Anna Trippel

The importance of sleep as a key component of cardiovascular health has been increasingly recognized. Our previous research demonstrated that auditory‐enhanced slow waves increase cardiac function, but the underlying mechanisms behind these beneficial effects remain uncertain. In this study, we examined the influence of two types of slow waves on cardiovascular functions. 18 healthy middle‐aged men participated in a three‐night sleep lab experiment under three conditions: two auditory slow wave enhancement conditions and one SHAM control. We found that the strength of heart rate and blood pressure responses occurring concurrently with slow waves predicts post‐sleep cardiac function in men as measured through transthoracic echocardiography. Furthermore, we observed that highly synchronized type I slow waves, compared to lower‐amplitude type II slow waves, are primarily associated with increased cardiovascular responses (transient increase in heart rate and blood pressure). While auditory stimulation enhances both types of slow waves, they display distinct temporal dynamics, suggesting different underlying brain and body microstates. These distinct slow wave types may affect cardiovascular function differently, indicating that targeted slow wave stimulation could be a strategic approach to enhancing cardiac function. Trial Registration: This study was registered under clinicaltrials.gov (NCT04166916)

Background: Cocaine is the most frequently used stimulant worldwide, with increasing consumption rates in Europe. Cocaine use is associated with great harm to individuals and society. As of today, psychotherapeutic interventions for cocaine use disorder (CUD) demonstrate only modest effect sizes, and no pharmacotherapy has been approved due to gaps in understanding the disease. However, a novel pharmacotherapeutic target, i.e. glutamatergic neurotransmission, emerged from animal models of addiction. Specifically, after chronic cocaine administration, glutamate concentrations in the nucleus accumbens (NAcc) of rodents are reduced, while there is an overflow of glutamate during cue-induced cocaine-seeking. Recently, this glutamatergic imbalance has also been observed in humans with CUD. Additionally, promising findings with regard to novel psychotherapeutic approaches came from neurofeedback training (NFT) studies where participants use cognitive strategies to regulate their activity within a specific brain region based on “real-time” feedback about its activity as assessed by real-time functional magnetic resonance imaging (rt-fMRI). For example, participants with CUD successfully learned to regulate their brain activity in reward areas of the midbrain using reward imagery and to reconstitute reward sensitivity to non-drug related reinforcers like, e.g. social interactions, athletic or professional achievements. We therefore investigate the therapeutic potential and the underlying mechanisms of two interventions, a single dose of ketamine and a reward imagery rt-fMRI NFT in 120 participants with CUD. Methods: We examine a single ketamine infusion, three sessions of reward imagery rt-fMRI NFT, and the combination of those interventions contrasted to a placebo infusion or a sham NFT in 120 participants with CUD. The study is designed in a randomized, placebo-controlled, double-blind fashion with four study arms. Discussion: We expect both interventions to have a positive effect on the proportion of cocaine use days. We predict glutamate levels in the reward system to increase with the ketamine infusion and to reduce craving, a re-enhanced sensitivity towards natural rewards resulting from the rt-fMRI NFT, and synergistic effects of the combined interventions. This neurobiologically informed approach has the potential to open new avenues for the treatment of CUD through individualised and integrated pharmaco-psychotherapy. Trial registration. NCT06125054 ClinicalTrials.gov. Registered on October 26, 2023.

Background: Cocaine is the most frequently used stimulant worldwide, with increasing consumption rates in Europe. Cocaine use is associated with great harm to individuals and society. As of today, psychotherapeutic interventions for cocaine use disorder (CUD) demonstrate only modest effect sizes, and no pharmacotherapy has been approved due to gaps in understanding the disease. However, a novel pharmacotherapeutic target, i.e. glutamatergic neurotransmission, emerged from animal models of addiction. Specifically, after chronic cocaine administration, glutamate concentrations in the nucleus accumbens (NAcc) of rodents are reduced, while there is an overflow of glutamate during cue-induced cocaine-seeking. Recently, this glutamatergic imbalance has also been observed in humans with CUD. Additionally, promising findings with regards to novel psychotherapeutic approaches came from neurofeedback training (NFT) studies where participants use cognitive strategies to regulate their activity within a specific brain region based on “real-time” feedback about its activity as assessed by real-time functional magnetic resonance imaging (rt-fMRI). For example, participants with CUD successfully learned to regulate their brain activity in reward areas of the midbrain using reward imagery, and to reconstitute reward sensitivity to non-drug related reinforcers like e.g., social interactions, athletic or professional achievements. We therefore investigate the therapeutic potential and the underlying mechanisms of two interventions, a single dose of ketamine and a reward imagery rt-fMRI NFT in 120 participants with CUD. Methods: We examine a single ketamine infusion, three sessions of reward imagery rt-fMRI NFT, and the combination of those interventions contrasted to a placebo infusion or a sham NFT in 120 participants with CUD. The study is designed in a randomized, placebo-controlled, double-blind fashion with four study arms. Discussion: We expect both interventions to have a positive effect on the proportion of cocaine use days. We predict glutamate levels in the reward system to increase with the ketamine infusion and to reduce craving, a re-enhanced sensitivity towards natural rewards resulting from the rt-fMRI NFT, and synergistic effects of the combined interventions. This neurobiologically informed approach has the potential to open new avenues for the treatment of CUD through individualized and integrated pharmaco-psychotherapy. Trial registration: NCT06125054 ClinicalTrials.gov, registered on October 26, 2023. https://clinicaltrials.gov/study/NCT06125054

Summary: Deep sleep oscillations are proposed to be central in restoring brain function and to affect different aspects of motor performance such as facilitating the consolidation of motor sequences resulting in faster and more accurate sequence tapping. Yet, whether deep sleep modulates performance fatigability during fatiguing tasks remains unexplored. We investigated overnight changes in tapping speed and resistance against performance fatigability via a finger tapping task. During fast tapping, fatigability manifests as a reduction in speed (or “motor slowing”) which affects all tapping tasks, including motor sequences used to study motor memory formation. We further tested whether overnight changes in performance fatigability are influenced by enhancing deep sleep oscillations using auditory stimulation. We found an overnight increase in tapping speed alongside a reduction in performance fatigability and perceived workload. Auditory stimulation led to a global enhancement of slow waves and both slow and fast spindles during the stimulation window and a local increase in slow spindles in motor areas across the night. However, overnight performance improvements were not significantly modulated by auditory stimulation and changes in tapping speed or performance fatigability were not predicted by individual changes in deep sleep oscillations. Our findings demonstrate overnight changes in fatigability but revealed no evidence suggesting that this effect is causally linked to temporary augmentation of slow waves or sleep spindles. Our results are important for future studies using tapping tasks to test the relationship between sleep and motor memory consolidation, as overnight changes in objectively measured and subjectively perceived fatigue likely impact behavioural outcomes.

The interplay between slow-wave sleep and cardiovascular health is increasingly recognized. Our prior research showed that auditory-enhanced slow waves can boost cardiac function, yet the mechanisms behind this remain unclear. Advancing these findings, our current analysis dissected the effects of two slow wave types on cardiovascular function, using data from 18 middle-aged men across three nights. We found that the strength of heart rate and blood pressure responses concurrent with slow waves predicts cardiac function post-sleep. Notably, we identified that highly synchronized type I slow waves, as opposed to lower-amplitude type II slow waves, primarily co-occur with these cardiovascular pulsations. While auditory stimulation enhances both types of slow waves, they exhibit distinct temporal dynamics, pointing to different underlying biological mechanisms. This study crucially addresses how distinct slow wave types can affect cardiovascular function, implying that targeted slow wave stimulation could be a strategic approach to improve heart health.

Introduction The role of sleep in cardiovascular health, particularly the impact of deep non-rapid eye movement (NREM) sleep, is gaining interest in the prevention of cardiovascular diseases (Grandner et al., 2016). Essentially slow waves, prominent brain oscillations during deep sleep, seem to represent an important cardiovascular recovery process for the human body. However, to date, the specific mechanisms through which sleep affects cardiovascular function and whether slow waves accelerate recovery remain elusive. Methods Here, we explored the role of slow waves in promoting cardiovascular function. In this randomized, cross-over trial involving 18 healthy male participants (Huwiler et al., 2023), we investigated how experimentally enhancing slow waves via auditory stimulation (Huwiler et al., 2022) impacts cardiovascular dynamics during sleep and next-day cardiac function, assessed via an echocardiography. All participants underwent three experimental nights including two conditions for slow wave enhancement and one SHAM control condition while brain oscillatory, blood pressure, and cardiac dynamics were continuously measured during sleep. Results Using a linear mixed-effect model approach, we found auditory stimulation to significantly increase slow wave activity (F(2, 33.095) = 11.397, p < 0.001) during times of stimulation. This slow wave enhancement coincided with a dynamic cardiovascular activation, indicated through short increases in blood pressure and a biphasic heart rate response. After sleep, we found a significant increase in general longitudinal strain (F(2, 34) = 81.17, p < 0.001), an increase in left-ventricular ejection fraction (F(2, 34) = 4.55, p = 0.018), and a decrease in E/e’ ratio (F(2, 34) = 3.38, p = 0.046) for both slow wave stimulation conditions compared to SHAM. Discussion/Conclusion We show that slow wave stimulation induces a cardiovascular activation response possibly related to increasing cardiovascular stability during sleep (De Zambotti et al., 2016). Moreover, we demonstrate that slow wave stimulation enhances left-ventricular systolic and diastolic function, both together indicating improved cardiac function. Altogether, this points towards the functional involvement of slow waves in promoting cardiovascular health. Therefore, sleep slow wave stimulation may be considered a potential supplementary method in treating cardiovascular diseases involving decreased left-ventricular function. Furthermore, our findings hint that enhancing slow waves could potentially optimize post-exercise recovery processes and increase cardiovascular well-being. References De Zambotti, M., Willoughby, A. R., Franzen, P. L., Clark, D. B., Baker, F. C., & Colrain, I. M. (2016). K-complexes: Interaction between the central and autonomic nervous systems during sleep. Sleep, 39(5), 1129–1137. https://doi.org/10.5665/sleep.5770 Grandner, M. A., Alfonso-Miller, P., Fernandez-Mendoza, J., Shetty, S., Shenoy, S., & Combs, D. (2016). Sleep: Important considerations for the prevention of cardiovascular disease. Current Opinion in Cardiology, 31(5), 551–565. https://doi.org/10.1097/HCO.0000000000000324 Huwiler, S., Carro-Domínguez, M., Stich, F. M., Sala, R., Aziri, F., Trippel, A., Ryf, T., Markendorf, S., Niederseer, D., Bohm, P., Stoll, G., Laubscher, L., Thevan, J., Spengler, C. M., Gawinecka, J., Osto, E., Huber, R., Wenderoth, N., Schmied, C., & Lustenberger, C. (2023). Auditory stimulation of sleep slow waves enhances left ventricular function in humans. European Heart Journal, 44(40), 4288–4291. https://doi.org/10.1093/eurheartj/ehad630 Huwiler, S., Carro Dominguez, M., Huwyler, S., Kiener, L., Stich, F. M., Sala, R., Aziri, F., Trippel, A., Schmied, C., Huber, R., Wenderoth, N., & Lustenberger, C. (2022). Effects of auditory sleep modulation approaches on brain oscillatory and cardiovascular dynamics. Sleep, 45(9), 1–36. https://doi.org/10.1093/sleep/zsac155

Although the impact of sleep on cardiovascular health is widely accepted,¹ precise mechanisms by which specific brain oscillations during sleep facilitate post-sleep cardiac function remain unclear. Slow waves, the prominent brain oscillations of non-rapid eye movement (NREM, here NREM Stage 2 + 3) sleep, are hypothesized to play a critical role in mediating the beneficial effects of sleep on cardiovascular functioning. Here, we used auditory stimulation to experimentally enhance slow waves and test whether that affects cardiovascular function during and after sleep.