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.

Evaluation of putative signatures of consciousness using specific definitions of responsiveness, connectedness, and consciousness.

BACKGROUND: Understanding the neural correlates of consciousness has important ramifications for the theoretical understanding of consciousness and for clinical anaesthesia. A major limitation of prior studies is the use of responsiveness as an index of consciousness. We identified a collection of measures derived from unresponsive subjects and more specifically their association with consciousness (any subjective experience) or connectedness (specific experience of environmental stimuli). METHODS: Using published data generated through the UNderstanding Consciousness Connectedness and Intra-Operative Unresponsiveness Study (NCT03284307), we evaluated 10 previously published resting-state EEG-based measures that were derived using unresponsiveness as a proxy for unconsciousness. Measures were tested across dexmedetomidine and propofol sedation and natural sleep. These markers represent the complexity, connectivity, cross-frequency coupling, graph theory, and power spectrum measures. RESULTS: Although many of the proposed markers were associated with consciousness per se (reported subjective experience), none were specific to consciousness alone; rather, each was also associated with connectedness (i.e. awareness of the environment). In addition, multiple markers showed no association with consciousness and were associated only with connectedness. Of the markers tested, loss of normalised-symbolic transfer entropy (front to back) was associated with connectedness across all three experimental conditions, whereas the transition from disconnected consciousness to unconsciousness was associated with significant decreases in permutation entropy and spectral exponent (P<0.05 for all conditions). CONCLUSIONS: None of the proposed EEG-based neural correlates of unresponsiveness corresponded solely to consciousness, highlighting the need for a more conservative use of the term (un)consciousness when assessing unresponsive participants. CLINICAL TRIAL REGISTRATION: NCT03284307.

Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice.

While correlations between drug-induced cortisol elevation, self-reported anxiety, and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy, the mechanistic relationship between psychedelic-associated alterations in plasma glucocorticoid responses and the time course of anxious responsiveness remains unclear. Using rodents, both time-bound manipulation of glucocorticoid concentrations and assessment of anxiety-like behaviors can be achieved. Here, 3 mg/kg IP psilocybin was found to have anxiolytic-like effects in C57BL/6 male mice at 4 h after treatment. These effects were not altered by pretreatment with a 5-HT2A antagonist but were blunted by pretreatment with a glucocorticoid receptor antagonist or suppression of psilocybin-induced corticosterone elevations. Anxiolytic-like effects were also observed at 4 h following treatment with the nonpsychedelic 5-HT2A agonist lisuride at a dose causing a similar increase in plasma glucocorticoids as that seen with psilocybin, as well as following stress-induced (via repeated injection) glucocorticoid release alone. Psilocybin's anxiolytic-like effects persisted at 7 days following administration. The long-term anxiolytic effects of psilocybin were lost when psilocybin was administered to animals with ongoing chronic elevations in plasma corticosterone concentrations. Overall, these experiments indicate that acute, resolvable psilocybin-induced glucocorticoid release drives the postacute anxiolytic-like effects of psilocybin in mice and that its long-term anxiolytic-like effects can be abolished in the presence of chronically elevated plasma glucocorticoid elevations.

Subanaesthetic doses of ketamine reduce but do not eliminate predictive coding responses: implications for mechanisms of sensory disconnection.

BACKGROUND: Sensory disconnection is a key feature of sleep and anaesthesia. We have proposed that predictive coding offers a framework for understanding the mechanisms of disconnection. Low doses of ketamine that do not induce disconnection should thus diminish predictive coding, but not abolish it. METHODS: Ketamine was administered to 14 participants up to a blood concentration of 0.3 µg ml-1 Participants were played a series of tones comprising a roving oddball sequence while electroencephalography evoked response potentials were recorded. We fit a Bayesian observer model to the tone sequence, correlating neural activity with the prediction errors generated by the model using linear mixed effects models and cluster-based statistics. RESULTS: Ketamine modulated prediction errors associated with the transition of one tone to the next (transitional probability), but not how often tones changed (environmental volatility), of the system. Transitional probability was reduced when blood concentrations of ketamine were increased to 0.2-0.3 µg ml-1 (96-208 ms, P=0.003); however, correlates of prediction error were still evident in the electroencephalogram (124-168 ms, P=0.003). Prediction errors related to environmental volatility were associated with electroencephalographic activity before ketamine (224-284 ms, P=0.028) and during 0.2-0.3 µg ml-1 ketamine (108-248 ms, P=0.003). At this subanaesthetic dose, ketamine did not exert a dose-dependent modulation of prediction error. CONCLUSIONS: Subanaesthetic dosing of ketamine reduced correlates of predictive coding but did not eliminate them. Future studies should evaluate whether states of sensory disconnection, including anaesthetic doses of ketamine, are associated with a complete absence of predictive coding responses. CLINICAL TRIAL REGISTRATION: NCT03284307.

Functional geometry of auditory cortical resting state networks derived from intracranial electrophysiology.

Understanding central auditory processing critically depends on defining underlying auditory cortical networks and their relationship to the rest of the brain. We addressed these questions using resting state functional connectivity derived from human intracranial electroencephalography. Mapping recording sites into a low-dimensional space where proximity represents functional similarity revealed a hierarchical organization. At a fine scale, a group of auditory cortical regions excluded several higher-order auditory areas and segregated maximally from the prefrontal cortex. On mesoscale, the proximity of limbic structures to the auditory cortex suggested a limbic stream that parallels the classically described ventral and dorsal auditory processing streams. Identities of global hubs in anterior temporal and cingulate cortex depended on frequency band, consistent with diverse roles in semantic and cognitive processing. On a macroscale, observed hemispheric asymmetries were not specific for speech and language networks. This approach can be applied to multivariate brain data with respect to development, behavior, and disorders.

Analogous cortical reorganization accompanies entry into states of reduced consciousness during anesthesia and sleep.

Theories of consciousness suggest that brain mechanisms underlying transitions into and out of unconsciousness are conserved no matter the context or precipitating conditions. We compared signatures of these mechanisms using intracranial electroencephalography in neurosurgical patients during propofol anesthesia and overnight sleep and found strikingly similar reorganization of human cortical networks. We computed the "effective dimensionality" of the normalized resting state functional connectivity matrix to quantify network complexity. Effective dimensionality decreased during stages of reduced consciousness (anesthesia unresponsiveness, N2 and N3 sleep). These changes were not region-specific, suggesting global network reorganization. When connectivity data were embedded into a low-dimensional space in which proximity represents functional similarity, we observed greater distances between brain regions during stages of reduced consciousness, and individual recording sites became closer to their nearest neighbors. These changes corresponded to decreased differentiation and functional integration and correlated with decreases in effective dimensionality. This network reorganization constitutes a neural signature of states of reduced consciousness that is common to anesthesia and sleep. These results establish a framework for understanding the neural correlates of consciousness and for practical evaluation of loss and recovery of consciousness.

High-dimensional multivariate autoregressive model estimation of human electrophysiological data using fMRI priors.

Multivariate autoregressive (MVAR) model estimation enables assessment of causal interactions in brain networks. However, accurately estimating MVAR models for high-dimensional electrophysiological recordings is challenging due to the extensive data requirements. Hence, the applicability of MVAR models for study of brain behavior over hundreds of recording sites has been very limited. Prior work has focused on different strategies for selecting a subset of important MVAR coefficients in the model to reduce the data requirements of conventional least-squares estimation algorithms. Here we propose incorporating prior information, such as resting state functional connectivity derived from functional magnetic resonance imaging, into MVAR model estimation using a weighted group least absolute shrinkage and selection operator (LASSO) regularization strategy. The proposed approach is shown to reduce data requirements by a factor of two relative to the recently proposed group LASSO method of Endemann et al (Neuroimage 254:119057, 2022) while resulting in models that are both more parsimonious and more accurate. The effectiveness of the method is demonstrated using simulation studies of physiologically realistic MVAR models derived from intracranial electroencephalography (iEEG) data. The robustness of the approach to deviations between the conditions under which the prior information and iEEG data is obtained is illustrated using models from data collected in different sleep stages. This approach allows accurate effective connectivity analyses over short time scales, facilitating investigations of causal interactions in the brain underlying perception and cognition during rapid transitions in behavioral state.

Surgeon-Specific Treatment Selection Bias and Heterogeneous Perioperative Practices in an Observational Spine Surgery Study. A Statistical Tutorial with Implications for Analysis of Observational Studies of Perioperative Interventions.

BACKGROUND: It is essential that treatment effects reported from retrospective observational studies are as reliable as possible. In a retrospective analysis of spine surgery patients, we obtained a spurious result: tranexamic acid (TXA) had no effect on intraoperative blood loss. This statistical tutorial explains how this result occurred and why statistical analyses of observational studies must consider the effects of individual surgeons. METHODS: We used an observational database of 580 elective adult spine surgery patients, supplemented with a review of perioperative medication records. We tested whether common statistical methods (multivariable regression or propensity score-based methods) could adjust for surgeons' selection bias in TXA administration. RESULTS: Because TXA administration (frequency, timing, and dose) and surgeon were linked (collinear), estimating and testing the independent effect of TXA on outcome using multivariable regression without including surgeon as a variable would provide biased (spurious) results. Likewise, because of surgeon/TXA linkage, assumptions of propensity score-based analysis were violated, statistical methods to improve comparability between groups failed, and spurious blood loss results were worsened. Others numerous differences among surgeons existed in intraoperative and postoperative practices and outcomes. CONCLUSIONS: In observational studies in which individual surgeons determine whether their patients receive the treatment of interest, consideration must be given to inclusion of surgeon as an independent variable in all analyses. Failure to include the surgeon in an analysis of observational data carries a substantial risk of obtaining spurious results, either creating a spurious treatment effect or failing to detect a true treatment effect.

Dynamic causal modelling of auditory surprise during disconnected consciousness: The role of feedback connectivity.

The neural mechanisms through which individuals lose sensory awareness of their environment during anesthesia remains poorly understood despite being of vital importance to the field. Prior research has not distinguished between sensory awareness of the environment (connectedness) and consciousness itself. In the current study, we investigated the neural correlates of sensory awareness by contrasting neural responses to an auditory roving oddball paradigm during consciousness with sensory awareness (connected consciousness) and consciousness without sensory awareness (disconnected consciousness). These states were captured using a serial awakening paradigm with the sedative alpha2 adrenergic agonist dexmedetomidine, chosen based on our published hypothesis that suppression of noradrenaline signaling is key to induce a state of sensory disconnection. High-density electroencephalography was recorded from 18 human subjects before and after administration of dexmedetomidine. By investigating event-related potentials and taking advantage of advances in Dynamic Causal Modeling (DCM), we assessed alterations in effective connectivity between nodes of a previously established auditory processing network. We found that during disconnected consciousness, the scalp-level response to standard tones produced a P3 response that was absent during connected consciousness. This P3 response resembled the response to oddball tones seen in connected consciousness. DCM showed that disconnection produced increases in standard tone feedback signaling throughout the auditory network. Simulation analyses showed that these changes in connectivity, most notably the increase in feedback from right superior temporal gyrus to right A1, can explain the new P3 response. Together these findings show that during disconnected consciousness there is a disruption of normal predictive coding processes, so that all incoming auditory stimuli become similarly surprising.

Multivariate autoregressive model estimation for high-dimensional intracranial electrophysiological data.

Fundamental to elucidating the functional organization of the brain is the assessment of causal interactions between different brain regions. Multivariate autoregressive (MVAR) modeling techniques applied to multisite electrophysiological recordings are a promising avenue for identifying such causal links. They estimate the degree to which past activity in one or more brain regions is predictive of another region's present activity, while simultaneously accounting for the mediating effects of other regions. Including as many mediating variables as possible in the model has the benefit of drastically reducing the odds of detecting spurious causal connectivity. However, effective bounds on the number of MVAR model coefficients that can be estimated reliably from limited data make exploiting the potential of MVAR models challenging for even modest numbers of recording sites. Here, we utilize well-established dimensionality-reduction techniques to fit MVAR models to human intracranial data from ∼100 - 200 recording sites spanning dozens of anatomically and functionally distinct cortical regions. First, we show that high-dimensional MVAR models can be successfully estimated from long segments of data and yield plausible connectivity profiles. Next, we use these models to generate synthetic data with known ground-truth connectivity to explore the utility of applying principal component analysis and group least absolute shrinkage and selection operator (gLASSO) to reduce the number of parameters (connections) during model fitting to shorter data segments. We show that gLASSO is highly effective for recovering ground-truth connectivity in the limited data regime, capturing important features of connectivity for high-dimensional models with as little as 10 seconds of data. The methods presented here have broad applicability to the analysis of high-dimensional time series data in neuroscience, facilitating the elucidation of the neural basis of sensation, cognition, and arousal.

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.

Arousal State-Dependence of Interactions Between Short- and Long-Term Auditory Novelty Responses in Human Subjects.

In everyday life, predictable sensory stimuli are generally not ecologically informative. By contrast, novel or unexpected stimuli signal ecologically salient changes in the environment. This idea forms the basis of the predictive coding hypothesis: efficient sensory encoding minimizes neural activity associated with predictable backgrounds and emphasizes detection of changes in the environment. In real life, the brain must resolve multiple unexpected sensory events occurring over different time scales. The local/global deviant experimental paradigm examines auditory predictive coding over multiple time scales. For short-term novelty [hundreds of milliseconds; local deviance (LD)], sequences of identical sounds (/xxxxx/) are interspersed with sequences that contain deviants (/xxxxy/). Long-term novelty [several seconds; global deviance (GD)] is created using either (a) frequent /xxxxx/ and infrequent /xxxxy/ sequences, or (b) frequent /xxxxy/ and infrequent /xxxxx/ sequences. In scenario (a), there is both an LD and a GD effect (LDGD, "double surprise"). In (b), the global deviant is a local standard, i.e., sequence of identical sounds (LSGD). Cortical responses reflecting LD and GD originate in different brain areas, have a different time course, and are differentially sensitive to general anesthesia. Neural processes underlying LD and GD have been shown to interact, reflecting overlapping networks subserving the detection of novel auditory stimuli. This study examined these interactions using intracranial electroencephalography in neurosurgical patients. Subjects performed a GD target detection task before and during induction of anesthesia with propofol. Recordings were made from the auditory cortex, surrounding auditory-related and prefrontal cortex in awake, sedated, and unresponsive states. High gamma activity was used to measure the neural basis of local-by-global novelty interactions. Positive interaction was defined as a greater response to the double surprise LDGD condition compared to LSGD. Negative interaction was defined as a weaker response to LDGD. Positive interaction was more frequent than negative interaction and was primarily found in auditory cortex. Negative interaction typically occurred in prefrontal cortex and was more sensitive to general anesthesia. Temporo-parietal auditory-related areas exhibited both types of interaction. These interactions may have relevance in a clinical setting as biomarkers of conscious perception in the assessment of depth of anesthesia and disorders of consciousness.

Cortical Responses to Vowel Sequences in Awake and Anesthetized States: A Human Intracranial Electrophysiology Study.

Elucidating neural signatures of sensory processing across consciousness states is a major focus in neuroscience. Noninvasive human studies using the general anesthetic propofol reveal differential effects on auditory cortical activity, with a greater impact on nonprimary and auditory-related areas than primary auditory cortex. This study used intracranial electroencephalography to examine cortical responses to vowel sequences during induction of general anesthesia with propofol. Subjects were adult neurosurgical patients with intracranial electrodes placed to identify epileptic foci. Data were collected before electrode removal surgery. Stimuli were vowel sequences presented in a target detection task during awake, sedated, and unresponsive states. Averaged evoked potentials (AEPs) and high gamma (70-150 Hz) power were measured in auditory, auditory-related, and prefrontal cortex. In the awake state, AEPs were found throughout studied brain areas; high gamma activity was limited to canonical auditory cortex. Sedation led to a decrease in AEP magnitude. Upon LOC, there was a decrease in the superior temporal gyrus and adjacent auditory-related cortex and a further decrease in AEP magnitude in core auditory cortex, changes in the temporal structure and increased trial-to-trial variability of responses. The findings identify putative biomarkers of LOC and serve as a foundation for future investigations of altered sensory processing.

Catalysts for change: the cellular neurobiology of psychedelics.

The resurgence of interest in the therapeutic potential of psychedelics for treating psychiatric disorders has rekindled efforts to elucidate their mechanism of action. In this Perspective, we focus on the ability of psychedelics to promote neural plasticity, postulated to be central to their therapeutic activity. We begin with a brief overview of the history and behavioral effects of the classical psychedelics. We then summarize our current understanding of the cellular and subcellular mechanisms underlying these drugs' behavioral effects, their effects on neural plasticity, and the roles of stress and inflammation in the acute and long-term effects of psychedelics. The signaling pathways activated by psychedelics couple to numerous potential mechanisms for producing long-term structural changes in the brain, a complexity that has barely begun to be disentangled. This complexity is mirrored by that of the neural mechanisms underlying psychiatric disorders and the transformations of consciousness, mood, and behavior that psychedelics promote in health and disease. Thus, beyond changes in the brain, psychedelics catalyze changes in our understanding of the neural basis of psychiatric disorders, as well as consciousness and human behavior.

Corticothalamic gating of population auditory thalamocortical transmission in mouse.

The mechanisms that govern thalamocortical transmission are poorly understood. Recent data have shown that sensory stimuli elicit activity in ensembles of cortical neurons that recapitulate stereotyped spontaneous activity patterns. Here, we elucidate a possible mechanism by which gating of patterned population cortical activity occurs. In this study, sensory-evoked all-or-none cortical population responses were observed in the mouse auditory cortex in vivo and similar stochastic cortical responses were observed in a colliculo-thalamocortical brain slice preparation. Cortical responses were associated with decreases in auditory thalamic synaptic inhibition and increases in thalamic synchrony. Silencing of corticothalamic neurons in layer 6 (but not layer 5) or the thalamic reticular nucleus linearized the cortical responses, suggesting that layer 6 corticothalamic feedback via the thalamic reticular nucleus was responsible for gating stochastic cortical population responses. These data implicate a corticothalamic-thalamic reticular nucleus circuit that modifies thalamic neuronal synchronization to recruit populations of cortical neurons for sensory representations.

Electrophysiological signatures of acute systemic lipopolysaccharide-induced inflammation: potential implications for delirium science.

BACKGROUND: Novel preventive therapies are needed for postoperative delirium, which especially affects older patients. A mouse model is presented that captures inflammation-associated cortical slow wave activity (SWA) observed in patients, allowing exploration of the mechanistic role of prostaglandin-adenosine signalling. METHODS: EEG and cortical cytokine measurements (interleukin 6, monocyte chemoattractant protein-1) were obtained from adult and aged mice. Behaviour, SWA, and functional connectivity were assayed before and after systemic administration of lipopolysaccharide (LPS)+piroxicam (cyclooxygenase inhibitor) or LPS+caffeine (adenosine receptor antagonist). To avoid the confounder of inflammation-driven changes in movement which alter SWA and connectivity, electrophysiological recordings were classified as occurring during quiescence or movement, and propensity score matching was used to match distributions of movement magnitude between baseline and post-LPS administration. RESULTS: LPS produces increases in cortical cytokines and behavioural quiescence. In movement-matched data, LPS produces increases in SWA (likelihood-ratio test: χ2(4)=21.51, P<0.001), but not connectivity (χ2(4)=6.39, P=0.17). Increases in SWA associate with interleukin 6 (P<0.001) and monocyte chemoattractant protein-1 (P=0.001) and are suppressed by piroxicam (P<0.001) and caffeine (P=0.046). Aged animals compared with adult animals show similar LPS-induced SWA during movement, but exaggerated cytokine response and increased SWA during quiescence. CONCLUSIONS: Cytokine-SWA correlations during wakefulness are consistent with observations in patients with delirium. Absence of connectivity effects after accounting for movement changes suggests decreased connectivity in patients is a biomarker of hypoactivity. Exaggerated effects in quiescent aged animals are consistent with increased hypoactive delirium in older patients. Prostaglandin-adenosine signalling may link inflammation to neural changes and hence delirium.

Cortical responses to auditory novelty across task conditions: An intracranial electrophysiology study.

Elucidating changes in sensory processing across attentional and arousal states is a major focus in neuroscience. The local/global deviant (LGD) stimulus paradigm engages auditory predictive coding over short (local deviance, LD) and long (global deviance, GD) time scales, and has been used to assay disruption of auditory predictive coding upon loss of consciousness. Our previous work (Nourski et al., 2018, J Neurosci 38:8441-52) examined effects of general anesthesia on short- and long-term novelty detection. GD effects were suppressed at subhypnotic doses of propofol, suggesting that they may be more related to task engagement than consciousness per se. The present study addressed this hypothesis by comparing cortical responses to auditory novelty during passive versus active listening conditions in awake listeners. Subjects were seven adult neurosurgical patients undergoing chronic invasive monitoring for medically intractable epilepsy. LGD stimuli were sequences of four identical vowels followed by a fifth identical or different vowel. In the passive condition, the stimuli were presented to subjects as they watched a silent TV program and were instructed to attend to its content. In the active condition, stimuli were presented in the absence of a TV program, and subjects were instructed to press a button in response to GD target stimuli. Intracranial recordings were made from multiple brain regions, including core and non-core auditory, auditory-related, prefrontal and sensorimotor cortex. Metrics of task performance included hit rate, sensitivity index, and reaction times. Cortical activity was measured as averaged auditory evoked potentials (AEPs) and event-related band power in high gamma (70-150 Hz) and alpha (8-14 Hz) frequency bands. The vowel stimuli and LD elicited robust AEPs in all studied brain areas in both passive and active conditions. High gamma responses to stimulus onset and LD were localized predominantly to the auditory cortex in the superior temporal plane and had a comparable prevalence and spatial extent between the two conditions. In contrast, GD effects (AEPs, high gamma and alpha suppression) were greatly enhanced during the active condition in all studied brain areas. The prevalence of high gamma GD effects was positively correlated with individual subjects' task performance. The data demonstrate distinct task engagement-related effects on responses to auditory novelty across the auditory cortical processing hierarchy. The results motivate a closer examination of effective connectivity underlying attentional modulation of cortical sensory responses, and serve as a foundation for examining changes in sensory processing associated with general anesthesia, sleep and disorders of consciousness.

Electrophysiology of the Human Superior Temporal Sulcus during Speech Processing.

The superior temporal sulcus (STS) is a crucial hub for speech perception and can be studied with high spatiotemporal resolution using electrodes targeting mesial temporal structures in epilepsy patients. Goals of the current study were to clarify functional distinctions between the upper (STSU) and the lower (STSL) bank, hemispheric asymmetries, and activity during self-initiated speech. Electrophysiologic properties were characterized using semantic categorization and dialog-based tasks. Gamma-band activity and alpha-band suppression were used as complementary measures of STS activation. Gamma responses to auditory stimuli were weaker in STSL compared with STSU and had longer onset latencies. Activity in anterior STS was larger during speaking than listening; the opposite pattern was observed more posteriorly. Opposite hemispheric asymmetries were found for alpha suppression in STSU and STSL. Alpha suppression in the STS emerged earlier than in core auditory cortex, suggesting feedback signaling within the auditory cortical hierarchy. STSL was the only region where gamma responses to words presented in the semantic categorization tasks were larger in subjects with superior task performance. More pronounced alpha suppression was associated with better task performance in Heschl's gyrus, superior temporal gyrus, and STS. Functional differences between STSU and STSL warrant their separate assessment in future studies.

Optogenetic Activation of Afferent Pathways in Brain Slices and Modulation of Responses by Volatile Anesthetics.

Anesthetics influence consciousness in part via their actions on thalamocortical circuits. However, the extent to which volatile anesthetics affect distinct cellular and network components of these circuits remains unclear. Ex vivo brain slices provide a means by which investigators may probe discrete components of complex networks and disentangle potential mechanisms underlying the effects of volatile anesthetics on evoked responses. To isolate potential cell type- and pathway-specific drug effects in brain slices, investigators must be able to independently activate afferent fiber pathways, identify non-overlapping populations of cells, and apply volatile anesthetics to the tissue in aqueous solution. In this protocol, methods to measure optogenetically-evoked responses to two independent afferent pathways to neocortex in ex vivo brain slices are described. Extracellular responses are recorded to assay network activity and targeted whole-cell patch clamp recordings are conducted in somatostatin- and parvalbumin-positive interneurons. Delivery of physiologically relevant concentrations of isoflurane via artificial cerebral spinal fluid to modulate cellular and network responses is described.