Sleep: Plasticity, Excitability and Brain Disorders

May 2-9, 2026

Director: Chiara Cirelli

University of Wisconsin – Madison, Madison, USA

Faculty:

Derk-Jan Dijk, UK Dementia Research Institute at the University of Surrey, UK

Inna Slutsky, Tel Aviv University, Israel

Giulio Tononi, University of Wisconsin-Madison, Madison, USA

Laurent Sheybani, University College London, UK

Melanie Boly, University of Wisconsin School of Medicine and Public Health, USA

Marc Aurel Busche, University of Basel, Switzerland & University College London, UK 

Chiara Cirelli, University of Wisconsin-Madison, Madison, USA

Sleep plays a key role in the maintenance of synaptic homeostasis and the regulation of neuronal excitability. Both functions are impaired in diverse brain pathologies, including neurodegenerative diseases, epilepsy, and major depressive disorder, all of which are also associated with sleep disturbances. Is poor sleep a consequence of brain pathology, or does it contribute to its aetiology? By discussing mechanistic studies in animal models and clinical evidence from patient populations, this course will review the current evidence for the role of sleep in synaptic homeostasis and discuss the complex link between sleep and these pathologies.

Chiara Cirelli

Sleep and renormalization of synaptic weight and excitatory strength

There is converging evidence that sleep promotes the renormalization of excitatory synaptic weights after ongoing learning during waking leads to a net increase in excitatory synaptic strength in many brain circuits. Using electrophysiological, molecular, and ultrastructural markers of synaptic strength, emerging evidence in different brain regions and across animal species will be discussed. Also, the candidate molecular mechanisms that account for this process’s selectivity and its beneficial effects—saving energy, avoiding synaptic saturation, and promoting memory consolidation — will be analysed in depth.
Novel results point to the crucial role of slow wave sleep, and the underlying ON/OFF pattern of cortical activity, in promoting sleep-dependent synaptic down-selection. There is also converging evidence, in animal models and humans, that early features of many neurodegenerative diseases include synaptic dysfunction and neuronal hyperexcitability, often confined to the sleep state. Dedicated attention will be devoted to the evidence that suggests how sleep-dependent synaptic down-selection can therefore contribute to reducing the risk of neurodegeneration.

Giulio Tononi

Innovative neuromodulatory tools for the increase of slow waves

During non-rapid eye movement (NREM) sleep, which comprises 75–80% of total sleep time, individual slow waves are detected on the EEG when many cortical neurons switch nearly synchronously between ON periods of firing and OFF periods of silence. Slow waves are believed to mediate key restorative functions attributed to NREM sleep, including synaptic renormalisation and memory consolidation. Disrupted slow wave activity is linked to impaired cognitive functioning, including poorer performance on visuomotor and perceptual learning tasks. Conversely, the enhancement of slow waves has been shown to improve memory performance. Two common methods to boost slow waves are acoustic stimulation and transcranial electrical stimulation (TES). However, acoustic stimulation strong enough to evoke slow waves can be close to the threshold for awakening the participant. Conventional TES, which typically employs frequencies below 1 kHz, results in electrical artefacts during stimulation that prevent adequate evaluation of simultaneous EEG recordings, particularly at the stimulation frequency. Furthermore, conventional TES stimulates broadly, affecting superficial regions with decreasing effectiveness over deeper brain regions when using parameters that do not produce scalp discomfort. I will discuss an innovative neuromodulatory tool that may overcome these limitations—Transcranial Electrical Stimulation with Temporal Interference (TES-TI), and present new results showing that TES-TI targeting the left ventromedial prefrontal cortex increases slow wave activity during stimulation, with effects persisting afterwards. Additionally, participants exhibiting the greatest increases in slow wave activity between the first and last intervention nights of the four-week protocol also showed the most significant improvements in restorative sleep ratings. I will also discuss the extensive potential of TES-TI to promote sleep spindles and several aspects of REM sleep.

Marc Aurel Busche

Sleep, Alzheimer’s disease and neurodegeneration

Sleep is not just a time for rest; it is when the brain reorganises itself to strengthen memories and maintain stable networks. During healthy sleep, slow waves and hippocampal sharp-wave ripples help reinforce important connections and weaken others to support learning and memory. In Alzheimer’s disease (AD), this delicate balance breaks down. The two key pathological proteins, β-amyloid and tau, accumulate in vulnerable brain regions and disrupt normal patterns of neuronal communication. I will present evidence from humans and animal models showing that β-amyloid causes brain networks to become overactive at night, especially during non-REM sleep, leading to epileptiform activities and impairing the slow oscillations that normally organise memory consolidation. I will also show how tau further disrupts this process by interfering with hippocampal neuronal complex-spike burst patterns and sharp-wave ripple events that replay memories during sleep. Together, these pathologies distort the nightly dialogue between hippocampus and cortex, preventing the brain from stabilising memories and regulating excitability. Finally, I will discuss whether restoring normal sleep rhythms by enhancing slow waves or reducing nocturnal hyperactivity could protect brain function and delay neurodegeneration. Sleep, in this view, is not a passive victim of disease but a modifiable process that may help stabilise networks and safeguard memory.

Inna Slutsky

The plasticity-stability dilemma and the role of sleep in homeostasis

The hippocampus is a central hub for experience-dependent neuronal plasticity, essential for encoding and retrieving memories. It undergoes continual structural and functional remodelling that enables adaptation to ongoing experience. While Hebbian plasticity is fundamental for memory formation and storage, it also poses challenges to network stability. This plasticity–stability dilemma, observed in both biological and artificial networks, is especially pronounced in the hippocampus, which must preserve access to stored information while adapting to internal and external perturbations. Disruptions in this delicate balance contribute to memory disorders such as Alzheimer’s disease, highlighting the need to understand how the hippocampus maintains functional stability amid constant change. Despite extensive research, the mechanisms operating in vivo that confer resilience—the capacity to recover from perturbations—remain poorly understood. Homeostatic plasticity provides a conceptual solution through slow, negative-feedback mechanisms that regulate neuronal and network activity around a set point. I will discuss key open questions: (1) Which features of hippocampal activity are regulated in response to persistent perturbations? (2) How do stabilizing mechanisms operate across sleep–wake states? How do they avoid interfering with Hebbian plasticity? Which nodes of homeostatic control are influenced by sleep? (3) Can homeostatic mechanisms preserve access to stored memories without compromising memory specificity? (4) Is homeostatic regulation altered during specific vigilance states in the presymptomatic stages of Alzheimer’s disease? I will show new results addressing the plasticity–stability dilemma and the role of sleep in homeostatic regulation of hippocampal activity and function. Finally, I will discuss principles of network homeostasis that support memory resilience and strategies to stabilize cognition by engaging endogenous homeostatic mechanisms.

Derk-Jan Dijk

Sleep disturbance and brain function in dementia

Sleep plays a role in maintaining brain health, and sleep disturbances are both a risk factor for, and highly common in, dementia. The specific features of sleep that contribute to brain health and dementia risk, as well as the mechanisms involved, remain under discussion. Evidence has been found for various aspects of sleep, including slow waves, sleep spindles, slow-oscillation-spindle coupling, REM sleep, sleep continuity, total sleep time, sleep regularity, and excessive napping. These aspects of sleep may bring about or reflect changes in brain excitability and plasticity or contribute to glymphatic clearance. Advances in sleep monitoring technology and blood-based biomarkers for dementia provide new opportunities to address these relationships both in sleep laboratories and at community scale. Recent studies exploring the connection between sleep, circadian rhythms, blood biomarkers, and brain function in ageing and Alzheimer’s disease will also be a focus of discussion during the lectures.

Laurent Sheybani

Sleep and epilepsy

Epileptic seizures present as symptoms and signs displayed by patients as a consequence of abnormal neuronal activity. The term “abnormal” encompasses many meanings, including excessively or synchronously abnormal neuronal activity. At its core, a disruption of neuronal excitability is fundamental to seizure development.
Importantly, the sleep-wake cycle is a powerful modulator of neuronal excitability and has also been recognised as a significant factor influencing the risk of epileptic seizures. While the former observation could help explain the latter, only limited evidence of a causal relationship exists. This interplay between epilepsy and sleep offers a unique opportunity to utilise the naturally occurring modulation of brain excitability – namely, the sleep-wake cycle – to assess its impact on a prevalent neurological condition, i.e., epilepsy.
During the lectures, I will examine the interaction between epilepsy and sleep across three levels of analysis: cellular, network, and systems. The aim is to move beyond correlational findings that characterise much of the current literature and to investigate recent findings on causal mechanisms. I will then focus on a key sleep phenomenon involved in the regulation of excitability: sleep slow waves. I will then introduce basic mechanisms of the generation of sleep slow waves and discuss how these processes contribute to their homeostatic role in regulating brain excitability. This will lead me to present recent research on how slow waves might be involved in reducing excitability associated with epileptic activities.

Melanie Boly

Disrupted sleep homeostasis and synaptic dysregulation in focal epilepsy

Sleep, and in particular non-rapid eye movement (NREM) slow-wave activity (SWA), provides a unique window into the homeostatic regulation of cortical excitability and synaptic renormalization. Using high-density EEG recordings, we demonstrated that patients with focal epilepsy show a marked disruption of sleep homeostasis, characterized by abnormally high NREM SWA in a bilateral fronto-temporal network, proportional to the number of seizures with impaired awareness experienced by patients over the previous days. In addition, we found that a higher frequency of interictal spikes during NREM sleep was associated with a dampened overnight SWA decline, which in turn predicted next-day cognitive performance.
Our more recent work using intracranial recordings also provided direct evidence for maximally abnormal sleep homeostasis in the seizure-onset zone, with excessive SWA persisting towards the end of the night and a dampened local SWA decline compared to neighbouring regions. At the local level, the severity of intracranial sleep homeostasis abnormalities was also proportional to ictal phase-locked high-gamma, a validated marker of local octal recruitment. Altogether, these findings suggest that epileptic network highjack normal learning mechanisms to escape from normal sleep homeostasis, and that such an escape is worsened, in a deleterious feedback loop, by recurrent epileptiform activities and seizures. Potential implications for epileptogenesis mechanisms and for neuromodulation therapies will be discussed.