Ketamine for postoperative avoidance of depressive symptoms: the K-PASS feasibility randomised trial.

Background: Surgical patients with previous depression frequently experience postoperative depressive symptoms. This study's objective was to determine the feasibility of a placebo-controlled trial testing the impact of a sustained ketamine infusion on postoperative depressive symptoms. Methods: This single-centre, triple-blind, placebo-controlled randomised clinical trial included adult patients with depression scheduled for inpatient surgery. After surgery, patients were randomly allocated to receive ketamine (0.5 mg kg-1 over 10 min followed by 0.3 mg kg-1 h-1 for 3 h) or an equal volume of normal saline. Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale. On post-infusion day 1, participants guessed which intervention they received. Feasibility endpoints included the fraction of patients approached who were randomised, the fraction of randomised patients who completed the study infusion, and the fraction of scheduled depression assessments that were completed. Results: In total, 32 patients were allocated a treatment, including 31/101 patients approached after a protocol change (31%, 1.5 patients per week). The study infusion was completed without interruption in 30/32 patients (94%). In each group, 7/16 participants correctly guessed which intervention they received. Depression assessments were completed at 170/192 scheduled time points (89%). Between baseline and post-infusion day 4 (pre-specified time point of interest), median depressive symptoms decreased in both groups, with difference-in-differences of -1.00 point (95% confidence interval -3.23 to 1.73) with ketamine compared with placebo. However, the between-group difference did not persist at other time points. Conclusions: Patient recruitment, medication administration, and clinical outcome measurement appear to be highly feasible, with blinding maintained. A fully powered trial may be warranted. Clinical trial registration: NCT05233566.

American Delirium Society 2022 Year in Review: Highlighting the Year's Most Impactful Delirium Research.

Background: Since 2015, the American Delirium Society (ADS) Research Committee has conducted an annual survey of the delirium literature for presentation in its year-in-review session. Our objectives were to describe the review process used for the 2021-2022 and to summarise the selected publications. Methods: Each member of the ADS Research Committee nominated up to 6 publications considered to be the most impactful primary delirium research published from September 1, 2021, to July 31, 2022. The 24 nominated studies were divided into three categories balanced by number of articles: medical intervention trials, non-medical intervention trials, and delirium detection/basic science studies. Each ADS Research Committee member ranked all studies in their assigned category for methodological rigor and for impact, each being scored as 0-10, for a total score of 0-20. It was decided a priori to select the top three highest-scoring articles in each category for presentation, with ties adjudicated by Committee consensus. Results: Nineteen Research Committee members served as reviewers. Scores for each category were similar: medical interventions mean (standard deviation) 12.8 (1.1), non-medical interventions 13.1 (1.1), and detection/basic science 12.6 (1.0). We summarise the results of the papers presented in the 2022 ADS year-in-review session. Conclusion: The diversity of studies presented for the 2022 ADS year-in-review session illustrates the breadth of the delirium field and the growing number of clinical trials. The dissemination of publications across a broad, diverse array of journals provides further justification of the need for delirium-specific journals.

Quiescence during burst suppression and postictal generalized EEG suppression are distinct patterns of activity.

OBJECTIVE: Periods of low-amplitude electroencephalographic (EEG) signal (quiescence) are present during both anesthetic-induced burst suppression (BS) and postictal generalized electroencephalographic suppression (PGES). PGES following generalized seizures induced by electroconvulsive therapy (ECT) has been previously linked to antidepressant response. The commonality of quiescence during both BS and PGES motivated trials to recapitulate the antidepressant effects of ECT using high doses of anesthetics. However, there have been no direct electrographic comparisons of these quiescent periods to address whether these are distinct entities. METHODS: We compared periods of EEG quiescence recorded from two human studies: BS induced in 29 healthy adult volunteers by isoflurane general anesthesia and PGES in 11 patients undergoing right unilateral ECT for treatment-resistant depression. An automated algorithm allowed detection of EEG quiescence based on a 10-microvolt amplitude threshold. Spatial, spectral, and temporal analyses compared quiescent epochs during BS and PGES. RESULTS: The median (interquartile range) voltage for quiescent periods during PGES was greater than during BS (1.81 (0.22) microvolts vs 1.22 (0.33) microvolts, p < 0.001). Relative power was greater for quiescence during PGES than BS for the 1-4 Hz delta band (p < 0.001), at the expense of power in the theta (4-8 Hz, p < 0.001), beta (13-30 Hz, p = 0.04) and gamma (30-70 Hz, p = 0.006) frequency bands. Topographic analyses revealed that amplitude across the scalp was consistently higher for quiescent periods during PGES than BS, whose voltage was within the noise floor. CONCLUSIONS: Quiescent epochs during PGES and BS have distinct patterns of EEG signals across voltage, frequency, and spatial domains. SIGNIFICANCE: Quiescent epochs during PGES and BS, important neurophysiological markers for clinical outcomes, are shown to have distinct voltage and frequency characteristics.

Protocol for the Ketamine for Postoperative Avoidance of Depressive Symptoms (K-PASS) feasibility study: A randomized clinical trial.

Background: Postoperative depressive symptoms are associated with pain, readmissions, death, and other undesirable outcomes. Ketamine produces rapid but transient antidepressant effects in the perioperative setting. Longer infusions confer lasting antidepressant activity in patients with treatment-resistant depression, but it is unknown whether a similar approach may produce a lasting antidepressant effect after surgery. This protocol describes a pilot study that will assess the feasibility of conducting a larger scale randomized clinical trial addressing this knowledge gap. Methods: This single-center, double-blind, placebo-controlled pilot trial involves the enrollment of 32 patients aged 18 years or older with a history of depression scheduled for surgery with planned intensive care unit admission. On the first day following surgery and extubation, participants will be randomized to an intravenous eight-hour infusion of either ketamine (0.5 mg kg -1 over 10 minutes followed by a continuous rate of 0.3 mg kg -1 h -1) or an equal volume of normal saline. Depressive symptoms will be quantified using the Montgomery-Asberg Depression Rating Scale preoperatively and serially up to 14 days after the infusion. To detect ketamine-induced changes on overnight sleep architecture, a wireless headband will be used to record electroencephalograms preoperatively, during the study infusion, and after infusion. The primary feasibility endpoints will include the fraction of patients approached who enroll, the fraction of randomized patients who complete the study infusion, and the fraction of randomized patients who complete outcome data collection. Conclusions: This pilot study will evaluate the feasibility of a future large comparative effectiveness trial of ketamine to reduce depressive symptoms in postsurgical patients. Registration: K-PASS is registered on ClinicalTrials.gov: NCT05233566; registered February 10, 2022.

Postictal generalized electroencephalographic suppression following electroconvulsive therapy: Temporal characteristics and impact of anesthetic regimen.

OBJECTIVE: Postictal generalized electroencephalographic suppression (PGES) has been defined as electroencephalographic (EEG) activity of less than 10 microvolts following a generalized seizure. PGES is associated with an increased risk of sudden unexplained death in epilepsy, as well as treatment efficacy of electroconvulsive therapy (ECT). We investigated the impact of anesthetic on PGES expression and temporal characteristics. METHODS: We recorded postictal EEG in 50 ECT sessions in 11 patients with treatment resistant depression (ClinicalTrials.gov NCT02761330). For each participant, repeated sessions included either ketamine or etomidate general anesthesia during ECT. An automated algorithm was employed to detect PGES within 5 minutes after seizure termination. RESULTS: PGES was detected in 31/50 recordings, with intermittent epochs recurring up to five minutes after seizure termination. PGES total duration was greater following ketamine than etomidate anesthesia (p = 0.04). PGES expression declined loglinearly as a function of time (r = -0.89, p < 10-4). EEG amplitude during PGES did not vary linearly with time. CONCLUSIONS: PGES can occur intermittently for several minutes following seizure termination. Anesthetic effects should be considered when correlating PGES duration to clinical outcomes. SIGNIFICANCE: Prolonged EEG monitoring several minutes following seizure termination may be necessary to fully evaluate the presence and total duration of PGES.

Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression.

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.

Protocol for the Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography (P-DROWS-E) study: a prospective observational study of delirium in elderly cardiac surgical patients.

INTRODUCTION: Delirium is a potentially preventable disorder characterised by acute disturbances in attention and cognition with fluctuating severity. Postoperative delirium is associated with prolonged intensive care unit and hospital stay, cognitive decline and mortality. The development of biomarkers for tracking delirium could potentially aid in the early detection, mitigation and assessment of response to interventions. Because sleep disruption has been posited as a contributor to the development of this syndrome, expression of abnormal electroencephalography (EEG) patterns during sleep and wakefulness may be informative. Here we hypothesise that abnormal EEG patterns of sleep and wakefulness may serve as predictive and diagnostic markers for postoperative delirium. Such abnormal EEG patterns would mechanistically link disrupted thalamocortical connectivity to this important clinical syndrome. METHODS AND ANALYSIS: P-DROWS-E (Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography) is a 220-patient prospective observational study. Patient eligibility criteria include those who are English-speaking, age 60 years or older and undergoing elective cardiac surgery requiring cardiopulmonary bypass. EEG acquisition will occur 1-2 nights preoperatively, intraoperatively, and up to 7 days postoperatively. Concurrent with EEG recordings, two times per day postoperative Confusion Assessment Method (CAM) evaluations will quantify the presence and severity of delirium. EEG slow wave activity, sleep spindle density and peak frequency of the posterior dominant rhythm will be quantified. Linear mixed-effects models will be used to evaluate the relationships between delirium severity/duration and EEG measures as a function of time. ETHICS AND DISSEMINATION: P-DROWS-E is approved by the ethics board at Washington University in St. Louis. Recruitment began in October 2018. Dissemination plans include presentations at scientific conferences, scientific publications and mass media. TRIAL REGISTRATION NUMBER: NCT03291626.

Cognitive and Neurophysiological Recovery Following Electroconvulsive Therapy: A Study Protocol.

Electroconvulsive therapy (ECT) employs the elective induction of generalizes seizures as a potent treatment for severe psychiatric illness. As such, ECT provides an opportunity to rigorously study the recovery of consciousness, reconstitution of cognition, and electroencephalographic (EEG) activity following seizures. Fifteen patients with major depressive disorder refractory to pharmacologic therapy will be enrolled (Clinicaltrials.gov, NCT02761330). Adequate seizure duration will be confirmed following right unilateral ECT under etomidate anesthesia. Patients will then undergo randomization for the order in which they will receive three sequential treatments: etomidate + ECT, ketamine + ECT, and ketamine + sham ECT. Sessions will be repeated in the same sequence for a total of six treatments. Before each session, sensorimotor speed, working memory, and executive function will be assessed through a standardized cognitive test battery. After each treatment, the return of purposeful responsiveness to verbal command will be determined. At this point, serial cognitive assessments will begin using the same standardized test battery. The presence of delirium and changes in depression severity will also be ascertained. Sixty-four channel EEG will be acquired throughout baseline, ictal, and postictal epochs. Mixed-effects models will correlate the trajectories of cognitive recovery, clinical outcomes, and EEG metrics over time. This innovative research design will answer whether: (1) time to return of responsiveness will be prolonged with ketamine + ECT compared with ketamine + sham ECT; (2) time of restoration to baseline function in each cognitive domain will take longer after ketamine + ECT than after ketamine + sham ECT; (3) postictal delirium is associated with delayed restoration of baseline function in all cognitive domains; and (4) the sequence of reconstitution of cognitive domains following the three treatments in this study is similar to that occurring after an isoflurane general anesthetic (NCT01911195). Sub-studies will assess the relationships of cognitive recovery to the EEG preceding, concurrent, and following individual ECT sessions. Overall, this study will lead the development of biomarkers for tailoring the cogno-affective recovery of patients undergoing ECT.

Network Efficiency and Posterior Alpha Patterns Are Markers of Recovery from General Anesthesia: A High-Density Electroencephalography Study in Healthy Volunteers.

Recent studies have investigated local oscillations, long-range connectivity, and global network patterns to identify neural changes associated with anesthetic-induced unconsciousness. These studies typically employ anesthetic protocols that either just cross the threshold of unconsciousness, or induce deep unconsciousness for a brief period of time-neither of which models general anesthesia for major surgery. To study neural patterns of unconsciousness and recovery in a clinically-relevant context, we used a realistic anesthetic regimen to induce and maintain unconsciousness in eight healthy participants for 3 h. High-density electroencephalogram (EEG) was acquired throughout and for another 3 h after emergence. Seven epochs of 5-min eyes-closed resting states were extracted from the data at baseline as well as 30, 60, 90, 120, 150, and 180-min post-emergence. Additionally, 5-min epochs were extracted during induction, unconsciousness, and immediately prior to recovery of consciousness, for a total of 10 analysis epochs. The EEG data in each epoch were analyzed using source-localized spectral analysis, phase-lag index, and graph theoretical techniques. Posterior alpha power was significantly depressed during unconsciousness, and gradually approached baseline levels over the 3 h recovery period. Phase-lag index did not distinguish between states of consciousness or stages of recovery. Network efficiency was significantly depressed and network clustering coefficient was significantly increased during unconsciousness; these graph theoretical measures returned to baseline during the 3 h recovery period. Posterior alpha power may be a potential biomarker for normal recovery of functional brain networks after general anesthesia.

Sevoflurane Alters Spatiotemporal Functional Connectivity Motifs That Link Resting-State Networks during Wakefulness.

Background: The spatiotemporal patterns of correlated neural activity during the transition from wakefulness to general anesthesia have not been fully characterized. Correlation analysis of blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) allows segmentation of the brain into resting-state networks (RSNs), with functional connectivity referring to the covarying activity that suggests shared functional specialization. We quantified the persistence of these correlations following the induction of general anesthesia in healthy volunteers and assessed for a dynamic nature over time. Methods: We analyzed human fMRI data acquired at 0 and 1.2% vol sevoflurane. The covariance in the correlated activity among different brain regions was calculated over time using bounded Kalman filtering. These time series were then clustered into eight orthogonal motifs using a K-means algorithm, where the structure of correlated activity throughout the brain at any time is the weighted sum of all motifs. Results: Across time scales and under anesthesia, the reorganization of interactions between RSNs is related to the strength of dynamic connections between member pairs. The covariance of correlated activity between RSNs persists compared to that linking individual member pairs of different RSNs. Conclusions: Accounting for the spatiotemporal structure of correlated BOLD signals, anesthetic-induced loss of consciousness is mainly associated with the disruption of motifs with intermediate strength within and between members of different RSNs. In contrast, motifs with higher strength of connections, predominantly with regions-pairs from within-RSN interactions, are conserved among states of wakefulness and sevoflurane general anesthesia.

Bispectral index monitoring, duration of bispectral index below 45, patient risk factors, and intermediate-term mortality after noncardiac surgery in the B-Unaware Trial.

BACKGROUND: Postoperative mortality has been associated with cumulative anesthetic duration below an arbitrary processed electroencephalographic threshold (bispectral index [BIS] <45). This substudy of the B-Unaware Trial tested whether cumulative duration of BIS values lower than 45, cumulative anesthetic dose, comorbidities, or intraoperative events were independently associated with postoperative mortality. METHODS: The authors studied 1,473 patients (mean ± SD age, 57.9 ± 14.4 yr; 749 men) who underwent noncardiac surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Multivariable Cox regression analysis was used to determine whether perioperative factors were independently associated with all-cause mortality. RESULTS: A total of 358 patients (24.3%) died during a follow-up of 3.2 ± 1.1 yr. There were statistically significant associations among various perioperative risk factors, including malignancy and intermediate-term mortality. BIS-monitored patients did not have lower mortality than unmonitored patients (24.9 vs. 23.7%; difference = 1.2%, 95% CI, -3.3 to 5.6%). Cumulative duration of BIS values less than 45 was not associated with mortality (multivariable hazard ratio, 1.03; 95% CI, 0.93-1.14). Increasing mean and cumulative end-tidal anesthetic concentrations were not associated with mortality. The multivariable Cox regression model showed a good discriminative ability (c-index = 0.795). CONCLUSIONS: This study found no evidence that either cumulative BIS values below a threshold of 40 or 45 or cumulative inhalational anesthetic dose is injurious to patients. These results do not support the hypothesis that limiting depth of anesthesia either by titration to a specific BIS threshold or by limiting end-tidal volatile agent concentrations will decrease postoperative mortality.

Association of perioperative risk factors and cumulative duration of low bispectral index with intermediate-term mortality after cardiac surgery in the B-Unaware Trial.

BACKGROUND: Current data suggest that mortality after noncardiac surgery may be associated with persistent hypotension and the cumulative duration of low processed electroencephalogram-based bispectral index (BIS). This study assessed the relationships among cumulative duration of low BIS (BIS < 45), intermediate-term mortality, and anesthetic dose after cardiac surgery. METHODS: The authors studied 460 patients (mean age, 63.0 +/- 13.1 yr; 287 men) who underwent cardiac surgery between September 2005 and October 2006 at Washington University Medical Center, St Louis, Missouri. By using multivariable Cox regression analysis, perioperative factors were evaluated for their potential association with intermediate-term all-cause mortality. RESULTS: A total of 82 patients (17.8%) died during a median follow-up of 3 yr (interquartile range, 2.7-3.3 yr). Comparing patients who died with those who survived, there was no statistically significant difference in the relationship between end-tidal anesthetic gas concentrations during the anesthetic maintenance phase and the BIS. Cumulative duration of low BIS was independently associated with intermediate-term mortality. The 1.29 adjusted hazard ratio (95% CI, 1.12-1.49) for intermediate-term mortality with cumulative duration of low BIS translated into a 29% increased risk of death for every cumulative hour spent with a BIS less than 45. The final multivariable Cox regression model showed a good discriminative ability (c-index of 0.78). CONCLUSIONS: This study found an association between cumulative duration of low BIS and mortality in the setting of cardiac surgery. Notably, this association was independent of both volatile anesthetic concentration and duration of anesthesia, suggesting that intermediate-term mortality after cardiac surgery was not causally related to excessive anesthetic dose.

Does neuronal synchrony underlie visual feature grouping?

Previous research suggests that synchronous neural activity underlies perceptual grouping of visual image features. The generality of this mechanism is unclear, however, as previous studies have focused on pairs of neurons with overlapping or collinear receptive fields. By sampling more broadly and employing stimuli that contain partially occluded objects, we have conducted a more incisive test of the binding by synchrony hypothesis in area MT. We find that synchrony in spiking activity shows little dependence on feature grouping, whereas gamma band synchrony in field potentials can be significantly stronger when features are grouped. However, these changes in gamma band synchrony are small relative to the variability of synchrony across recording sites and do not provide a robust population signal for feature grouping. Moreover, these effects are reduced when stimulus differences nearby the receptive fields are eliminated using partial occlusion. Our findings suggest that synchrony does not constitute a general mechanism of visual feature binding.

Macaque middle temporal neurons signal depth in the absence of motion.

The middle temporal (MT) visual area is widely accepted to play important roles in motion processing. It is unclear, however, whether MT contributes to visual perception during the viewing of static scenes, when there is little retinal image motion during the interval between saccades. Some previous studies suggest that MT neurons give little or no response to stationary stimuli that are flashed onto the receptive field, but no previous study has directly examined the fidelity with which MT neurons code visual information in moving versus stationary stimuli. In this study, we compare the ability of MT neurons to signal binocular disparity in moving versus stationary random-dot stereograms. Although responses to moving stimuli are typically stronger, many MT neurons give robust responses to stationary stereograms, and some MT neurons actually prefer stationary patterns to those moving at any tested speed. These responses to stationary stimuli are not caused by monitor refresh or microsaccades. Disparity tuning curves for moving and stationary stimuli are nearly identical in shape for most neurons. Although the disparity discriminability of MT neurons is generally higher for moving stereograms when responses are averaged over the entire 1.5 sec trial epoch, discriminability is comparable for moving and stationary stimuli during the first 200-300 msec of the response. Thus, in a normal time interval between saccades, MT neurons signal the binocular disparity of stationary stimuli with high fidelity. These findings show that MT can be a reliable source of visual information during the viewing of static scenes.

Flow cytometric analysis of the cell cycle phase specificity of DNA damage induced by radiation, hydrogen peroxide and doxorubicin.

We have optimized a flow cytometric DNA alkaline unwinding assay to increase the sensitivity in detecting low levels of DNA damage (strand breaks and alkali-labile sites) and to permit the measurement of the extent of DNA damage within each cell cycle compartment. The lowest gamma radiation dose that induced detectable DNA damage in each cell cycle phase of HeLa and CEM cells was 10 cGy. The lowest H(2)O(2) concentration that induced detectable DNA damage in each cell cycle phase was 0.5 microM in HeLa cells, and 1-2.5 TmicroM in CEM cells. For both HeLa cells and CEM cells, DNA damage in each cell cycle compartment increased approximately linearly with increasing doses of gamma radiation and H(2)O(2). Although untreated HeLa and CEM cells in S phase consistently exhibited greater DNA unwinding than did G(1) or G(2) cells (presumably due to DNA strand breaks associated with replication forks), there was no difference between the susceptibility of G(0)/G(1), S and G(2)/M phase cells to DNA damage induced by gamma radiation or H(2)O(2), or in the rate of repair of this damage. In each cell cycle phase, the susceptibility to gamma radiation-induced DNA damage was greater in CEM cells than in HeLa cells. In contrast to the lack of cell cycle phase-specific DNA damage induced by exposure to gamma radiation or H(2)O(2), the cancer chemotherapeutic drug doxorubicin (adriamycin) predominantly induced DNA damage in G(2) phase cells.