Contributed by Nadia Lunardi, M.D., Ph.D., Associate Professor of Anesthesiology and Critical Care, University of Virginia and Michal Jedrusiak, M.D., Visiting Graduate Student, Anesthesiology Department, University of Virginia
Introduction
In 2020, our research group introduced a novel mouse model designed to investigate postoperative delirium.1 This model aimed to emulate the combination of surgical stress, anesthetic exposure, and Intensive Care Unit (ICU) conditions, mirroring the realism of the clinical setting. Understanding that delirium diagnosis primarily relies on clinical observations and serial behavioral assessments in patients, we initially validated our model by probing impairments in attention, memory and thought organization in mice via a series of neurocognitive tests.
Expanding on this groundwork, we next sought to further authenticate our model by testing whether anesthesia, surgery and a simulated ICU environment could induce another set of neurophysiological changes in mice similar to those commonly observed in patients experiencing ICU delirium.2 Specifically, we tested the presence of sleep fragmentation, EEG slowing, and circadian rhythm disarray.3
Methods
In our study we used aged mice (18-20 month old), comparable to human subjects aged between 60 and 70 year old.4 The mice were implanted with cortical EEG and electromyographic electrodes to facilitate sleep recording.5
Following a recovery period of at least one week, they were randomly assigned to either a control group or an ASI (Anesthesia, Surgery, ICU) group. The ASI mice were subjected to 3 hours of sevoflurane anesthesia during which a complex laparotomy was performed. This was followed by a two- hour sedation period with propofol and exposure to simulated ICU conditions for 12 hours. ICU conditions included exposure to a bright 33 W light, 90 dB ICU sounds, and periodic cage rattling using a horizontal shaker for one minute every 20 minutes.
Control mice were housed separately and did not receive ASI. Sleep was recorded at the end of ICU/control conditions and hippocampal tissue was collected upon completion of EEG recording to quantify the expression of key genes/proteins for circadian regulation.
Results
ASI mice experienced sleep fragmentation, as demonstrated by more frequent arousals compared to the control mice. Additionally, they exhibited signs of frontal EEG slowing – as evidenced by a reduced ratio of fast to slow band power – when compared to the control group. Remarkably, among the ASI mice with greater slow band power, the EEG slowing correlated with behavioral quiescence.
This was notably illustrated by higher instances of quiet wakefulness, where the mice were awake but not moving, potentially mimicking hypoactive delirium in humans. ASI mice had difficulty aligning their sleep-wake state with light cues, as evidenced by an increased tendency to sleep during the dark phases of the circadian cycle, which are typically the awake periods for mice. The expression of critical genes associated with circadian function was also notably reduced in the ASI mice, further indicating disturbances in their circadian regulation.
Conclusions
When aged mice were subjected to conditions resembling major surgery experienced by older patients, several EEG and circadian outcomes mirrored patterns commonly observed in clinical delirium. High-quality animal models capable of replicating neurophysiological changes akin to human delirium are vital. These models play a critical role in advancing delirium research from mere association studies to a deeper understanding of the underlying mechanisms responsible for delirium.
Future directions
Since completing this study, we have leveraged our mouse model to pursue novel mechanisms and potential therapeutic targets for delirium. We are exploring the role of epigenetic modifications, particularly changes in histone acetylation-deacetylation, in the pathogenesis of delirium. We are also launching our next project, aimed at testing the role of perineuronal nets in ICU delirium. These supportive structures surround neurons specialized in aiding cognitive functions and will be studied in the context of ICU delirium.
References
- Illendula M, Osuru HP, Ferrarese B, et al. Surgery, Anesthesia and Intensive Care Environment Induce Delirium-Like Behaviors and Impairment of Synaptic Function-Related Gene Expression in Aged Mice. Front Aging Neurosci. 2020;12:542421. Published 2020 Sep 25. doi:10.3389/fnagi.2020.542421
- Vasunilashorn SM, Lunardi N, Newman JC, et al. Preclinical and translational models for delirium: Recommendations for future research from the NIDUS delirium network. Alzheimers Dement. 2023;19(5):2150-2174. doi:10.1002/alz.12941
- Dulko E, Jedrusiak M, Osuru HP, et al. Sleep Fragmentation, Electroencephalographic Slowing, and Circadian Disarray in a Mouse Model for Intensive Care Unit Delirium. Anesth Analg. 2023;137(1):209-220. doi:10.1213/ANE.0000000000006524
- Agoston DV. How to Translate Time? The Temporal Aspect of Human and Rodent Biology. Front Neurol. 2017;8:92. Published 2017 Mar 17. doi:10.3389/fneur.2017.00092
- Lunardi N, Sica R, Atluri N, et al. Disruption of Rapid Eye Movement sleep homeostasis in adolescent rats after neonatal anesthesia. Anesthesiology. 2019;130(6):981-994. doi: 10.1097/ALN.0000000000002660.
Suggested Citation
Lunardi, Nadia; Jedrusiak, Michal. Sleep Fragmentation, EEG Slowing and Circadian Disarray in a Mouse Model for Intensive Care Unit Delirium; January, 2024, Available at: https://deliriumnetwork.org/sleep-fragmentation-eeg-slowing-and-circadian-disarray-in-a-mouse-model-for-intensive-care-unit-delirium/ (accessed today’s date)