The Systems Neuroscience of Perioperative Neurocognitive Disorders: In work led by Dr. Joseph P. Mathew and Dr. Jeffrey Browndyke, our group has performed several of the first functional neuroimaging studies of postoperative cognitive dysfunction, utilizing resting- and task-based functional magnetic resonance imaging (fMRI) in older (age >60) adults. Our work, now confirmed by independent research labs in the field, suggests possible dysregulation of the brain’s default mode network (DMN) is associated with the severity of cognitive dysfunction 6 weeks after cardiac surgery in older adults. We have found reduced degree centrality of the posterior cingulate cortex, a major DMN “hub,” suggesting reduced intranetwork coherence in patients with postoperative cognitive dysfunction. This DMN “hub” paradoxically demonstrates reduced anticorrelation during cognitive task performance in patients with postoperative cognitive dysfunction, suggesting that poor task performance in these patients may be due, in part, to dynamic brain inter-network dysregulation. For more information on this work, please see https://pubmed.ncbi.nlm.nih.gov/27858963/ and https://pubmed.ncbi.nlm.nih.gov/29164774/. Additional and ongoing laboratory studies in these cardiac and non-cardiac surgical patients are examining the structural and functional neuroimaging variable associations with perioperative biomarker changes and more granular changes in cognition and mood after surgery.
A large body of work in recent years has described specific electroencephalography (EEG) patterns detectable on the scalp surface in response to distinct anesthetic drugs (such as propofol and the volatile anesthetics, among others). Key work by Patrick Purdon and colleagues demonstrated that EEG alpha (i.e. 8-12 Hz) signal amplitude (or power) declines with age in older adults. Our group was then the first to show that older adults have significant variability in alpha oscillation power in response to propofol and the inhaled volatile anesthetics, and that the magnitude of frontal EEG alpha oscillation power correlates with baseline/preoperative cognitive function in older adults. We found this result in two different cohorts using both the raw EEG signal from a proprietary BIS monitor, and the EEG data from the frontal electrodes of a 32 channel EEG electrode array. For more on this work, please see https://pubmed.ncbi.nlm.nih.gov/28533746/.
In parallel with this line of work, we have also examined anesthetic dosage and brain monitoring practices as a function of increasing. It has long been none that the minimum alveolar concentration (MAC) of the volatile inhaled anesthetics declines by age; our recent systematic literature search and meta-regression analysis demonstrated that MAC declines by 6.47% per decade after 1 year of age, with an R2 value of 0.98 (https://www.sciencedirect.com/science/article/pii/S000709121930755X?via%3Dihub). We hypothesized that clinicians at a major academic medical center would decrease the amount of volatile inhaled anesthetics delivered to older adults by less than this 6.47% decrease per decade, which would result in a relative increase in volatile inhaled anesthetic dosage in older adults. In a study of over 17,000 patients, we found that this hypothesis was correct. Yet, we found that a processed EEG measure of so-called “anesthetic depth” (the BIS index) actually increased in older adults, despite the fact that higher anesthetic dosage in older adults would be predicted to result in lower BIS numbers. For more information on this “paradox of age”, please see https://pubmed.ncbi.nlm.nih.gov/31279479/. This work suggests the need for better EEG monitors for use in clinical practice on older adults undergoing general anesthesia, and that more careful anesthetic titration in older adults could reduce dose-dependent side effects of the inhaled volatile anesthetics and propofol.
The Relationship between Alzheimer’s Disease, Anesthesia and Surgery, and Human Perioperative Neurocognitive Disorders: Numerous investigators have theorized that there may be a link between human perioperative neurocognitive disorders and Alzheimer’s Disease and Related Dementias (ADRD). We know that patients with preclinical ADRD are at increased risk for developing postoperative delirium and cognitive dysfunction, and patients who develop these perioperative neurocognitive disorders develop ADRD at increased rates. We have found that there are significant increases in CSF levels of the microtubule associated protein tau (a neural injury biomarker) at 10 and 24 hours following surgery in old adults, and these was no difference in these CSF tau increases among patients whom we randomized to propofol versus isoflurane for anesthesia maintenance. For more on this work, please see https://pubmed.ncbi.nlm.nih.gov/27079717/.
To determine whether the magnitude of these postoperative CSF tau increases are associated with the severity of postoperative cognitive dysfunction, we then initiated the Markers of Alzheimer’s Disease and neuroCognitive Outcomes following Perioperative Care (MADCO-PC) cohort study in older adults (manuscripts under preparation). The MADCO-PC study also examines whether postoperative CSF tau increases are associated with postoperative changes in functional brain connectivity (as measured by fMRI).
The Role of Neuroinflammation in Human Perioperative Neurocognitive Disorders: Several groups (including our own) have found that anesthesia and surgery are associated with an increase in inflammation within the central nervous system. We were the first to demonstrate a possible influx of peripheral monocytes into the cerebrospinal fluid following major surgery in older adults (https://pubmed.ncbi.nlm.nih.gov/31085945/). We have also found significant increases in pro-inflammatory cytokines within human CSF following surgery (https://pubmed.ncbi.nlm.nih.gov/29181002/). We are currently examining the role of both cellular and molecular markers of inflammation in the pathogenesis of human perioperative neurocognitive disorders and associated brain functional connectivity changes in both the INTUIT and MARBLE studies. INTUIT stands for Investigating NeuroinflammaTion Underlying postoperative neurocognITive and MARBLE stands for Modulating ApoE to Reduce Brain inflammation, deLirium and cognitivE dysfunction after surgery in older adults. For more on the INTUIT study please see our study methods paper at https://pubmed.ncbi.nlm.nih.gov/30674067/ and our study registration page at https://www.clinicaltrials.gov/ct2/show/NCT03273335?term=INTUIT&draw=2&rank=2. For more information about the MARBLE study, please see our study methods paper at https://pubmed.ncbi.nlm.nih.gov/32417770/ and our study registration page at https://www.clinicaltrials.gov/ct2/show/NCT03802396?term=MARBLE+Berger&draw=2&rank=1.