Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence

Short sleep duration has a substantial influence on the overall health of an individual. Short sleep time can
be a consequence of lifestyle habits, environmental factors, or the presence of a sleep disorder, such as
insomnia or sleep-disordered breathing. Short sleep time is associated with increased morbidity and
mortality, mainly from cardiovascular disorders (including coronary artery disease, arrhythmias, and
hypertension). Several biological mechanisms have been proposed as a possible link between short sleep
duration and these diseases, such as involvement of the autonomic nervous system, endothelial function,
metabolic regulation, inflammation, and the coagulation system. In this Review, we provide an overview
on the effects of short sleep duration on cardiovascular health and diseases and discuss the main
pathophysiological mechanisms involved, taking into account both experimental data and clinical
evidence.

Sleep loss causes social withdrawal and loneliness

Loneliness and social isolation markedly increase mortality risk, and are linked to numerous mental and
physical comorbidities, including sleep disruption. But does sleep loss causally trigger loneliness? Here,
we demonstrate that a lack of sleep leads to a neural and behavioral phenotype of social withdrawal and
loneliness; one that can be perceived by other members of society, and reciprocally, makes those societal
members lonelier in return. We propose a model in which sleep loss instigates a propagating, self-
reinforcing cycle of social separation and withdrawal.

Response to therapeutic sleep deprivation: a naturalistic study of clinical and genetic factors and
post-treatment depressive symptom trajectory

Research has shown that therapeutic sleep deprivation (SD) has rapid antidepressant effects in the
majority of depressed patients. Investigation of factors preceding and accompanying these effects may
facilitate the identification of the underlying biological mechanisms. This exploratory study aimed to
examine clinical and genetic factors predicting response to SD and determine the impact of SD on illness
course. Mood during SD was also assessed via visual analogue scale. Depressed inpatients (n = 78) and
healthy controls (n = 15) underwent ~36 h of SD. Response to SD was defined as a score of ≤ 2 on the
Clinical Global Impression Scale for Global Improvement. Depressive symptom trajectories were
evaluated for up to a month using self/expert ratings. Impact of genetic burden was calculated using
polygenic risk scores for major depressive disorder. In total, 72% of patients responded to SD.
Responders and non-responders did not differ in baseline self/expert depression symptom ratings, but
mood differed. Response was associated with lower age (p = 0.007) and later age at life-time disease
onset (p = 0.003). Higher genetic burden of depression was observed in non-responders than healthy
controls. Up to a month post SD, depressive symptoms decreased in both patients groups, but more in
responders, in whom effects were sustained. The present findings suggest that re-examining SD with a
greater focus on biological mechanisms will lead to better understanding of mechanisms of depression.
Selective neuronal lapses precede human cognitive lapses following sleep deprivation

Sleep deprivation is a major source of morbidity with widespread health effects, including increased risk
of hypertension, diabetes, obesity, heart attack, and stroke1. Moreover, sleep deprivation brings about
vehicle accidents and medical errors and is therefore an urgent topic of investigation. During sleep
deprivation, homeostatic and circadian processes interact to build up sleep pressure, which results in slow
behavioral performance (cognitive lapses) typically attributed to attentional thalamic and frontoparietal
circuits, but the underlying mechanisms remain unclear. Recently, through study of
electroencephalograms (EEGs) in humans and local field potentials (LFPs) in nonhuman primates and
rodents it was found that, during sleep deprivation, regional 'sleep-like' slow and theta (slow/theta) waves
co-occur with impaired behavioral performance during wakefulness. Here we used intracranial electrodes
to record single-neuron activities and LFPs in human neurosurgical patients performing a face/nonface
categorization psychomotor vigilance task (PVT) over multiple experimental sessions, including a session
after full-night sleep deprivation. We find that, just before cognitive lapses, the selective spiking
responses of individual neurons in the medial temporal lobe (MTL) are attenuated, delayed, and
lengthened. These 'neuronal lapses' are evident on a trial-by-trial basis when comparing the slowest
behavioral PVT reaction times to the fastest. Furthermore, during cognitive lapses, LFPs exhibit a relative
local increase in slow/theta activity that is correlated with degraded single-neuron responses and with
baseline theta activity. Our results show that cognitive lapses involve local state-dependent changes in
neuronal activity already present in the MTL.

Exploring phylogeny to find the function of sleep

During sleep, animals do not eat, reproduce or forage. Sleeping animals are vulnerable to predation. Yet,
the persistence of sleep despite evolutionary pressures, and the deleterious effects of sleep deprivation,
indicate that sleep serves a function or functions that cannot easily be bypassed. Recent research
demonstrates sleep to be phylogenetically far more pervasive than previously appreciated; it is possible
that the very first animals slept. Here, we give an overview of sleep across various species, with the aim
of determining its original purpose. Sleep exists in animals without cephalized nervous systems and can
be influenced by non-neuronal signals, including those associated with metabolic rhythms. Together,
these observations support the notion that sleep serves metabolic functions in neural and non-neural
tissues.

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.
Degradation of neural representations in higher visual cortex by sleep deprivation

A night of total sleep deprivation (TSD) impairs selective attention and is accompanied by attenuated
activation within ventral visual cortex (VVC). However, finer details of how TSD compromises
selectivity of visual processing remain unclear. Drawing from prior work in cognitive aging, we predicted
that TSD would result in dedifferentiation of neural responses for faces and houses within the VVC.
Instead, we found preservation of category selectivity. This was observed both in voxels highly selective
for each category, and also across multiple voxels evaluated using MVPA. Based on prior findings of
impaired attentional modulation following TSD, we also predicted reduced biasing of neural
representations towards the attended category when participants viewed ambiguous face/house images.
When participants were well rested, attention to houses (or faces) caused activation patterns to more
closely resemble those elicited by isolated house (face) images than face (house) images. During TSD,
attention to faces enhanced neural similarity to both target (face) and distractor (house) representations,
signifying reduced suppression of irrelevant information. Degraded sensory processing reflected in
reduced VVC activation following TSD, thus appears to be a result of impaired top-down modulation of
sensory representations instead of degraded selectivity of maximally category sensitive voxels, or the
dedifferentiation of neural activation patterns.

Procedural performance following sleep deprivation remains impaired despite extended practice
and an afternoon nap

The negative impact of sleep loss on procedural memory is well established, yet it remains unclear how
extended practice opportunities or daytime naps can modulate the effect of a night of sleep deprivation.
Here, participants underwent three training and test conditions on a sequential finger tapping task (SFTT)
separated by at least one week. In the first condition they were trained in the evening followed by a night
of sleep. Two further conditions took place where evening training was followed by a night of total sleep
deprivation (TSD). One of the TSD conditions included a one-hour nap opportunity (15:00). Compared to
the condition in which sleep was permitted, a night of TSD resulted in poorer performance across 4
practices the following day (10:00–19:00). The deleterious effect of a single night of TSD on procedural
performance, was neither clearly alleviated by an afternoon nap nor by multiple practice opportunities.
Interestingly, significant gains in performance were observed in all conditions after a one-week delay.
Recovery sleep on subsequent nights thus appeared to nullify the effect of a single night of sleep
deprivation, underscoring the importance of offline consolidation on the acquisition of procedural skill.

Estimating individual optimal sleep duration and potential sleep debt

In this study, we hypothesized that dynamics of sleep time obtained over consecutive days of extended
sleep in a laboratory reflect an individual’s optimal sleep duration (OSD) and that the difference between
OSD and habitual sleep duration (HSD) at home represents potential sleep debt (PSD). We found that
OSD varies among individuals and PSD showed stronger correlation with subjective/objective sleepiness
than actual sleep time, interacting with individual’s vulnerability of sleep loss. Furthermore, only 1 h of
PSD takes four days to recover to their optimal level. Recovery from PSD was also associated with the
improvement in glycometabolism, thyrotropic activity and hypothalamic-pituitary-adrenocortical axis.
Additionally, the increase (rebound) in total sleep time from HSD at the first extended sleep would be a
simple indicator of PSD. These findings confirmed self-evaluating the degree of sleep debt at home as a
useful clinical marker. To establish appropriate sleep habits, it is necessary to evaluate OSD, vulnerability
to sleep loss, and sleep homeostasis characteristics on an individual basis.