Chantal Kerssens

Functional connectivity changes with concentration of sevoflurane anesthesia

Low-frequency oscillations (<0.08 Hz) have been detected in functional magnetic resonance imaging studies, and appear to be synchronized between functionally related areas. The effect of anesthetic agents on cortical activity is not completely characterized. This study assessed the effect of anesthesia on the temporal relations in activity in the motor cortices. Resting-state magnetic resonance data were acquired on six volunteers under different anesthetic states (using 0.0%, 2.0% and 1.0% stable end-tidal sevoflurane). Across all volunteers, the number of significant voxels (p<2.5×10−5) in the functional connectivity maps was reduced by 78% for light anesthesia and by 98% for deep anesthesia, compared with the awake state. Additionally, significant correlations in the connectivity maps were bilateral in the awake state but unilateral in the light anesthesia state.

Dependence of Explicit and Implicit Memory on Hypnotic State in Trauma Patients.

BACKGROUND It is still unclear whether memory of intraoperative events results entirely from moments of inadequate anesthesia. The current study was designed to determine whether the probability of memory declines with increasing depth of the hypnotic state. METHOD A list of words was played via headphones during surgery to patients who had suffered acute trauma. Several commonly used indicators of anesthetic effect, including the bispectral index, were recorded during word presentation. First, these indicators served as predictors of the memory performance in a postoperative word stem completion test. Second, general memory performance observed in the first part was separated into explicit and implicit memory using the process dissociation procedure, and then two models of memory were compared: One model assumed that the probability of explicit and implicit memory decreases with increasing depth of hypnotic state (individual differences model), whereas the other assumed equal memory performance for all patients regardless of their level of hypnotic state. RESULTS General memory performance declined with decreasing bispectral index values. None of the other indicators of hypnotic state were related to general memory performance. Memory was still significant at bispectral index levels between 60 and 40. A comparison of the two models of memory resulted in a better fit of the individual differences model, thus providing evidence of a dependence of explicit and implicit memory on the hypnotic state. Quantification of explicit and implicit memory revealed a significant implicit but no reliable explicit memory performance. CONCLUSIONS This study clearly indicates that memory is related to the depth of hypnosis. The observed memory performance should be interpreted in terms of implicit memory. Auditory information processing occurred at bispectral index levels between 60 and 40.

Altered local coherence in the default mode network due to sevoflurane anesthesia.

Recently we introduced a robust measure, integrated local correlation (ILC), of local connectivity in the brain using fMRI data which reflects the temporal correlation of brain activity in every voxel neighborhood. The current work studies ILC in fMRI data obtained in the absence and presence of sevoflurane anesthesia (0%, 2%, and 1% end-tidal concentration, respectively) administered to healthy volunteers. ILC was determined specifically in regions of the default mode network (DMN) to address local changes in each state. In addition, a potential confound in analyses based on correlations due to signal-to-noise variations was addressed by wavelet denoising. This accommodated decreases in signal power commonly seen during anesthesia without artificially reducing derived correlations. Results showed that ILC was significantly reduced in the entire DMN during 2% sevoflurane yet recovered in the posterior and anterior cingulate cortices as well as inferior parietal cortex during 1% sevoflurane. By contrast, ILC remained attenuated prefrontally in the 1% condition, which indicates uncoupling of the frontal areas of DMN during light anesthesia. These results confirm widespread anesthetic-induced cortical suppression but also demonstrate that the local connectivity of the prefrontal cortex is rapidly reduced by sevoflurane. It remains to be seen whether these alterations arise locally as a direct consequence of anesthetic action on local neurons or are driven by distant changes in oscillations and activity elsewhere in the brain.

Memory Formation during general anesthesia for emergency cesarean sections.

Background: Occurrence of explicit memory (i.e., conscious recall) has been reported especially after surgical procedures in which anesthesia is considered to be “light.” In addition, previous research has shown that implicit memory (e.g., improved memory test performance in absence of conscious recall) decreases with increasing hypnotic state. The current study investigated explicit and implicit memory during emergency cesarean sections with consistently light levels of hypnotic state. Method: Words were presented via headphones, and the bispectral index was recorded throughout surgery. Memory for the presented words was tested after recovery with a word-stem completion test. Using both parts of the process dissociation procedure allowed separation of explicit and implicit memory. In the “inclusion” part of the process dissociation procedure, patients are asked to complete word stems, if possible, with the corresponding words recalled from the intraoperative presentation. In the “exclusion” part, patients are instructed to avoid the words presented intraoperatively and to use other words instead. In the absence of recall, patients are asked to use the first word that comes to mind. Results: The mean bispectral index during word presentation was 76.3 (±3.0). On average, the 24 patients were able to make correct inclusion–exclusion decisions: In the inclusion part, hit rates (i.e., the probability of responding with a word presented during surgery) were higher than base rates (0.37 vs. 0.31), whereas in the exclusion part hit rates were lower (0.23 vs. 0.28). Importantly, the patients made these inclusion–exclusion decisions without being able to consciously recall the words presented during surgery. Conclusions: This study shows that if words are presented at relatively light levels of anesthesia, patients are able to control their inclusion–exclusion decisions. This weak form of explicit memory can occur in the absence of conscious recall.

Attenuated Brain Response to Auditory Word Stimulation with Sevoflurane A Functional Magnetic Resonance Imaging Study in Humans

Background:Functional magnetic resonance imaging offers a compelling, new perspective on altered brain function but is sparsely used in studies of anesthetic effect. To examine effects on verbal memory encoding, the authors imaged human brain response to auditory word stimulation using functional magnetic resonance imaging at different concentrations of an agent not previously studied, and tested memory after recovery. Methods:Six male volunteers were studied breathing 0.0, 2.0, and 1.0% end-tidal sevoflurane (awake, deep, and light states, respectively) via laryngeal mask. In each condition, they heard 15 two-syllable English nouns via closed headphones. Each word was repeated 15 times (1/s), followed by 15 s of rest. Blood oxygenation level–dependent brain activations during blocks of stimulation versus rest were assessed with a 3-T Siemens Trio scanner and a 20-voxel spatial extent threshold. Memory was tested approximately 1.5 h after recovery with an auditory recognition task (chance performance = 33% correct). Results:Scans showed widespread activations (P < 0.005, uncorrected) in the awake state, including bilateral superior temporal, frontal, and parietal cortex, right occipital cortex, bilateral thalamus, striatum, hippocampus, and cerebellum; more limited activations in the light state (bilateral superior temporal gyrus, right thalamus, bilateral parietal cortex, left frontal cortex, and right occipital cortex); and no significant auditory-related activation in the deep state. During recognition testing, subjects correctly selected 77 ± 12% of words presented while they were awake as “old,” versus 32 ± 15 and 42 ± 8% (P < 0.01) correct for the light and deep stages, respectively. Conclusions:Sevoflurane induces dose-dependent suppression of auditory blood oxygenation level–dependent signals, which likely limits the ability of words to be processed during anesthesia and compromises memory.

Memory function during propofol and alfentanil anesthesia: predictive value of individual differences.

Background Conscious recall and implicit memory have been shown to depend on hypnotic state as measured by electroencephalographic (EEG) bispectral index (BIS). A third expression of memory (unconscious–controlled memory) was recently observed after moderate to light sedation (BIS, 70–80). The present study investigated memory function during deep sedation (BIS, 60–70). As memory effects are small, the authors studied potential predictors of individual differences in memory performance. Methods Memory function and speed of information processing were assessed in 56 outpatients before surgery. During propofol anesthesia supplemented with alfentanil, patients heard a series of words while anesthesia was titrated to BIS, 60–70. In between words, response to command was assessed using the Isolated Forearm Technique. The authors tested memory with a word stem completion task and process dissociation procedure to distinguish explicit from implicit effects. Results Mean (± SD) BIS during word presentation was 64.0 ± 3. Patients with conscious recall of verbal commands (n = 9) did not recall or recognize presented words. Even so, the process dissociation procedure revealed evidence of memory by a significantly higher hit rate in the inclusion condition (0.26) than in the exclusion condition (0.12). Patients without conscious recall showed no evidence of memory for presented words. Hit scores correlated significantly with scores in the preoperative memory test (r = 0.35). Conclusions The authors found evidence of weak explicit memory function during anesthesia titrated to BIS, 60–70. The observations strongly suggest that postoperative memory relates to awareness during anesthesia, but the nature of this relation remains unclear. Memory seems more likely in patients with good preoperative memory performance.

No Evidence of Memory Function during Anesthesia with Propofol or Isoflurane with Close Control of Hypnotic State

Background: The authors previously demonstrated memory function during apparently adequate general anesthesia in trauma patients. Hypnotic state fluctuations, stress, and variable amnesic qualities of commonly used anesthetics could account for this effect. Methods: The authors replicated the trauma investigation in 90 elective surgical patients to enable anesthetic titration to a bispectral index value of 50–55 during auditory presentation of word stimuli. Patients were randomly assigned to maintenance with propofol (n = 48) or isoflurane (n = 42). Before surgery, state anxiety and trait anxiety were assessed using self-report measures. Postoperative memory assessment relied on the process dissociation procedure using a word stem completion task. Results: There were no differences between groups for relevant demographic, preoperative, or supplemental drug variables. Ninety-eight percent of words were presented within a bispectral index range of 40–60, with values averaging 48.8 (SD = 5.7) during word presentation. Neither the process dissociation procedure nor standard measures of conscious recall and recognition memory showed evidence of explicit or implicit memory. Preoperative stress levels did not correlate with postoperative memory test scores in either study group. Conclusions: In contrast to the results of their previous study, the authors found no evidence of memory function with close control of hypnotic state. This suggests that hypnotic state fluctuations are important to memory activation under anesthesia. Other variables may contribute to preserved memory function as well. Propofol and isoflurane block memory equally well during adequate anesthesia.

Preserved Memory Function during Bispectral Index–guided Anesthesia with Sevoflurane for Major Orthopedic Surgery

Background:Memory function under anesthesia is undesired but may arise from light hypnosis as well as stress-enhanced learning during surgery. The bispectral index (BIS, Aspect Medical Systems, Norwood, MA) is a monitor of hypnotic state that can help to avoid light hypnosis (i.e., BIS above 60). This study tested the hypothesis that BIS-guided anesthesia maintaining BIS 50–60 reduces the likelihood of memory function under anesthesia. Methods:After obtaining informed consent, 128 patients scheduled for joint replacement surgery under general anesthesia with sevoflurane were randomly assigned to BIS-guided anesthesia, titrating drugs to BIS 50–60 (BIS group), or a standard practice group in which BIS was recorded but did not guide drug administration. After induction, all patients were repeatedly played a list of 15 words. After recovery from anesthesia, all were interviewed about recall and completed a recognition memory test containing the presented words (targets, 33.3%) and new words (distractors). Preoperatively, patients filled out a stress questionnaire (Spielberger State-Trait Anxiety Inventory). Results:BIS values above 60 were recorded in both groups, but no patient recalled the presented words postoperatively. Only patients in the BIS group selected targets more often than distractors (37.1% vs. 31.5% hit rate, P = 0.001). Target hit rates correlated poorly to stress scores (P > 0.9), but were associated with the amount of fentanyl received preoperatively (P = 0.01) and pain management technique (P < 0.01). Conclusions:BIS titration to BIS 50–60 does not necessarily curb memory function under anesthesia when BIS values higher than 60 occur. Preoperative analgesia attenuated the likelihood of memory function under anesthesia.

To BIS or Not to BIS? That Is the Question

T his editorial accompanies two papers (1,2) on the use of the Bispectral Index (BIS) as a sedation index in children. Before discussing the salient elements and findings of these papers, it is instructive to consider what processed electroencephalogram (EEG) monitors actually measure. As an analogy, consider the dark days before the introduction of pulse oximetry into clinical practice, when clinicians generally used something that might approximate to a four-point scale (pink/slightly blue/ dark blue/black) to assess oxygenation. The introduction of pulse oximetry gave a continuous measure of oxygen saturation as a percentage of saturated hemoglobin and quickly became the gold standard for measuring oxygenation, despite the lack of prospective randomized trial evidence of improved outcomes (3). Similarly, we have multiple discontinuous clinical scales for describing sedation levels in adults, including the Observer’s Assessment of Alertness and Sedation (OAAS) and the Ramsay scales. The purpose of processed EEG monitors is to provide a continuous measure that encompasses the full range of sedation levels measured by the discontinuous scales. Pulse oximetry measures a physiological parameter that most physicians can readily understand (oxygen saturation). In contrast, processed EEG monitors calculate a mathematical abstraction of the electroencephalogram, a concept less familiar and less accessible to the practicing clinician. BIS was derived by empirically estimating the EEG parameters that best predicted OAAS measurements in a large patient and volunteer database of subjects receiving hypnotics and opioids. As a continuous measure that correlates to OAAS measures obtained from subjects receiving hypnotic drugs, BIS may be described as a “probability of state” measure, reflecting the complex nature of consciousness (4). Being derived from the OAAS, BIS should be expected to correlate well with the OAAS. The correlation would probably be less strong with other rating scales, such as the Ramsay scale, the modified maintenance of wakefulness test (MMWT) scale used in pediatrics, or the University of Michigan sedation scale (UMSS). These latter scales were not part of the database used to develop the BIS monitor, and the original database was entirely constructed from adult EEG data. Normal pediatric EEG differs markedly from adult EEG, displaying more variation than adult EEG (5,6). This may make processed EEG parameters less reliable in children. In general, the electrical activity of the brain changes during growth and development, warranting age-specific considerations and cautious interpretation of EEG data in the pediatric population. Despite such theoretical concerns, studies suggest that the performance of BIS in pediatric patients older than 6 months of age may be similar to that of adults (7–9). In younger infants, brain maturation and development may render processed EEG measures unreliable. However, McDermott et al. (8) still found a significant correlation between BIS and the UMSS in patients younger than 6 months of age in a small group of patients. In this issue of Anesthesia & Analgesia, Malviya et al. (1) report on the observed relationship between BIS and two observational measures, the UMSS and MMWT, in children 1 month to 17 years conceptual age. In lieu of clinical guidelines that call for delineation of sedation states, the investigators were particularly interested in the ability of different measures to discriminate conscious from deep sedation. Data from 39 patients were included, comprising repeated measurements (about 8 per individual on average) of sedation indices after unspecified procedures that required sedation/analgesia or general anesthesia. The authors report good correlation between UMSS and BIS ( 0.73), indicating reasonable concordance between these discontinuous and continuous scales. This supports the validity of BIS as a pediatric sedation monitor and complements similar reports by this group (10) and others (8). MMWT scores, by contrast, correlated weakly (0.36) with BIS, in contrast to earlier Dr. Peter S. Sebel is a paid consultant to Aspect Medical Systems. Accepted for publication November 16, 2005. Address correspondence and reprint requests to Peter S. Sebel, MB BS, PhD, MBA, Department of Anesthesiology, Emory University School of Medicine, 49 Jesse Hill Jr. Drive, SE, Atlanta, GA 30303. Address e-mail to peter_sebel@emoryhealthcare.org.

Simultaneous investigation of local and distributed functional brain connectivity from fMRI data

In this paper we propose a new method for simultaneous assessment of local and distributed functional brain connectivity from functional magnetic resonance imaging (fMRI) data. Our method maps fMRI time series from brain voxels into a high dimensional feature space where in clustering and vector quantization are performed in order to aggregate voxels with similar temporal evolution and segregate those with low temporal correlation. An iterative algorithm is proposed based on the Eigen structure of the geodesic distance matrix of the high dimensional manifold for selecting the number of clusters. The choice is then verified by unfolding the manifold using ISOMAP. A combined connectivity index (CCI) is then defined for every brain region based on the percentage of its voxels connected to each other and to voxels from other regions. The CCI maps local and distributed connectivity on a continuum from 0 to 1. This method was applied to resting state fMRI data obtained from humans in one of the two states: normal awake state and a sedated state induced by propofol anesthesia. Our results demonstrate that propofol anesthesia makes the connectivity in the brain become more local and less distributed as compared to awake state. In addition, our results show that the distributed connectivity between the thalamus and the cortex is greatly impacted by anesthesia, lending support to the thalamo-cortical disconnection hypothesis. However, our results indicate the thalamus was still connected to the cortex via the amygdala, providing a pathway for sensory information to reach the cortex during sedation. In the cortex, the connectivity also tended to become more local than distributed, supporting the cortico-cortical disconnection hypothesis. Therefore, our conclusions reconcile both the hypotheses of anesthetic action and altered states of consciousness, and demonstrate the utility of our approach for addressing important neuroscientific questions.