Jared M. Saletin

Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging

Aging has independently been associated with regional brain atrophy, reduced slow wave activity (SWA) during non–rapid eye movement (NREM) sleep and impaired long-term retention of episodic memories. However, whether the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. We found that age-related medial prefrontal cortex (mPFC) gray-matter atrophy was associated with reduced NREM SWA in older adults, the extent to which statistically mediated the impairment of overnight sleep–dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex functional connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represents a contributing factor to age-related cognitive decline in later life.

Sleep, plasticity and memory from molecules to whole-brain networks.

Despite the ubiquity of sleep across phylogeny, its function remains elusive. In this review, we consider one compelling candidate: brain plasticity associated with memory processing. Focusing largely on hippocampus-dependent memory in rodents and humans, we describe molecular, cellular, network, whole-brain and behavioral evidence establishing a role for sleep both in preparation for initial memory encoding, and in the subsequent offline consolidation of memory. Sleep and sleep deprivation bidirectionally alter molecular signaling pathways that regulate synaptic strength and control plasticity-related gene transcription and protein translation. At the cellular level, sleep deprivation impairs cellular excitability necessary for inducing synaptic potentiation and accelerates the decay of long-lasting forms of synaptic plasticity. In contrast, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep enhance previously induced synaptic potentiation, although synaptic de-potentiation during sleep has also been observed. Beyond single cell dynamics, large-scale cell ensembles express coordinated replay of prior learning-related firing patterns during subsequent NREM sleep. At the whole-brain level, somewhat analogous learning-associated hippocampal (re)activation during NREM sleep has been reported in humans. Moreover, the same cortical NREM oscillations associated with replay in rodents also promote human hippocampal memory consolidation, and this process can be manipulated using exogenous reactivation cues during sleep. Mirroring molecular findings in rodents, specific NREM sleep oscillations before encoding refresh human hippocampal learning capacity, while deprivation of sleep conversely impairs subsequent hippocampal activity and associated encoding. Together, these cross-descriptive level findings demonstrate that the unique neurobiology of sleep exerts powerful effects on molecular, cellular and network mechanisms of plasticity that govern both initial learning and subsequent long-term memory consolidation.

REM Sleep Depotentiates Amygdala Activity to Previous Emotional Experiences

Clinical evidence suggests a potentially causal interaction between sleep and affective brain function; nearly all mood disorders display co-occurring sleep abnormalities, commonly involving rapid-eye movement (REM) sleep. Building on this clinical evidence, recent neurobiological frameworks have hypothesized a benefit of REM sleep in palliatively decreasing next-day brain reactivity to recent waking emotional experiences. Specifically, the marked suppression of central adrenergic neurotransmitters during REM (commonly implicated in arousal and stress), coupled with activation in amygdala-hippocampal networks that encode salient events, is proposed to (re)process and depotentiate previous affective experiences, decreasing their emotional intensity. In contrast, the failure of such adrenergic reduction during REM sleep has been described in anxiety disorders, indexed by persistent high-frequency electroencephalographic (EEG) activity (>30 Hz); a candidate factor contributing to hyperarousal and exaggerated amygdala reactivity. Despite these neurobiological frameworks, and their predictions, the proposed benefit of REM sleep physiology in depotentiating neural and behavioral responsivity to prior emotional events remains unknown. Here, we demonstrate that REM sleep physiology is associated with an overnight dissipation of amygdala activity in response to previous emotional experiences, altering functional connectivity and reducing next-day subjective emotionality.

β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation

Independent evidence associates β-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that β-amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.

Wake deterioration and sleep restoration of human learning

Summary While the benefit of sleep after learning in offline consolidation is established [1], a role for sleep before learning in promoting initial memory formation remains largely uncharacterized. Existing theoretical frameworks speculate that accrued time awake, associated with ongoing experience, decreases learning capacity, while specific non-rapid-eye-movement (NREM) oscillations support restoration of learning ability [1,2]. Despite these model predictions, it remains untested whether episodic learning capacity remains stable across the day, or is progressively compromised by continued time awake. Furthermore, it is similarly unclear whether the presence, rather than the detrimental absence, of sleep restores efficient learning ability, and if so, what aspect(s) of sleep physiology support such reinstatement [3,4]. We have tested these related hypotheses, and report here a learning interaction, such that episodic encoding capacity deteriorates across a daytime waking interval, but sleep and associated NREM spindle oscillations restore efficient learning ability.

The Role of Sleep in Directed Forgetting and Remembering of Human Memories

Ample evidence supports a role for sleep in the offline consolidation of memory. However, circumstances exist where forgetting can be as critical as remembering, both in daily life and clinically. Using a directed forgetting paradigm, here, we investigate the impact of explicit cue instruction during learning, prior to sleep, on subsequent remembering and forgetting of memory, after sleep. We demonstrate that sleep, relative to time awake, can selectively ignore the facilitation of items previously cued to be forgotten, yet preferentially enhance recall for items cued to be remembered; indicative of specificity based on prior waking instruction. Moreover, the success of this differential remember/forget effect is strongly correlated with fast sleep spindles over the left superior parietal cortex. Furthermore, electroencephalography source analysis of these spindles revealed a repeating loop of current density between selective memory-related regions of the superior parietal, medial temporal, and right prefrontal cortices. These findings move beyond the classical notion of sleep universally strengthening information. Instead, they suggest a model in which sleep may be more ecologically attuned to instructions present during learning while awake, supporting both remembering and targeted forgetting of human memories.

Impaired Prefrontal Sleep Spindle Regulation of Hippocampal-Dependent Learning in Older Adults

A hallmark feature of cognitive aging is a decline in the ability to form new memories. Parallel to these cognitive impairments are marked disruptions in sleep physiology. Despite recent evidence in young adults establishing a role for sleep spindles in restoring hippocampal-dependent memory formation, the possibility that disrupted sleep physiology contributes to age-related decline in hippocampal-dependent learning remains unknown. Here, we demonstrate that reduced prefrontal sleep spindles by over 40% in older adults statistically mediates the effects of old age on next day episodic learning, such that the degree of impaired episodic learning is explained by the extent of impoverished prefrontal sleep spindles. In addition, prefrontal spindles significantly predicted the magnitude of impaired next day hippocampal activation, thereby determining the influence of spindles on post-sleep learning capacity. These data support the hypothesis that disrupted sleep physiology contributes to age-related cognitive decline in later life, the consequence of which has significant treatment intervention potential.

The sleep-deprived human brain

How does a lack of sleep affect our brains? In contrast to the benefits of sleep, frameworks exploring the impact of sleep loss are relatively lacking. Importantly, the effects of sleep deprivation (SD) do not simply reflect the absence of sleep and the benefits attributed to it; rather, they reflect the consequences of several additional factors, including extended wakefulness. With a focus on neuroimaging studies, we review the consequences of SD on attention and working memory, positive and negative emotion, and hippocampal learning. We explore how this evidence informs our mechanistic understanding of the known changes in cognition and emotion associated with SD, and the insights it provides regarding clinical conditions associated with sleep disruption.

Nocturnal mnemonics: sleep and hippocampal memory processing.

As critical as waking brain function is to learning and memory, an established literature now describes an equally important yet complementary role for sleep in information processing. This overview examines the specific contribution of sleep to human hippocampal memory processing; both the detriments caused by a lack of sleep, and conversely, the proactive benefits that develop following the presence of sleep. First, a role for sleep before learning is discussed, preparing the hippocampus for initial memory encoding. Second, a role for sleep after learning is considered, modulating the post-encoding consolidation of hippocampal-dependent memory. Third, a model is outlined in which these encoding and consolidation operations are symbiotically accomplished, associated with specific NREM sleep physiological oscillations. As a result, the optimal network outcome is achieved: increasing hippocampal independence and hence overnight consolidation, while restoring next-day sparse hippocampal encoding capacity for renewed learning ability upon awakening. Finally, emerging evidence is considered suggesting that, unlike previous conceptions, sleep does not universally consolidate all information. Instead, and based on explicit as well as saliency cues during initial encoding, sleep executes the discriminatory offline consolidation only of select information. Consequently, sleep promotes the targeted strengthening of some memories while actively forgetting others; a proposal with significant theoretical and clinical ramifications.

Tired and Apprehensive: Anxiety Amplifies the Impact of Sleep Loss on Aversive Brain Anticipation

Anticipation is an adaptive process, aiding preparatory responses to potentially threatening events. However, excessive anticipatory responding and associated hyper-reactivity in the amygdala and insula are integral to anxiety disorders. Despite the co-occurrence of sleep disruption and anxiety disorders, the impact of sleep loss on affective anticipatory brain mechanisms, and the interaction with anxiety, remains unknown. Here, we demonstrate that sleep loss amplifies preemptive responding in the amygdala and anterior insula during affective anticipation in humans, especially for cues with high predictive certainty. Furthermore, trait anxiety significantly determined the degree of such neural vulnerability to sleep loss: individuals with highest trait anxiety showed the greatest increase in anticipatory insula activity when sleep deprived. Together, these data support a neuropathological model in which sleep disruption may contribute to the maintenance and/or exacerbation of anxiety through its impact on anticipatory brain function. They further raise the therapeutic possibility that targeted sleep restoration in anxiety may ameliorate excessive anticipatory responding and associated clinical symptomatology.