Delirium is associated with loss of feedback cortical connectivity.

INTRODUCTION: Post-operative delirium (POD) is associated with increased morbidity and mortality but is bereft of treatments, largely due to our limited understanding of the underlying pathophysiology. We hypothesized that delirium reflects a disturbance in cortical connectivity that leads to altered predictions of the sensory environment. METHODS: High-density electroencephalogram recordings during an oddball auditory roving paradigm were collected from 131 patients. Dynamic causal modeling (DCM) analysis facilitated inference about the neuronal connectivity and inhibition-excitation dynamics underlying auditory-evoked responses. RESULTS: Mismatch negativity amplitudes were smaller in patients with POD. DCM showed that delirium was associated with decreased left-sided superior temporal gyrus (l-STG) to auditory cortex feedback connectivity. Feedback connectivity also negatively correlated with delirium severity and systemic inflammation. Increased inhibition of l-STG, with consequent decreases in feed-forward and feed-back connectivity, occurred for oddball tones during delirium. DISCUSSION: Delirium is associated with decreased feedback cortical connectivity, possibly resulting from increased intrinsic inhibitory tone. HIGHLIGHTS: Mismatch negativity amplitude was reduced in patients with delirium. Patients with postoperative delirium had increased feedforward connectivity before surgery. Feedback connectivity was diminished from left-side superior temporal gyrus to left primary auditory sensory area during delirium. Feedback connectivity inversely correlated with inflammation and delirium severity.

Prospective analysis of plasma amyloid beta and postoperative delirium in the Interventions for Postoperative Delirium: Biomarker-3 study.

BACKGROUND: The effect of postoperative delirium on the amyloid cascade of Alzheimer's dementia is poorly understood. Using early postoperative plasma biomarkers, we explored whether surgery and delirium are associated with changes in amyloid pathways. METHODS: We analysed data from 100 participants in the Interventions for Postoperative Delirium: Biomarker-3 (IPOD-B3) cohort study in the USA (NCT03124303 and NCT01980511), which recruited participants aged >65 yr undergoing non-intracranial surgery. We assessed the relationship between the change in plasma amyloid beta ratio (AßR; Aß42:Aß40) and delirium incidence (defined by the 3-Minute Diagnostic Confusion Assessment Method) and severity (quantified by the Delirium Rating Scale-Revised-98, the study's primary outcome). We also tested the relationship between plasma amyloid beta and intraoperative variables. RESULTS: Across all participants, the plasma AßR increased from the preoperative period to postoperative Day 1 (Wilcoxon P<0.001). However, this increase was not associated with delirium incidence (Wilcoxon P=0.22) or peak severity after adjusting for confounders (log[incidence rate ratio]=0.43; P=0.14). Postoperative Day 1 change in plasma AßR was not associated with postoperative Day 1 change in plasma tau, neurofilament light, or inflammatory markers (interleukin [IL]-1ß, IL-1Ra, IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12), or with operative time or low intraoperative arterial pressure. CONCLUSIONS: Perioperative changes in plasma amyloid do not appear to be associated with postoperative delirium. Our findings do not support associations of dynamic changes in amyloid with postoperative delirium. CLINICAL TRIAL REGISTRATION: .NCT03124303 and NCT01980511.

Resolution of elevated interleukin-6 after surgery is associated with return of normal cognitive function.

BACKGROUND: Unresolved surgical inflammation might induce chronic cognitive decline in older adults. Although inflammatory biomarkers have been correlated with perioperative cognitive impairment and delirium, the effects of prolonged inflammation on cognition are not well studied. This prospective cohort study investigated 1-yr dynamics in plasma interleukin-6 levels and executive function. METHODS: Patients undergoing major surgery (n=170) aged ≥65 yr completed Trail Making Test B and other neuropsychological assessments with plasma interleukin-6 levels collected on postoperative days 1-9 and 90, and at 1-yr. Mixed-effects analyses were conducted for Trail Making Test B (and other assessments), including interleukin-6 levels, time, and additional confounders (fixed effects), and a random effect for participant. RESULTS: Changes in interleukin-6 levels were associated with changes in Trail Making Test B over 1 yr in a generalised additive model (ß=0.074, P<0.001) supporting that unresolved inflammation impaired executive function. This result was robust to confounders, outlier rejection, and fitting to non-linear models. Changes in interleukin-6 levels also correlated with changes in Trail Making Test A and Controlled Oral Word Association Test. Sensitivity analyses conducted on binary definitions of cognitive decline (>1, >1.5, or >2 standard deviations from baseline) were also associated with interleukin-6 changes. CONCLUSIONS: Delayed resolution of inflammation is associated with cognitive impairment after surgery. Monitoring interleukin-6 might provide an opportunity to intervene with anti-inflammatory therapies in vulnerable patients. CLINICAL TRIAL REGISTRATION: NCT01980511, NCT03124303.

Sevoflurane dose and postoperative delirium: a prospective cohort analysis.

BACKGROUND: Recent trials are conflicting as to whether titration of anaesthetic dose using electroencephalography monitoring reduces postoperative delirium. Titration to anaesthetic dose itself might yield clearer conclusions. We analysed our observational cohort to clarify both dose ranges for trials of anaesthetic dose and biological plausibility of anaesthetic dose influencing delirium. METHODS: We analysed the use of sevoflurane in an ongoing prospective cohort of non-intracranial surgery. Of 167 participants, 118 received sevoflurane and were aged >65 yr. We tested associations between age-adjusted median sevoflurane (AMS) minimum alveolar concentration fraction or area under the sevoflurane time×dose curve (AUC-S) and delirium severity (Delirium Rating Scale-98). Delirium incidence was measured with 3-minute Diagnostic Confusion Assessment Method (3D-CAM) or CAM-ICU. Associations with previously identified delirium biomarkers (interleukin-8, neurofilament light, total tau, or S100B) were tested. RESULTS: Delirium severity did not correlate with AMS (Spearman's ρ=-0.014, P=0.89) or AUC-S (ρ=0.093, P=0.35), nor did delirium incidence (AMS Wilcoxon P=0.86, AUC-S P=0.78). Further sensitivity analyses including propofol dose also demonstrated no relationship. Linear regression confirmed no association for AMS in unadjusted (log (IRR)=-0.06 P=0.645) or adjusted models (log (IRR)=-0.0454, P=0.735). No association was observed for AUC-S in unadjusted (log (IRR)=0.00, P=0.054) or adjusted models (log (IRR)=0.00, P=0.832). No association of anaesthetic dose with delirium biomarkers was identified (P>0.05). CONCLUSION: Sevoflurane dose was not associated with delirium severity or incidence. Other biological mechanisms of delirium, such as inflammation and neuronal injury, appear more plausible than dose of sevoflurane. CLINICAL TRIAL REGISTRATION: NCT03124303, NCT01980511.

Perioperative ischaemic brain injury and plasma neurofilament light: a secondary analysis of two prospective cohort studies.

BACKGROUND: Ischaemic brain infarction can occur without acute neurological symptoms (covert strokes) or with symptoms (overt strokes), both associated with poor health outcomes. We conducted a pilot study of the incidence of preoperative and postoperative (intraoperative or postoperative) covert strokes, and explored the relationship of postoperative ischaemic brain injury to blood levels of neurofilament light, a biomarker of neuronal damage. METHODS: We analysed 101 preoperative (within 2 weeks of surgery) and 58 postoperative research MRIs on postoperative days 2-9 from two prospective cohorts collected at the University of Wisconsin (NCT01980511 and NCT03124303). Participants were aged >65 yr and undergoing non-intracranial, non-carotid surgery. RESULTS: Preoperative covert stroke was identified in 2/101 participants (2%; Bayesian 95% confidence interval [CI], 0.2-5.4). This rate was statistically different from the postoperative ischaemic brain injury rate of 7/58 (12%, 4.9-21.3%; P=0.01) based on postoperative imaging. However, in a smaller group of participants with paired imaging (n=30), we did not identify the same effect (P=0.67). Patients with postoperative brain injury had elevated peak neurofilament light levels (median [inter-quartile range], 2.34 [2.24-2.64] log10 pg ml-1) compared with those without (1.86 [1.48-2.21] log10 pg ml-1; P=0.025). Delirium severity scores were higher in those with postoperative brain injury (19 [17-21]) compared with those without (7 [4-12]; P=0.01). CONCLUSION: Although limited by a small sample size, these data suggest that preoperative covert stroke occurs more commonly than previously anticipated. Plasma neurofilament light is a potential screening biomarker for postoperative ischaemic brain injury.

Connected consciousness after tracheal intubation in young adults: an international multicentre cohort study.

BACKGROUND: Connected consciousness, assessed by response to command, occurs in at least 5% of general anaesthetic procedures and perhaps more often in young people. Our primary objective was to establish the incidence of connected consciousness after tracheal intubation in young people aged 18-40 yr. The secondary objectives were to assess the nature of these responses, identify relevant risk factors, and determine their relationship to postoperative outcomes. METHODS: This was an international, multicentre prospective cohort study using the isolated forearm technique to assess connected consciousness shortly after tracheal intubation. RESULTS: Of 344 enrolled subjects, 338 completed the study (mean age, 30 [standard deviation, 6.3] yr; 232 [69%] female). Responses after intubation occurred in 37/338 subjects (11%). Females (13%, 31/232) responded more often than males (6%, 6/106). In logistic regression, the risk of responsiveness was increased with female sex (odds ratio [ORadjusted]=2.7; 95% confidence interval [CI], 1.1-7.6; P=0.022) and was decreased with continuous anaesthesia before laryngoscopy (ORadjusted=0.43; 95% CI, 0.20-0.96; P=0.041). Responses were more likely to occur after a command to respond (and not to nonsense, 13 subjects) than after a nonsense statement (and not to command, four subjects, P=0.049). CONCLUSIONS: Connected consciousness occured after intubation in 11% of young adults, with females at increased risk. Continuous exposure to anaesthesia between induction of anaesthesia and tracheal intubation should be considered to reduce the incidence of connected consciousness. Further research is required to understand sex-related differences in the risk of connected consciousness.

Postoperative delirium and changes in the blood-brain barrier, neuroinflammation, and cerebrospinal fluid lactate: a prospective cohort study.

BACKGROUND: Case-control studies have associated delirium with blood-brain barrier (BBB) permeability. However, this approach cannot determine whether delirium is attributable to high pre-existing permeability or to perioperative changes. We tested whether perioperative changes in cerebrospinal fluid/plasma albumin ratio (CPAR) and plasma S100B were associated with delirium severity. METHODS: Participants were recruited to two prospective cohort studies of non-intracranial surgery (NCT01980511, NCT03124303, and NCT02926417). Delirium severity was assessed using the Delirium Rating Scale-98. Delirium incidence was diagnosed with the 3D-Confusion Assessment Method (3D-CAM) or CAM-ICU (CAM for the ICU). CSF samples from 25 patients and plasma from 78 patients were analysed for albumin and S100B. We tested associations between change in CPAR (n=11) and S100B (n=61) and delirium, blood loss, CSF interleukin-6 (IL-6), and CSF lactate. RESULTS: The perioperative increase in CPAR and S100B correlated with delirium severity (CPAR ρ=0.78, P=0.01; S100B ρ=0.41, P<0.001), delirium incidence (CPAR P=0.012; S100B P<0.001) and CSF IL-6 (CPAR ρ=0.66 P=0.04; S100B ρ=0.75, P=0.025). Linear mixed-effect analysis also showed that decreased levels of S100B predicted recovery from delirium symptoms (P=0.001). Linear regression demonstrated that change in plasma S100B was independently associated with surgical risk, cardiovascular surgery, blood loss, and hypotension. Blood loss also correlated with CPAR (ρ=0.64, P=0.04), S100B (ρ=0.70, P<0.001), CSF lactate (R=0.81, P=0.01), and peak delirium severity (ρ=0.36, P=0.01). CONCLUSION: Postoperative delirium is associated with a breakdown in the BBB. This increased permeability is dynamic and associated with a neuroinflammatory and lactate response. Strategies to mitigate blood loss may protect the BBB.

Relationships between preoperative cortical thickness, postoperative electroencephalogram slowing, and postoperative delirium.

BACKGROUND: It is unclear how preoperative neurodegeneration and postoperative changes in EEG delta power relate to postoperative delirium severity. We sought to understand the relative relationships between neurodegeneration and delta power as predictors of delirium severity. METHODS: We undertook a prospective cohort study of high-risk surgical patients (>65 yr old) to identify predictors of peak delirium severity (Delirium Rating Scale-98) with twice-daily delirium assessments (NCT03124303). Participants (n=86) underwent preoperative MRI; 54 had both an MRI and a postoperative EEG. Cortical thickness was calculated from the MRI and delta power from the EEG. RESULTS: In a linear regression model, the interaction between delirium status and preoperative mean cortical thickness (suggesting neurodegeneration) across the entire cortex was a significant predictor of delirium severity (P<0.001) when adjusting for age, sex, and performance on preoperative Trail Making Test B. Next, we included postoperative delta power and repeated the analysis (n=54). Again, the interaction between mean cortical thickness and delirium was associated with delirium severity (P=0.028), as was postoperative delta power (P<0.001). When analysed across the Desikan-Killiany-Tourville atlas, thickness in multiple individual cortical regions was also associated with delirium severity. CONCLUSIONS: Preoperative cortical thickness and postoperative EEG delta power are both associated with postoperative delirium severity. These findings might reflect different underlying processes or mechanisms. CLINICAL TRIAL REGISTRATION: NCT03124303.

Association between plasma tau and postoperative delirium incidence and severity: a prospective observational study.

BACKGROUND: Postoperative delirium is associated with increases in the neuronal injury biomarker, neurofilament light (NfL). Here we tested whether two other biomarkers, glial fibrillary acidic protein (GFAP) and tau, are associated with postoperative delirium. METHODS: A total of 114 surgical patients were recruited into two prospective biomarker cohort studies with assessment of delirium severity and incidence. Plasma samples were sent for biomarker analysis including tau, NfL, and GFAP, and a panel of 10 cytokines. We determined a priori to adjust for interleukin-8 (IL-8), a marker of inflammation, when assessing associations between biomarkers and delirium incidence and severity. RESULTS: GFAP concentrations showed no relationship to delirium. The change in tau from preoperative concentrations to postoperative Day 1 was greater in patients with postoperative delirium (P<0.001) and correlated with delirium severity (ρ=0.39, P<0.001). The change in tau correlated with increases in IL-8 (P<0.001) and IL-10 (P=0.0029). Linear regression showed that the relevant clinical predictors of tau changes were age (P=0.037), prior stroke/transient ischaemic attack (P=0.001), and surgical blood loss (P<0.001). After adjusting for age, sex, preoperative cognition, and change in IL-8, tau remained significantly associated with delirium severity (P=0.026). Using linear mixed effect models, only tau (not NfL or IL-8) predicted recovery from delirium (P<0.001). CONCLUSIONS: The change in plasma tau was associated with delirium incidence and severity, and resolved over time in parallel with delirium features. The impact of this putative perioperative neuronal injury biomarker on long-term cognition merits further investigation. CLINICAL TRIAL REGISTRATION: NCT02926417 and NCT03124303.

Postoperative troponin increases after noncardiac surgery are associated with raised neurofilament light: a prospective observational cohort study.

BACKGROUND: Myocardial and neuronal injury occur commonly after noncardiac surgery. We examined whether patients who had perioperative myocardial injury (PMI) also incurred neuronal injury, and whether myocardial and neuronal injury were associated with similar changes in inflammatory markers or overlapping clinical predictors. METHODS: A total of 114 individuals >65 yr old were recruited from two ongoing perioperative cohort studies (NCT02926417; NCT03124303). Plasma samples were collected before and daily after surgery to process assays for troponin I (PMI), neurofilament light (NfL; neuronal injury) and multiplexed plasma cytokines (inflammation). The primary outcome was the change in NfL in individuals with PMI (>40 pg ml-1 increase in troponin above preoperative values). We conducted logistic regression to identify if there were shared clinical predictors for myocardial and neuronal injury. RESULTS: Ninety-six patients had paired NfL and troponin data. Twenty-three of 94 subjects (24%) with PMI had greater increases in NfL (median [inter-quartile range, IQR]: 29 pg ml-1 [3-95 pg ml-1]; 2.8-fold increase) compared with subjects with no troponin increase (8 pg ml-1 [3-20]; 1.3-fold increase; P=0.008). PMI was associated with increased interleukin (IL)-1ra (P=0.005), IL-2 (P=0.045), IL-8 (P=0.002), and IL-10 (P<0.001). Logistic regression showed that intraoperative hypotension was associated with PMI (P=0.043). Preoperative stroke (P=0.041) and blood loss (P=0.002), but not intraoperative hypotension, were associated with increased NfL. CONCLUSIONS: Postoperative troponin increases were associated with changes in NfL and inflammatory cytokines. Increases in troponin, but not NfL, were associated with intraoperative hypotension, suggesting differences in the mechanisms contributing to neuronal and myocardial injury.

A 'toothache tree' alkylamide inhibits Aδ mechanonociceptors to alleviate mechanical pain.

In traditional medicine, the 'toothache tree' and other plants of the Zanthoxylum genus have been used to treat inflammatory pain conditions, such as toothache and rheumatoid arthritis. Here we examined the cellular and molecular mechanisms underlying the analgesic properties of hydroxy-α-sanshool, the active alkylamide produced by Zanthoxylum plants. Consistent with its analgesic effects in humans, sanshool treatment in mice caused a selective attenuation of mechanical sensitivity under naïve and inflammatory conditions, with no effect on thermal sensitivity. To elucidate the molecular mechanisms by which sanshool attenuates mechanical pain, we performed single fibre recordings, calcium imaging and whole-cell electrophysiology of cultured sensory neurons. We found that: (1) sanshool potently inhibits Aδ mechanonociceptors that mediate both sharp acute pain and inflammatory pain; (2) sanshool inhibits action potential firing by blocking voltage-gated sodium currents in a subset of somatosensory neurons, which express a unique combination of voltage-gated sodium channels; and (3) heterologously expressed Nav1.7 is most strongly inhibited by sanshool as compared to other sodium channels expressed in sensory neurons. These results suggest that sanshool targets voltage-gated sodium channels on Aδ mechanosensory nociceptors to dampen excitability and thus induce 'fast pain' analgesia.

Control of contextual memory through interneuronal α5-GABAA receptors.

γ-Aminobutyric acid type A receptors that incorporate α5 subunits (α5-GABAARs) are highly enriched in the hippocampus and are strongly implicated in control of learning and memory. Receptors located on pyramidal neuron dendrites have long been considered responsible, but here we report that mice in which α5-GABAARs have been eliminated from pyramidal neurons (α5-pyr-KO) continue to form strong spatial engrams and that they remain as sensitive as their pseudo-wild-type (p-WT) littermates to etomidate-induced suppression of place cells and spatial engrams. By contrast, mice with selective knockout in interneurons (α5-i-KO) no longer exhibit etomidate-induced suppression of place cells. In addition, the strength of spatial engrams is lower in α5-i-KO mice than p-WT littermates under control conditions. Consistent with the established role of the hippocampus in contextual fear conditioning, α5-i-KO mice resisted etomidate's suppression of freezing to context, but so too did α5-pyr-KO mice, supporting a role for extra-hippocampal regions in the development of contextual fear memory. Overall, our results indicate that interneuronal α5-GABAARs serve a physiological role in promoting spatial learning and that they mediate suppression of hippocampus-dependent contextual memory by etomidate.

Reduced Electroencephalogram Complexity in Postoperative Delirium.

Delirium is associated with electroencephalogram (EEG) slowing and impairments in connectivity. We hypothesized that delirium would be accompanied by a reduction in the available cortical information (ie, there is less information processing occurring), as measured by a surrogate, Lempil-Ziv Complexity (LZC), a measure of time-domain complexity. Two ongoing perioperative cohort studies (NCT03124303, NCT02926417) contributed EEG data from 91 patients before and after surgery; 89 participants were used in the analyses. After cleaning and filtering (0.1-50Hz), the perioperative change in LZC and LZC normalized (LZCn) to a phase-shuffled distribution were calculated. The primary outcome was the correlation of within-patient paired changes in delirium severity (Delirium Rating Scale-98 [DRS]) and LZC. Scalp-wide threshold-free cluster enhancement was employed for multiple comparison correction. LZC negatively correlated with DRS in a scalp-wide manner (peak channel r2 = .199, p < .001). This whole brain effect remained for LZCn, though the correlations were weaker (peak channel r2 = .076, p = .010). Delirium diagnosis was similarly associated with decreases in LZC (peak channel p < .001). For LZCn, the topological significance was constrained to the midline posterior regions (peak channel p = .006). We found a negative correlation of LZC in the posterior and temporal regions with monocyte chemoattractant protein-1 (peak channel r2 = .264, p < .001, n = 47) but not for LZCn. Complexity of the EEG signal fades proportionately to delirium severity implying reduced cortical information. Peripheral inflammation, as assessed by monocyte chemoattractant protein-1, does not entirely account for this effect, suggesting that additional pathogenic mechanisms are involved.