand neuroprotective mechanisms ...against cognitive decline. One potential mechanism is redundancy: the existence of duplicate elements within a system that provide alternative functionality in case of failure. As the hippocampus is one of the earliest sites affected by AD pathology, we hypothesized that functional hippocampal redundancy is protective against cognitive decline. We compared hippocampal functional redundancy derived from resting-state functional MRI networks in cognitively normal older adults, with individuals with early and late MCI, as well as the relationship between redundancy and cognition. Posterior hippocampal redundancy was reduced between cognitively normal and MCI groups, plateauing across early and late MCI. Higher hippocampal redundancy was related to better memory performance only for cognitively normal individuals. Critically, functional hippocampal redundancy did not come at the expense of network efficiency. Our results provide support that hippocampal redundancy protects against cognitive decline in aging.
Though Parkinson's disease is primarily defined as a movement disorder, it is also characterized by a range of non-motor symptoms, including cognitive decline. The onset and progression of cognitive ...decline in individuals with Parkinson's disease is variable, and the neurobiological mechanisms that contribute to, or protect against, cognitive decline in Parkinson's disease are poorly understood. Using resting-state functional magnetic resonance imaging data collected from individuals with Parkinson's disease with and without cognitive decline, we examined the relationship between topological brain-network resilience and cognition in Parkinson's disease. By leveraging network attack analyses, we demonstrate that relative to individuals with Parkinson's disease experiencing cognitive decline, the frontoparietal network in cognitively stable individuals with Parkinson's disease is significantly more resilient to network perturbation. Our findings suggest that the topological robustness of the frontoparietal network is associated with the absence of cognitive decline in individuals with Parkinson's disease.
People with schizophrenia experience episodic memory impairments that have been theorized to reflect deficits in processing context (e.g., spatio-temporal features tied to a specific event). Although ...past research has reported episodic memory impairments in young people at-risk for schizophrenia, the extent to which these impairments reflect context processing deficits remains unknown. We addressed this gap in the literature by examining whether children and adolescents at risk for schizophrenia exhibit context processing deficits during free recall, a memory task with high contextual demands. Our sample included three groups (N = 58, 9–16 years old) varying in risk for schizophrenia:16 high-risk, unaffected first-degree relatives of patients with schizophrenia, bipolar disorder, and/or schizoaffective disorder, 22 clinical control participants with a comorbid disorder (ADHD and/or an anxiety disorder), and 20 healthy control participants. Participants first completed a free recall task and then completed a recognition memory task. Based on established theories of episodic memory, we assumed that context processing played a more pivotal role in free recall than recognition memory. Consequently, if schizophrenia risk is associated with context processing deficits, then memory impairment should be present in free recall measures that are most sensitive to context processing (i.e., recall accuracy and temporal contiguity). Consistent with this prediction, free recall accuracy and temporal contiguity were lower for the high-risk group than the healthy controls, whereas recognition memory was comparable across groups. These findings suggest that episodic memory impairments associated with schizophrenia in unaffected, first-degree relatives may reflect context processing deficits.
•Low hippocampal volume is associated with low memory in aging.•Hippocampal functional redundancy mediates the volume-memory relationship.•Hippocampal local efficiency is not related to volume-memory ...association.•Low hippocampal volume, redundancy, and memory predict future dementia conversion.
Hippocampal neurodegeneration, a primary component of Alzheimer's disease pathology, relates to poor cognition; however, the mechanisms underlying this relationship are not well understood. Using a sample of cognitively normal older adults and individuals with mild cognitive impairment, this study aims to determine the topological properties of functional networks accompanying hippocampal atrophy in aging, along with their association to cognition and clinical progression. We considered two conceptually differing topological properties: redundancy (the existence of alternative channels of functional commutation) and local efficiency (the efficiency of local information exchange). Hippocampal redundancy, but not local efficiency, mediated the association between low hippocampal volume and low memory in both the whole sample and in ß-amyloid positive participants. Additionally, participants with high hippocampal volume, redundancy, and memory clustered separately from those with low values on all three measures, with the latter group showing higher conversion rates to dementia within three years. Together, these results demonstrate that reduced hippocampal redundancy is one mechanism through which hippocampal atrophy associates with memory impairment in healthy and pathological aging.
•Female mice showed greater preference for EPM open arms regardless of housing.•EE attenuated sensory gating in male and female mice.•EE enhanced spatial learning in male and female mice.•EE resulted ...in greater use of spatially precise strategies in the water maze.•Swim speed and escape latency in SE females were slow relative to the other groups.
The influence of housing on cognition and emotional regulation in mice presents a problem for the study of genetic and environmental risk factors for neuropsychiatric disorders: standard laboratory housing may result in low levels of cognitive function or altered levels of anxiety that leave little room for assessment of deleterious effects of experimental manipulations. The use of enriched environment (EE) may allow for the measurement of a wider range of performance in cognitive domains. Cognitive and behavioral effects of EE in male mice have not been widely reproduced, perhaps due to variability in the application of enrichment protocols, and the effects of EE in female mice have not been widely studied. We have developed an EE protocol using common laboratory equipment that, without a running wheel for exercise, results in significant cognitive and behavioral effects relative to standard laboratory housing conditions. We compared male and female wild-type C57BL/6J mice reared from weaning age in an EE to those reared in a standard environment (SE), using common measures of anxiety-like behavior, sensory gating, sociability, and spatial learning and memory. Sex was a significant factor in relevant elevated plus maze (EPM) measures, and bordered on significance in a social interaction (SI) assay. Effects of EE on anxiety-like behavior and sociability were indicative of a general increase in exploratory activity. In male and female mice, EE resulted in reduced prepulse inhibition (PPI) of the acoustic startle response, and enhanced spatial learning and use of spatially precise strategies in a Morris water maze task.
Aging is accompanied by declines in episodic memory and altered hippocampal function, each of which are exacerbated in response to the development of Alzheimer’s disease. Therefore, it is critical to ...identify factors which support resilience to such pathological aging. One proposed factor is redundancy, the existence of duplicate elements within a system that offers protection against failure. Redundancy is hypothesized to operate within the brain as a neuroprotective mechanism, though this hypothesis has not been tested in the context of neurodegenerative diseases. This dissertation presents initial evidence that hippocampal redundancy, quantified from resting-state functional brain networks, operates as a neuroprotective mechanism in aging.The role of hippocampal functional redundancy is examined in the context of clinical, cognitive, pathological, and experiential factors across three studies. The first study demonstrates that posterior hippocampal redundancy is lower in mild cognitive impairment, a precursor stage to Alzheimer’s disease, than in healthy aging, though redundancy does not differ between early and late stages of mild cognitive impairment. Further, posterior hippocampal redundancy is related to better memory performance. The second study expands upon these results, relating hippocampal redundancy to pathological markers of Alzheimer’s disease, showing that hippocampal redundancy mediates the relationship between hippocampal volume and memory performance. Additionally, the combination of low hippocampal redundancy, volume, and memory is associated with subsequent dementia conversion. The final study reveals that the positive mnemonic benefit of redundancy weakens throughout healthy older adulthood and is specific to posterior rather than anterior hippocampus. However, this study finds no evidence that redundancy is influenced by either education or physical activity, two prominent protective factors for healthy aging.Across these three studies, hippocampal redundancy, particularly in posterior regions, is shown to be associated with better clinical and cognitive outcomes. Future studies will benefit from longitudinal analysis of redundancy in relation to clinical progression and long-term measures of physical activity. Together, the results presented in this dissertation provide the initial evidence that hippocampal redundancy supports resilience to pathological aging.
Background
The disruption of brain functional connections has been linked to cognitive impairment in Alzheimer’s disease. The functional architecture of the brain can be modeled using graph theory, ...which provides metrics to describe both local and global network properties. Autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to study brain changes in preclinical AD since carriers of ADAD mutations are destined to develop dementia at young age and have a well‐characterized disease trajectory. Here, we applied a graph theory approach to examine the functional network topology in Presenilin‐1 (PSEN1) E280A carriers and non‐carriers.
Methods
A total of 43 cognitively‐unimpaired individuals (18 PSEN1 carriers, 25 non‐carriers; mean age = 36.6±5.2) from the Colombia‐Boston biomarker study were included. Participants underwent resting‐state fMRI in a 3T scanner, and a comprehensive multi‐domain neuropsychological battery. fMRI data were preprocessed using C‐PAC. Global functional connectivity (FC) was derived from the nodal strength of the Pearson correlation matrix between time‐series of 400 ROIs Shaeffer‐2016 within 6 different functional networks Yeo‐2011. The strength of within‐ (z) and between‐network (h) functional integration was derived from a consensus modularity analysis Dwyer‐2014. Differences in cognitive variables were evaluated using Mann‐Whitney tests. Differences in FC were assessed using permutation methods: global FC using FSL‐randomize and integration parameters were based on a consensus analysis applied to random controlled matrices. Both methods were repeated 1000 times, with a p<0.05 significance threshold.
Results
There were no group differences in cognitive variables. Compared to non‐carriers, carriers exhibited decreased local FC in higher‐order association areas, and increased connectivity in somatosensory areas. There were no group differences in the within‐network integration. Carriers showed decreased between‐network integration, especially in higher‐order association networks, mainly the default mode network (Fig.1).
Conclusions
Findings support the hypothesis that alterations of functional network topology are evident in preclinical ADAD, primarily in the higher‐order cognitive networks. Early identification of abnormalities within these networks may be useful in understanding how FC changes may lead to subsequent cognitive decline in individuals at increased risk for AD. Future work with larger samples should investigate the relationships between FC changes and the neurobiological factors underlying AD.
The hippocampus is integral for encoding and retrieving associative information and consists of anatomically distinct subfields that contribute differentially to mnemonic processing. To date, these ...processes have only been examined in the context of the hippocampus and the immediate surrounding areas; however, cortical regions provide critical support in successful encoding and retrieval. The current study employed a novel functional imaging sequence for examining whole brain activity using ultrahigh resolution, examining concurrent cortical and hippocampal subfield activity encoding and retrieval of an associative memory task in healthy young adults. Diffuse regions throughout cortex were involved in successful retrieval, suggesting both common cortical activity across mnemonic processes and separable activity by condition. Hippocampal activity at encoding was not related to retrieval accuracy, nor did hippocampal subfield activity differ as a function of retrieval condition. Future studies will employ multivariate methods to further probe the relationship between hippocampal subfields and cortex.
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