Matthew P. Walker - US grants

DESCRIPTION (provided by applicant): Converging evidence from molecular genetics, neurophysiology, and the cognitive neurosciences continues to suggest that sleep plays an important role in the process of learning and memory formation. More specifically, studies in humans have established that learning of procedural sensory and motor skills depends explicitly on sleep for the development of additional performance gains following task acquisition, while equivalent periods of daytime (or nighttime) waking offer no such improvements. Despite these advances, there remains a complete paucity of studies focusing on the underlying neural mechanisms associated with sleep-dependent learning in the human brain. Proposed here is an experimental approach specifically designed to investigate the neural correlates of sleep-dependent human motor skill learning using functional magnetic resonance imaging (fMRI). The aims of this proposal are to (a) determine whether a post-training time period containing sleep leads to a different pattern of task-dependent neural activation, relative to a post-training time period without sleep, and (b) determine whether changes in brain activation occurring specifically across the sleep time period correlate both with overnight performance improvements and sleep-stage recordings. Subjects will therefore be trained on a motor skill task and, following an intervening time period containing either wake or sleep, will be retested while undergoing fMRI scanning. The respective patterns of task-dependent regional brain activity will then be contrasted to dissociate the contributions of each respective brain-state on motor skill learning, and correlated with overnight sleep-stage recordings. Understanding how sleep-dependent learning is manifest in brain plasticity has wide reaching practical, clinical and scientific implications, such as determining the role of sleep in developmental neuronal plasticity; in the functional reorganization of brain regions following trauma or stroke; in the potential relationship between sleep disturbances and impaired memory function in a variety of patho-physiological conditions; as well as expanding our scientific understanding of mechanisms underlying memory consolidation processes in general.

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DESCRIPTION (provided by applicant): Sleep quality, efficiency and continuity are all known to decrease in with age. Co-occurring with these sleep impairments is the cognitive hallmark of aging a progressive deterioration of memory, reducing the ability to acquire and retain facts in later life. Moreover, it is now widely acknowledged that sleep plays a critical role in learning, memory and brain plasticity. However, the possibility that age-related memory decline results, at least in part, from disrupted sleep, remains enigmatic and unexplored. If correct, inadequate sleep would represent an important, but as yet uncharacterized, feature of cognitive aging that is treatable. Combining brain imaging (fMRI) with cognitive measures, we will determine the impact of age-associated sleep loss, and recovery, on the ability to form new human memories. A first series of experiments will determine the relationship between age-related sleep deficits and impaired memory encoding ability in a cohort of medically healthy older adults (age 65-85). These neural and behavioral changes will be compared to young healthy subjects with experimentally manipulated sleep patterns matching those of the older adults; dissociating the effects of age from sleep loss. A second series of experiments will investigate whether daytime naps provide a restorative benefit to memory encoding in older adults, and similarly sleep deprived young adults; overcoming these neural and behavioral effects resulting from sleep loss. Furthermore, these studies will determine whether naps composed of different sleep-stage architectures and of varying durations are more or less recuperative in enhancement learning ability in older and young subjects. Across these programs of research, we will also determine whether high- and low-sleep functioning older adults (i.e. sleep quality and quantity), express differential neural and behavioral memory profiles, as would be predicted by the above hypothesis.

DESCRIPTION (provided by applicant): Sleep disruption is a recognized and problematic symptom across the anxiety disorders spectrum. Individuals suffering anxiety additionally display a hallmark signature of enhanced amygdala reactivity to aversive stimuli. Independently, sleep loss in healthy participants results in amplified amygdala reactivity, together with raised levels of anxiety, while the beneficial presence of sleep conversely offers a palliative reduction in next-day aversive reactivity and anxiety. Despite these parallel lines of evidence, the relationship between sleep, anxiety and emotional brain reactivity remains uncharacterized. The need to explore this potentially causal interaction is not only imperative for gaining a deeper understanding of the pathophysiological etiology underlying anxiety, but also for the development of improved preventative strategies and effective treatments for amelioration of anxiety. Across separate experiments combining functional MRI (fMRI), sleep EEG recordings and neurobehavioral assessments, this proposal will test the hypothesis that high anxiety status (1) prevents the normal physiological benefit of sleep in regulating next-day amygdala reactivity, (2) imposes greater vulnerability of the amygdala to the aggravating effects of sleep loss, and (3) negates the benefit of recovery sleep in restoring normative amygdala reactivity, following sleep loss. As such, this proposal represents a systematic evaluation of how anxiety status alters the sleep-dependent regulation of optimal emotional brain function, and how a lack of sleep contributes to the amplified neural signature associated with high anxiety status. Understanding the causal associations between anxiety, sleep impairment, and emotional brain reactivity has considerable clinical and public health ramifications, as well as direct translational treatment applicability. Moreover, considering the continued erosion of sleep time across society, particularly in young populations susceptible to anxiety-related emotion difficulties, the applicability of these studies further increases in relevance.

DESCRIPTION (provided by applicant): Optimal interpretation of pleasurable, rewarding experiences favors decisions that enhance survival. However, pleasure seeking can also lead to deleterious and life- threatening behaviors, exemplified by abusive drug addiction, impulsive thrill seeking and adverse risk taking. These reward mechanisms are supported, in part, by activity in dopamine pathways of the brain, including the ventral tegmental nuclei and striatum. One circumstance increasingly related to altered dopaminergic brain reward sensitivity is the state of sleep deprivation. Sleep loss can trigger amplified reactivity in dopaminergic networks in response to pleasurable experiences, elevate levels of dopamine within these circuits, and further enhance dopamine receptor sensitivity throughout these networks. Despite such emerging evidence, the impact of sleep loss on human brain reward processing and associated behaviors remains largely uncharacterized. Furthermore, the degree to which these neural and behavioral processes can be restored by recovery sleep, following deprivation, is similarly unknown. The need to characterize this potentially causal interaction is worthy of attention considering the known disruption of sleep in numerous addiction disorders associated with altered reward brain activity. Identifying such an interaction would implicate sleep loss as a predisposing risk factor in heightened responsivity and hence addiction potential to reward-stimulating drugs. It would further indicate a role for sleep disruption in the maintenance of addiction habits, especially during attempted withdrawal. Using functional MRI scanning in combination with established reward paradigms and sleep physiological recordings, here we propose to test the central hypothesis that (i) sleep deprivation amplifies sensitivity of the huma dopaminergic system in response to reward incentives, which additionally (ii) biases the brain towards disproportionate hippocampal reward-driven learning, and (iii) one night of recovery sleep, following deprivation, is sufficient to restore optimal functioning of these neural and behavioral reward processes. Therefore, this R21 proposal represents a systematic evaluation of how sleep loss and sleep recovery causally amplify human brain reward sensitivity, altering associated behaviors, and whether such dysfunction is reversed by recovery sleep. Considering the high prevalence and comorbidity of sleep disruption in addiction disorders, the proposed research holds substantive and direct clinical as well as broad public-health ramifications, with logical next-step translational targets.

? DESCRIPTION (provided by applicant): Cognitive decline is a problematic and disabling consequence of aging, with memory impairment being one of the most debilitating symptoms. These cognitive changes are paralleled by a dramatic decrease in non-rapid eye movement (NREM) sleep quality, indexed by a reduction in electroencephalographic (EEG) slow wave activity (SWA). Here, we propose that ß-Amyloid accumulation-a leading candidate underlying cognitive decline both in aging and Alzheimer's disease-is one neuropathological factor contributing to disrupted NREM SWA and impaired memory consolidation in older adults. Specifically, we seek to test the hypothesis that ß-Amyloid in a set of midline cortical brain regions disrupts the neural generation of NREM SWA-both cross-sectionally, and longitudinally-thereby impairing hippocampal-dependent memory consolidation in the elderly. As such, these experiments will determine whether or not ß-Amyloid exerts an effect on memory through sleep, and if so, exactly how ß- Amyloid disrupts NREM sleep physiology, resulting in memory impairment in older adults. Translationally, these experiments may reveal new treatment pathways targeting NREM SWA enhancements that improve memory, thereby moderating the cognitive burden associated with ß-Amyloid aggregation.

Project Summary/Abstract: Early biomarkers of Alzheimer's disease are urgently required for at least three reasons: (i) to determine which individuals are at greatest Alzheimer's disease risk, thereby (ii) offering preventative intervention, pre-disease onset, and (iii) further allowing nascent treatment intervention as early as possible in the disease process. All three goals demand a sensitive, non-invasive, affordable, accessible biomarker of Alzheimer's disease pathology/progression. Addressing these needs, we propose to test the hypothesis that a unique NREM sleep EEG signature provides a candidate early biomarker of A? pathology, one that may accurately track and forecast Alzheimer's disease risk and Alzheimer's disease pathophysiological progression. If correct, the proposal would establish a novel, inexpensive, and early diagnostic tool for determining Alzheimer's disease risk and pathology progression before clinical symptoms emerge, and one that is suitable for community settings. Moreover, such data would motivate an increased medical awareness regarding the importance of treating sleep difficulties across the lifespan, and further motivate the development (clinical or commercial) of sleep-based interventions that improve adult sleep and thus reduce Alzheimer's disease prevalence and its societal burden. More generally, such findings would argue for improved public health policies advocating for sufficient quality sleep throughout adulthood?a memorandum that may lower dementia risk and maintain cognitive health across the populous.

Project Summary/Abstract: Marked sleep disruption has long been recognized as a prevalent feature of Alzheimer's disease. However, a corpus of new data suggests that sleep abnormalities are not simply a symptom of aging and Alzheimer's disease, but an intimate and bi-directional component of their pathophysiology that further contributes to impairments in long-term memory consolidation. Despite these emerging links, the pathological role of tau protein aggregation in disrupting human NREM sleep physiology remains un-investigated, as does the potential consequence of such disruption for explaining impaired long-term memory consolidation in Alzheimer's disease. Moreover, the longitudinal inter-relationship between tau aggregation, NREM sleep physiology deterioration, and the impairment in hippocampal memory that typifies Alzheimer's disease, is also unknown. Addressing these questions, this proposal will test the hypothesis that early accumulation of tau in the human medial temporal lobe selectively impairs NREM sleep oscillations, thereby diminishing long-term memory consolidation and associated aspect of cognition, both cross-sectionally and longitudinally. Such findings may help identify a unique mechanistic pathway (sleep disruption) through which Alzheimer's disease pathology transacts memory impairment, and further define a new therapeutic target (sleep restoration) for intervention in aging and Alzheimer's disease. Additionally, such data would motivate a greater sensitivity of physicians to inquire about, diagnose and treat sleep difficulties across all ages. More generally, support for our hypothesis would argue for improved public health policies advocating for sufficient quality sleep throughout adulthood?a memorandum that may lower dementia risk and maintain cognitive health across the populous.

Project Summary/Abstract: Alzheimer?s disease (AD) and its related neuropathology are linked to a set of neuropsychiatric symptoms (NPS) that come with marked clinical, personal and real-life burden. However, the underlying neural mechanisms of NPS are poorly defined, hindering novel treatment approaches. Core among these NPS are: 1) sleep disturbance, and 2) anxiety. Moreover, both sleep impairment and anxiety are independently associated with a faster rate of longitudinal cognitive decline, reinforcing a particular focus on their overlap. However, the possibility that AD pathology, impaired non-rapid eye movement (NREM) sleep and the NPS feature of anxiety are actually inter-related, representing a novel brain mechanism explaining why A? is associated with increased anxiety, has not been examined. Here, we seek to test a core mechanistic hypothesis: The impact of A? burden on anxiety is orchestrated through beta- amyloid (A?)-related impairment of NREM slow-wave sleep, which in turn, amplifies next-day anxiety through impaired mPFC-amygdala emotional brain regulation. If supportive, these studies would (i) advance our basic understanding of how AD-related pathology mechanistically impacts the NPS feature of anxiety through impairment of NREM sleep, and (ii) establish sleep improvement as a novel modifiable therapeutic intervention target that may de-escalate anxiety linked with the AD disease state, and potentially the rate of longitudinal disease/cognitive decline.