Accuracy of the composite variability index as a measure of the balance between nociception and antinociception during anesthesia.

BACKGROUND: The Composite Variability Index (CVI), derived from the electroencephalogram, was developed to assess the antinociception-nociception balance, whereas the Bispectral Index (BIS) was developed to assess the hypnotic state during anesthesia. We studied the relationships between these indices, level of hypnosis (BIS level), and antinociception (predicted remifentanil effect-site concentrations, CeREMI) before and after stimulation. Also, we measured their association with movement in response to a noxious stimulus. METHODS: We randomized 120 patients to one of 12 groups targeting different hypnotic levels (BIS 70, 50, and 30) and various CeREMI (0, 2, 4, or 6 ng/mL). At pseudo-steady state, baseline values were observed, and a series of stimuli were applied. Changes in BIS, CVI, heart rate (HR), and mean arterial blood pressure (MAP) between baseline and response period were analyzed in relation to level of hypnosis, antinociception, and somatic response to the stimuli. RESULTS: CVI and BIS more accurately correlate with somatic response to an Observer Assessment of Alertness and Sedation-noxious stimulation than HR, MAP, CeREMI, and propofol effect-site concentration (Tukey post hoc tests P < 0.01). Change in CVI is more adequate to monitor response to stimulation than changes in BIS, HR, or MAP (as described by the Mathews Correlation Coefficient with significance level set at P < 0.001). In contrast, none of the candidate analgesic state indices was uniquely related to a specific opioid concentration and is extensively influenced by the hypnotic state as measured by BIS. CONCLUSIONS: CVI appears to correlate with somatic responses to noxious stimuli. However, unstimulated CVI depends more on hypnotic drug effect than on opioid concentration.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Increases in electroencephalogram and electromyogram variability are associated with an increased incidence of intraoperative somatic response.

BACKGROUND: sBIS, the variability of the Bispectral Index (BIS), sEMG, the variability of facial electromyogram power (EMG), and the Composite Variability Index (CVI) are 3 new measures of electroencephalogram and EMG variability. CVI is a single measure of the combined variability in BIS and EMG. We investigated whether increases in these variables are associated with intraoperative somatic responses. METHODS: This multicenter study included 120 patients undergoing elective, noncardiac surgery from 4 different sites. General anesthesia was maintained using propofol and remifentanil at 2 of the sites and sevoflurane and remifentanil at the 2 other sites. Propofol or sevoflurane was adjusted to maintain BIS between 45 and 60. Clinicians were blinded to CVI (v2.0) at all times, and remifentanil infusions were adjusted at the discretion of the clinician. The times of all intraoperative somatic events, defined as movement, grimacing, or eye opening, were recorded. Offline, the maintenance phase of each case was divided into consecutive, nonoverlapping, 10-minute segments. Segments were identified as containing a somatic event or containing no events. For each segment, mean sBIS, sEMG, and CVI and the heart rate (HR) range and mean arterial blood pressure range were calculated. To quantify how effectively each variable discriminated between somatic event segments and nonevent segments, we computed the area under the receiver operating characteristic (ROC) curve for each variable. Finally, we observed the time course of sBIS, sEMG, CVI, and the HR range before each somatic event and characterized the earliest time before the somatic event at which each variable was able to discriminate between the somatic events and a specified set of nonevents. RESULTS: The analysis included 33 somatic event segments and 829 nonevent segments from 105 surgical cases. The areas under the ROC curve (±SE) for sBIS, sEMG, and CVI were 0.83 ± 0.04, 0.92 ± 0.02, and 0.89 ± 0.03, respectively. The areas under the ROC curve for HR range and mean arterial blood pressure range were 0.77 ± 0.03 and 0.68 ± 0.05, respectively. CVI, sBIS, and sEMG all demonstrated higher average values before upcoming somatic events when compared with nonevents. HR range only showed a difference within a few seconds before the somatic event. CONCLUSION: sBIS, sEMG, and CVI, measures of electroencephalogram and EMG variability, increased when intraoperative somatic events occurred. sBIS, sEMG, and CVI discriminated between 10-minute segments that contained a somatic event and those segments that did not contain an event better than changes in HR and mean arterial blood pressure. Furthermore, CVI increases before somatic events began earlier than HR changes and may provide caregivers with an early warning of potentially inadequate antinociception.

Response properties of neighboring neurons in the auditory midbrain for pure-tone stimulation: a tetrode study.

The complex anatomical structure of the central nucleus of the inferior colliculus (ICC), the principal auditory nucleus in the midbrain, may provide the basis for functional organization of auditory information. To investigate this organization, we used tetrodes to record from neighboring neurons in the ICC of anesthetized cats and studied the similarity and difference among the responses of these neurons to pure-tone stimuli using widely used physiological characterizations. Consistent with the tonotopic arrangement of neurons in the ICC and reports of a threshold map, we found a high degree of correlation in the best frequencies (BFs) of neighboring neurons, which were mostly <3 kHz in our sample, and the pure-tone thresholds among neighboring neurons. However, width of frequency tuning, shapes of the frequency response areas, and temporal discharge patterns showed little or no correlation among neighboring neurons. Because the BF and threshold are measured at levels near the threshold and the characteristic frequency (CF), neighboring neurons may receive similar primary inputs tuned to their CF; however, at higher levels, additional inputs from other frequency channels may be recruited, introducing greater variability in the responses. There was also no correlation among neighboring neurons' sensitivity to interaural time differences (ITD) measured with binaural beats. However, the characteristic phases (CPs) of neighboring neurons revealed a significant correlation. Because the CP is related to the neural mechanisms generating the ITD sensitivity, this result is consistent with segregation of inputs to the ICC from the lateral and medial superior olives.