Author ORCID Identifier
https://orcid.org/0009-0003-4232-1574
Date Available
12-9-2026
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Engineering
Department/School/Program
Biomedical Engineering
Faculty
SRIDHAR SUNDERAM
Abstract
Sleep disturbances accompany many neurological disorders, including epilepsy and Alzheimer’s disease (AD). In epilepsy, pathological electrical discharges such as interictal spikes and seizures are modulated by both rapid eye movement (REM) and NREM stages of sleep. In AD, disrupted sleep impairs glymphatic clearance of amyloid-β and tau, accelerating neurodegeneration. These interactions are reciprocal: neuropathology affects sleep quality, while poor sleep worsens pathology, creating a vicious cycle. These interactions are reciprocal because neuropathology fragments sleep, and poor sleep worsens pathology. This highlights the need for safe, non-pharmacological approaches to restore sleep quality in neurological disease.
Exposure to thermoneutral temperature increases NREM and REM sleep in mice, yet prior studies used constant temperatures that overlook the polyphasic nature of mouse sleep with frequent bouts of wakefulness, in which lower temperatures are preferred, even during their primary sleep period (daytime). Similarly, rhythmic rocking has been reported to promote slow-wave activity through vestibular stimulation, yet its effects remain largely unexplored in models of neurodegenerative disease. This dissertation seeks to address these gaps by investigating the feasibility and effects of non-invasive sleep enhancement in mouse models of epilepsy and AD. Specifically, it evaluates both closed-loop and open-loop sensory interventions to determine how the timing and modality of stimulation influence sleep quality and pathology.
We first validated PiezoSleep scores against EEG/EMG scores to ensure accurate sleep-wake classification, confirming strong agreement between the two methods. We then characterized sleep and epileptiform activity in four distinct disease models: pilocarpine and kainic acid models of temporal lobe epilepsy, Cln3KO model of juvenile Batten Disease, and APP/PS1 knock-in (KI) model of AD, each being compared with age-matched C57BL/6 wild type (WT) controls. EEG and EMG recordings were analyzed to quantify sleep architecture and interictal spike burden. Although the extent of disruption differed across models, each exhibited alterations in sleep or epileptiform activity relative to controls. These observations informed the design and interpretation of subsequent intervention studies.
Next, we tested the feasibility of sleep enhancement using a closed-loop (CL) thermoregulatory protocol. Mice were housed in custom chambers where sleep was detected in real time using piezoelectric sensors. Ambient temperature was elevated from 22°C to 30°C during sleep bouts and returned to baseline upon waking. Compared to yoked control (YC) and SHAM control, CL thermoneutral exposure significantly increased NREM duration and bout length in both non-epileptic and epileptic mice. Spectral analysis revealed a shift of NREM EEG power toward lower delta frequencies, consistent with enhanced slow-wave activity. A trend toward reduced rates of interictal spiking further suggested that state-dependent thermoregulation may stabilize cortical excitability. To evaluate somatosensory stimulation in a neurodegenerative model, aged APP/PS1 KI mice were exposed to continuous lateral rocking at 1 Hz on a reciprocating platform. Rocking increased NREM duration and prolonged bout length, demonstrating improved sleep consolidation despite AD-related pathology.
Together, these studies demonstrate the feasibility of non-pharmacological sleep enhancement in neurological disease models. CL thermoregulation improved sleep quality and reduced epileptiform activity in epilepsy, while open-loop rocking enhanced NREM consolidation in AD. Both approaches preserved natural sleep architecture and established proof-of-concept that environmental and sensory interventions can be leveraged to modulate sleep in disease contexts. These protocols hold promise as preclinical assays for evaluating sleep modulation and its impact on neurological pathology.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.562
Funding Information
This study was supported by the University of Kentucky Neuroscience Research Priority Area (NRPA) Pilot Grants; National Institutes of Health (NIH) funding through the National Center for Research Resources and the National Center for Advancing Translational Sciences grant UL1TR001998 (Center for Clinical and Translational Science High Impact Pilot Grant) awarded to Qingjun Wang, PhD; NIH grant R42NS107148 awarded to Sridhar Sunderam, PhD; the EpiZode Small Business Technology Transfer (STTR) grant; the National Institute on Aging (NIA) grant no. 5R01AG068215-02; and internal research funds from the University of Kentucky.
Recommended Citation
Iradukunda, Diane, "SLEEP CHARACTERIZATION AND ENHANCEMENT IN MODELS OF EPILEPSY AND ALZHEIMER’S DISEASE" (2025). Theses and Dissertations--Biomedical Engineering. 87.
https://uknowledge.uky.edu/cbme_etds/87
