Sleep Deprivation Selectively Upregulates an Amygdala-Hypothalamic Circuit Involved in Food Reward.

Sleep loss is associated with increased obesity risk, as demonstrated by correlations between sleep duration and change in body mass index or body fat percentage. Whereas previous studies linked this weight gain to disturbed endocrine parameters after sleep deprivation or restriction, neuroimaging studies revealed upregulated neural processing of food rewards after sleep loss in reward-processing areas such as the anterior cingulate cortex, ventral striatum, and insula. To address this ongoing debate between hormonal versus hedonic factors underlying sleep-loss-associated weight gain, we rigorously tested the association between sleep deprivation and food cue processing using high-resolution fMRI and assessment of hormones. After taking blood samples from 32 lean, healthy, human male participants, they underwent fMRI while performing a neuroeconomic, value-based decision-making task with snack food and trinket rewards following a full night of habitual sleep and a night of sleep deprivation in a repeated-measures crossover design. We found that des-acyl ghrelin concentrations were increased after sleep deprivation compared with habitual sleep. Despite similar hunger ratings due to fasting in both conditions, participants were willing to spend more money on food items only after sleep deprivation. Furthermore, fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala-hypothalamic coupling after a single night of sleep deprivation. Behavioral and fMRI results were not significantly correlated with changes in acyl, des-acyl, or total ghrelin concentrations. Our results suggest that increased food valuation after sleep loss might be due to hedonic rather than hormonal mechanisms.SIGNIFICANCE STATEMENT Epidemiological studies suggest an association between overweight and reduced nocturnal sleep, but the relative contributions of hedonic and hormonal factors to overeating after sleep loss are a matter of ongoing controversy. Here, we tested the association between sleep deprivation and food cue processing in a repeated-measures crossover design using fMRI. We found that willingness to pay increased for food items only after sleep deprivation. fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala-hypothalamic coupling after a single night of sleep deprivation. However, there was no evidence for hormonal modulations of behavioral or fMRI findings. Our results suggest that increased food valuation after sleep loss is due to hedonic rather than hormonal mechanisms.

REM Sleep Is Causal to Successful Consolidation of Dangerous and Safety Stimuli and Reduces Return of Fear after Extinction.

Sleep has a profound impact on memory consolidation. In this study, human participants underwent Pavlovian conditioning and extinction before we manipulated nocturnal memory consolidation by a split-night protocol with 80 healthy male participants in four groups. Recall after a second (recovery) night of sleep revealed that sleeping the first half of the night, which is dominated by slow-wave sleep, did not improve recall. Conversely, sleeping the second half of the night, which is dominated by rapid eye movement (REM) sleep, led to better discrimination between fear-relevant and neutral stimuli in behavioral and autonomic measures. Meanwhile, staying awake in the second half of the night led to an increase of discrimination between extinguished and neutral stimuli, which was paralleled by an activation of the ventromedial prefrontal cortex and amygdala. We conclude that sleep, especially REM sleep, is causal to successful consolidation of dangerous and safety stimuli and reduces return of fear after extinction. SIGNIFICANCE STATEMENT: We use a split-night protocol to investigate the influence of different sleep phases on successful consolidation of conditioned fear and extinction. Such a protocol uses the fact that in humans the first half of the night is dominated by slow-wave sleep, whereas during the second half, rapid eye movement (REM) sleep is more predominant. Our data show that only REM-rich sleep during the second half of the night promoted good discrimination between fear-relevant and neutral stimuli during recall, while staying awake led to a recovery of discrimination between extinguished and neutral stimuli. This suggests that sleep following extinction contributes independently to successful extinction memory consolidation.

Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans.

In many patients with major depressive disorder, sleep deprivation, or wake therapy, induces an immediate but often transient antidepressant response. It is known from brain imaging studies that changes in anterior cingulate and dorsolateral prefrontal cortex activity correlate with a relief of depression symptoms. Recently, resting-state functional magnetic resonance imaging revealed that brain network connectivity via the dorsal nexus (DN), a cortical area in the dorsomedial prefrontal cortex, is dramatically increased in depressed patients. To investigate whether an alteration in DN connectivity could provide a biomarker of therapy response and to determine brain mechanisms of action underlying sleep deprivations antidepressant effects, we examined its influence on resting state default mode network and DN connectivity in healthy humans. Our findings show that sleep deprivation reduced functional connectivity between posterior cingulate cortex and bilateral anterior cingulate cortex (Brodmann area 32), and enhanced connectivity between DN and distinct areas in right dorsolateral prefrontal cortex (Brodmann area 10). These findings are consistent with resolution of dysfunctional brain network connectivity changes observed in depression and suggest changes in prefrontal connectivity with the DN as a brain mechanism of antidepressant therapy action.

Replay of conditioned stimuli during late REM and stage N2 sleep influences affective tone rather than emotional memory strength.

Emotional memories are reprocessed during sleep, and it is widely assumed that this reprocessing occurs mainly during rapid eye movement (REM) sleep. In support for this notion, vivid emotional dreams occur mainly during REM sleep, and several studies have reported emotional memory enhancement to be associated with REM sleep or REM sleep-related parameters. However, it is still unknown whether reactivation of emotional memories during REM sleep strengthens emotional memories. Here, we tested whether re-presentation of emotionally learned stimuli during REM sleep enhances emotional memory. In a split-night design, participants underwent Pavlovian conditioning after the first half of the night. Neutral sounds served as conditioned stimuli (CS) and were either paired with a negative odor (CS+) or an odorless vehicle (CS-). During sound replay in subsequent late REM or N2 sleep, half of the CS+ and half of the CS- were presented again. In contrast to our hypothesis, replay during sleep did not affect emotional memory as measured by the differentiation between CS+ and CS- in expectancy, arousal and valence ratings. However, replay unspecifically decreased subjective arousal ratings of both emotional and neutral sounds and increased positive valence ratings also for both CS+ and CS- sounds, respectively. These effects were slightly more pronounced for replay during REM sleep. Our results suggest that re-exposure to previously conditioned stimuli during late sleep does not affect emotional memory strength, but rather influences the affective tone of both emotional and neutral memories.

Reactivating memories during sleep by odors: odor specificity and associated changes in sleep oscillations.

Memories are reactivated during sleep. Re-exposure to olfactory cues during sleep triggers this reactivation and improves later recall performance. Here, we tested if the effects of odor-induced memory reactivations are odor-specific, that is, requiring the same odor during learning and subsequent sleep. We also tested whether odor-induced memory reactivation affects oscillatory EEG activity during sleep, as a putative mechanism underlying memory processing during sleep. Participants learned a visuospatial memory task under the presence of an odor. During subsequent SWS, the same odor, a different odor, or an odorless vehicle was presented. We found that odor re-exposure during sleep significantly improves memory only when the same odor was presented again, whereas exposure to a new odor or the odorless vehicle had no effect. The memory-enhancing effect of the congruent odor was accompanied by significant increases in frontal delta (1.5-4.5 Hz) and parietal fast spindle (13.0-15.0 Hz) power as well as by an increased negative-to-positive slope of the frontal slow oscillation. Our results indicate that odor-induced memory reactivations are odor specific and trigger changes in slow-wave and spindle power possibly reflecting a bottom-up influence of hippocampal memory replay on cortical slow oscillations as well as thalamo-cortical sleep spindles.

Re-presentation of Olfactory Exposure Therapy Success Cues during Non-Rapid Eye Movement Sleep did not Increase Therapy Outcome but Increased Sleep Spindles.

Exposure therapy induces extinction learning and is an effective treatment for specific phobias. Sleep after learning promotes extinction memory and benefits therapy success. As sleep-dependent memory-enhancing effects are based on memory reactivations during sleep, here we aimed at applying the beneficial effect of sleep on therapy success by cueing memories of subjective therapy success during non-rapid eye movement sleep after in vivo exposure-based group therapy for spider phobia. In addition, oscillatory correlates of re-presentation during sleep (i.e., sleep spindles and slow oscillations) were investigated. After exposure therapy, spider-phobic patients verbalized their subjectively experienced therapy success under presence of a contextual odor. Then, patients napped for 90 min recorded by polysomnography. Half of the sleep group received the odor during sleep while the other half was presented an odorless vehicle as control. A third group served as a wake control group without odor presentation. While exposure therapy significantly reduced spider-phobic symptoms in all subjects, these symptoms could not be further reduced by re-presenting the odor associated with therapy success, probably due to a ceiling effect of the highly effective exposure therapy. However, odor re-exposure during sleep increased left-lateralized frontal slow spindle (11.0-13.0 Hz) and right-lateralized parietal fast spindle (13.0-15.0 Hz) activity, suggesting the possibility of a successful re-presentation of therapy-related memories during sleep. Future studies need to further examine the possibility to enhance therapy success by targeted memory reactivation (TMR) during sleep.