Biomarker of cognitive susceptibility to sleep deprivation

Human Hippocampal Structure: A Novel Biomarker Predicting Mnemonic Vulnerability to, and Recovery from, Sleep Deprivation
Saletin JM, Goldstein-Piekarski AN, Greer SM, Stark S, Stark CE, Walker MP.
The Journal of Neuroscience, 24 February 2016, 36(8):2355-2363

Sleep deprivation impairs the formation of new memories. However, marked interindividual variability exists in the degree to which sleep loss compromises learning, the mechanistic reasons for which are unclear. Furthermore, which physiological sleep processes restore learning ability following sleep deprivation are similarly unknown. Here, we demonstrate that the structural morphology of human hippocampal subfields represents one factor determining vulnerability (and conversely, resilience) to the impact of sleep deprivation on memory formation. Moreover, this same measure of brain morphology was further associated with the quality of nonrapid eye movement slow wave oscillations during recovery sleep, and by way of such activity, determined the success of memory restoration. Such findings provide a novel human biomarker of cognitive susceptibility to, and recovery from, sleep deprivation. Moreover, this metric may be of special predictive utility for professions in which memory function is paramount yet insufficient sleep is pervasive (e.g., aviation, military, and medicine). 

Sleep deprivation does not impact all people equally. Some individuals show cognitive resilience to the effects of sleep loss, whereas others express striking vulnerability, the reasons for which remain largely unknown. Here, we demonstrate that structural features of the human brain, specifically those within the hippocampus, accurately predict which individuals are susceptible (or conversely, resilient) to memory impairments caused by sleep deprivation. Moreover, this same structural feature determines the success of memory restoration following subsequent recovery sleep. Therefore, structural properties of the human brain represent a novel biomarker predicting individual vulnerability to (and recovery from) the effects of sleep loss, one with occupational relevance in professions where insufficient sleep is pervasive yet memory function is paramount.

Curiosity changes brain to enhance learning and memory

States of Curiosity Modulate Hippocampus-Dependent Learning via the Dopaminergic Circuit
Matthias J. Gruber, Bernard D. Gelman, Charan Ranganath
Neuron , Volume 84 , Issue 2 , 486 - 496 

People find it easier to learn about topics that interest them, but little is known about the mechanisms by which intrinsic motivational states affect learning. We used functional magnetic resonance imaging to investigate how curiosity (intrinsic motivation to learn) influences memory. In both immediate and one-day-delayed memory tests, participants showed improved memory for information that they were curious about and for incidental material learned during states of high curiosity. Functional magnetic resonance imaging results revealed that activity in the midbrain and the nucleus accumbens was enhanced during states of high curiosity. Importantly, individual variability in curiosity-driven memory benefits for incidental material was supported by anticipatory activity in the midbrain and hippocampus and by functional connectivity between these regions. These findings suggest a link between the mechanisms supporting extrinsic reward motivation and intrinsic curiosity and highlight the importance of stimulating curiosity to create more effective learning experiences.

Link between sleep and Alzheimer's disease

β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation
Bryce A Mander, Shawn M Marks, Jacob W Vogel, Vikram Rao, Brandon Lu, Jared M Saletin, Sonia Ancoli-Israel, William J Jagust and Matthew P Walker
Nature Neuroscience

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.

Sleep and dreaming improves memory organization, emotion regulation and creativity

Sleep and dreaming are for important matters.
Perogamvros L, Dang-Vu TT, Desseilles M, Schwartz S.
Frontiers in Psychology, 25 July 2013 

Recent studies in sleep and dreaming have described an activation of emotional and reward systems, as well as the processing of internal information during these states. Specifically, increased activity in the amygdala and across mesolimbic dopaminergic regions during REM sleep is likely to promote the consolidation of memory traces with high emotional/motivational value. Moreover, coordinated hippocampal-striatal replay during NREM sleep may contribute to the selective strengthening of memories for important events. In this review, we suggest that, via the activation of emotional/motivational circuits, sleep and dreaming may offer a neurobehavioral substrate for the offline reprocessing of emotions, associative learning, and exploratory behaviors, resulting in improved memory organization, waking emotion regulation, social skills, and creativity. Dysregulation of such motivational/emotional processes due to sleep disturbances (e.g., insomnia, sleep deprivation) would predispose to reward-related disorders, such as mood disorders, increased risk-taking and compulsive behaviors, and may have major health implications, especially in vulnerable populations.

Good sleep = good memory

Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging
Bryce A Mander, Vikram Rao, Brandon Lu, Jared M Saletin, John R Lindquist, Sonia Ancoli-Israel, William Jagust & Matthew P Walker
Nature Neuroscience (2013) 

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.

Beneficial effects of sleep for memory consolidation

Offline consolidation of memory varies with time in slow wave sleep and can be accelerated by cuing memory reactivations.
Diekelmann S, Biggel S, Rasch B, Born J.
Neurobiology of Learning and Memory Volume 98, Issue 2, September 2012, Pages 103–111

Memory representations are reactivated during slow-wave sleep (SWS) after learning, and these reactivations cause a beneficial effect of sleep for memory consolidation. Memory reactivations can also be externally triggered during sleep by associated cues which enhance the sleep-dependent memory consolidation process. Here, we compared in humans the influence of sleep periods (i) of 40min and (ii) of 90min without externally triggered reactivations and (iii) of externally triggered reactivations by an associated odor cue during a 40-min sleep period on the consolidation of previously learned hippocampus-dependent visuo-spatial memories. We show that external reactivation by an odor cue during the 40-min sleep period enhanced memory stability to the same extent as 90min of sleep without odor reactivation. In contrast, 40min of sleep without external reactivations were not sufficient to benefit memory. In the 90-min sleep condition, memory enhancements were associated with time spent in SWS and were independent of the presence or absence of REM sleep. These results suggest that the efficacy of hippocampus-dependent memory consolidation depends on the duration of sleep and particularly SWS. External reactivation cues can accelerate the consolidation process even during shorter sleep episodes.

Preferential benefits of sleep

Sleep-Dependent Facilitation of Episodic Memory Details
PLoS ONE 6(11): e27421. doi:10.1371/journal.pone.0027421 (Link)
Els van der Helm, Ninad Gujar, Masaki Nishida, Matthew P. Walker

While a role for sleep in declarative memory processing is established, the qualitative nature of this consolidation benefit, and the physiological mechanisms mediating it, remain debated. Here, we investigate the impact of sleep physiology on characteristics of episodic memory using an item- (memory elements) and context- (contextual details associated with those elements) learning paradigm; the latter being especially dependent on the hippocampus. Following back-to-back encoding of two word lists, each associated with a different context, participants were assigned to either a Nap-group, who obtained a 120-min nap, or a No Nap-group. Six hours post-encoding, participants performed a recognition test involving item-memory and context-memory judgments. In contrast to item-memory, which demonstrated no between-group differences, a significant benefit in context-memory developed in the Nap-group, the extent of which correlated both with the amount of stage-2 NREM sleep and frontal fast sleep-spindles. Furthermore, a difference was observed on the basis of word-list order, with the sleep benefit and associated physiological correlations being selective for the second word-list, learned last (most proximal to sleep). These findings suggest that sleep may preferentially benefit contextual (hippocampal-dependent) aspects of memory, supported by sleep-spindle oscillations, and that the temporal order of initial learning differentially determines subsequent offline consolidation.

The memory function of sleep

Nature Reviews Neuroscience 11, 114-126 (February 2010) 
Susanne Diekelmann & Jan Born

Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory, depending on the specific conditions of learning and the timing of sleep. Consolidation during sleep promotes both quantitative and qualitative changes of memory representations. Through specific patterns of neuromodulatory activity and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement (REM) sleep support system consolidation and synaptic consolidation, respectively. During SWS, slow oscillations, spindles and ripples - at minimum cholinergic activity - coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity - at high cholinergic and theta activity - might favour the subsequent synaptic consolidation of memories in the cortex.

Impair human episodic memory

Single pulse electrical stimulation of the hippocampus is sufficient to impair human episodic memory.
Neuroscience. 2010 Jul 16
Lacruz ME, Valentín A, Seoane JJ, Morris RG, Selway RP, Alarcón G.

They used the single pulse electrical stimulation (SPES) technique to investigate whether more localized stimulation of the hippocampus can affect human episodic memory. A recognition memory test including words, object drawings, abstract drawings and unfamiliar faces was performed without stimulation (baseline) or synchronized with single 1 ms electrical pulses applied to the left, right or both hippocampi in 12 epileptic patients investigated with bilateral depth electrodes. No differences were found in memory performance between baseline and unilateral stimulation, either in the total score or in material-specific scores. In contrast, bilateral stimulation was associated with a pronounced decrease in the median of total memory scores (57%), and of material-specific sub-scores for words (38%), geometrical drawings (81%) and faces (100%). Additional study of stimulation at presentation of stimuli (encoding) versus the recognition memory (retrieval) test phase, showed only reduction in memory at encoding. The results provide causal evidence that the hippocampi are necessary for supporting episodic memory. The induction of memory deficits by bilateral stimulation with parameters that do not induce effects when applied unilaterally suggests that recognition memory can be processed independently by the hippocampus on either hemisphere

More faithful memories for those experiences

Awake replay of remote experiences in the hippocampus
Nature Neuroscience Volume 12, Number 7, July 2009
Published online at http://www.nature.com/natureneuroscience
Mattias P Karlsson & Loren M Frank

Hippocampal replay is thought to be essential for the consolidation of event memories in hippocampal-neocortical networks. Replay is present during both sleep and waking behavior, but although sleep replay involves the reactivation of stored representations in the absence of specific sensory inputs, awake replay is thought to depend on sensory input from the current environment. Here, we show that stored representations are reactivated during both waking and sleep replay. We found frequent awake replay of sequences of rat hippocampal place cells from a previous experience. This spatially remote replay was as common as local replay of the current environment and was more robust when the rat had recently been in motion than during extended periods of quiescence. Our results indicate that the hippocampus consistently replays past experiences during brief pauses in waking behavior, suggesting a role for waking replay in memory consolidation and retrieval.

Consolidation of Associative Memory

Hippocampal sharp wave/ripples during sleep for consolidation of associative memory.
Ramadan W, Eschenko O, Sara SJ.
PLoS One. 2009 Aug 20;4(8):e6697.


The beneficial effect of sleep on memory has been well-established by extensive research on humans, but the neurophysiological mechanisms remain a matter of speculation. This study addresses the hypothesis that the fast oscillations known as ripples recorded in the CA1 region of the hippocampus during slow wave sleep (SWS) may provide a physiological substrate for long term memory consolidation. We trained rats in a spatial discrimination task to retrieve palatable reward in three fixed locations. Hippocampal local field potentials and cortical EEG were recorded for 2 h after each daily training session. There was an increase in ripple density during SWS after early training sessions, in both trained rats and in rats randomly rewarded for exploring the maze. In rats learning the place -reward association, there was a striking further significant increase in ripple density correlated with subsequent improvements in behavioral performance as the rat learned the spatial discrimination aspect of the task. The results corroborate others showing an experience-dependent increase in ripple activity and associated ensemble replay after exploratory activity, but in addition, for the first time, reveal a clear further increase in ripple activity related to associative learning based on spatial discrimination.

Hippocampal theta oscillations are traveling waves

Hippocampal theta oscillations are traveling waves.
Lubenov EV, Siapas AG
Nature 2009;459(7246):534-9.

Theta oscillations clock hippocampal activity during awake behaviour and rapid eye movement (REM) sleep. These oscillations are prominent in the local field potential, and they also reflect the subthreshold membrane potential and strongly modulate the spiking of hippocampal neurons. The prevailing view is that theta oscillations are synchronized throughout the hippocampus, despite the lack of conclusive experimental evidence. In contrast, here we show that in freely behaving rats, theta oscillations in area CA1 are travelling waves that propagate roughly along the septotemporal axis of the hippocampus. Furthermore, we find that spiking in the CA1 pyramidal cell layer is modulated in a consistent travelling wave pattern. Our results demonstrate that theta oscillations pattern hippocampal activity not only in time, but also across anatomical space. The presence of travelling waves indicates that the instantaneous output of the hippocampus is topographically organized and represents a segment, rather than a point, of physical space.