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1.
IEEE Trans Biomed Eng ; PP2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38857143

RESUMEN

Real-time estimation of patient cardiovascular states, including cardiac output and systemic vascular resistance, is necessary for personalized hemodynamic monitoring and management. Highly invasive measurements enable reliable estimation of these states but increase patient risk. Prior methods using minimally invasive measurements reduce patient risk but have produced unreliable estimates limited due to trade-offs in accuracy and time resolution. Our objective was to develop an approach to estimate cardiac output and systemic vascular resistance with both a high time resolution and high accuracy from minimally invasive measurements. Using the two-element Windkessel model, we formulated a state-space method to estimate a dynamic time constant - the product of systemic vascular resistance and compliance - from arterial blood pressure measurements. From this time constant, we derived proportional estimates of systemic vascular resistance and cardiac output. We then validated our method with a swine cardiovascular dataset. Our estimates produced using arterial blood pressure measurements not only closely align with those using highly invasive measurements, but also closely align when derived from three separate locations on the arterial tree. Moreover, our estimates predictably change in response to standard cardiovascular drugs. Overall, our approach produces reliable, real-time estimates of cardiovascular states crucial for monitoring and control of the cardiovascular system.

2.
Proc Natl Acad Sci U S A ; 121(22): e2402732121, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38768339

RESUMEN

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.


Asunto(s)
Ketamina , Receptores de N-Metil-D-Aspartato , Ketamina/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Humanos , Cinética , Electroencefalografía , Antagonistas de Aminoácidos Excitadores/farmacología , Modelos Neurológicos
3.
Sci Transl Med ; 16(745): eadj4303, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38691619

RESUMEN

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.


Asunto(s)
Tronco Encefálico , Estado de Conciencia , Imagen por Resonancia Magnética , Vigilia , Humanos , Tronco Encefálico/diagnóstico por imagen , Tronco Encefálico/fisiología , Vigilia/fisiología , Estado de Conciencia/fisiología , Imagen por Resonancia Magnética/métodos , Imagen Multimodal/métodos , Conectoma , Vías Nerviosas/fisiología , Masculino , Femenino , Imagen de Difusión por Resonancia Magnética , Adulto , Nivel de Alerta/fisiología
4.
bioRxiv ; 2024 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-38766068

RESUMEN

BACKGROUND: Deep brain stimulation of central thalamus (CT-DBS) has potential for modulating states of consciousness, but it can also trigger spike-wave discharges (SWDs). OBJECTIVES: To report the probability of inducing SWDs during CT-DBS in awake mice. METHODS: Mice were implanted with electrodes to deliver unilateral and bilateral CT-DBS at different frequencies while recording EEG. We titrated stimulation current by gradually increasing it at each frequency until an SWD appeared. Subsequent stimulations to test arousal modulation were performed at the current one step below the current that caused an SWD during titration. RESULTS: In 2.21% of the test stimulations (10 out of 12 mice), CT-DBS caused SWDs at currents lower than the titrated current, at currents as low as 20 uA. CONCLUSION: Our study found a small but significant probability of inducing SWDs even after titration and at relatively low currents. EEG should be closely monitored for SWDs when performing CT-DBS in both research and clinical settings.

5.
bioRxiv ; 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38617266

RESUMEN

Ketamine is an NMDA-receptor antagonist that produces sedation, analgesia and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1-4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and non-human primate local field potential recordings. We have discovered how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported, and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

6.
bioRxiv ; 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38562734

RESUMEN

Many different anesthetics cause loss of responsiveness despite having diverse underlying molecular and circuit actions. To explore the convergent effects of these drugs, we examined how ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, and dexmedetomidine, an α2 adrenergic receptor agonist, affected neural oscillations in the prefrontal cortex of nonhuman primates. Previous work has shown that anesthesia increases phase locking of low-frequency local field potential activity across cortex. We observed similar increases with anesthetic doses of ketamine and dexmedetomidine in the ventrolateral and dorsolateral prefrontal cortex, within and across hemispheres. However, the nature of the phase locking varied between regions. We found that oscillatory activity in different prefrontal subregions within each hemisphere became more anti-phase with both drugs. Local analyses within a region suggested that this finding could be explained by broad cortical distance-based effects, such as a large traveling wave. By contrast, homologous areas across hemispheres increased their phase alignment. Our results suggest that the drugs induce strong patterns of cortical phase alignment that are markedly different from those in the awake state, and that these patterns may be a common feature driving loss of responsiveness from different anesthetic drugs.

7.
BJA Open ; 10: 100276, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38571816

RESUMEN

Background: The alpha-2 adrenergic agonist dexmedetomidine induces EEG patterns resembling those of non-rapid eye movement (NREM) sleep. Fulfilment of slow wave sleep (SWS) homeostatic needs would address the assumption that dexmedetomidine induces functional biomimetic sleep states. Methods: In-home sleep EEG recordings were obtained from 13 healthy participants before and after dexmedetomidine sedation. Dexmedetomidine target-controlled infusions and closed-loop acoustic stimulation were implemented to induce and enhance EEG slow waves, respectively. EEG recordings during sedation and sleep were staged using modified American Academy of Sleep Medicine criteria. Slow wave activity (EEG power from 0.5 to 4 Hz) was computed for NREM stage 2 (N2) and NREM stage 3 (N3/SWS) epochs, with the aggregate partitioned into quintiles by time. The first slow wave activity quintile served as a surrogate for slow wave pressure, and the difference between the first and fifth quintiles as a measure of slow wave pressure dissipation. Results: Compared with pre-sedation sleep, post-sedation sleep showed reduced N3 duration (mean difference of -17.1 min, 95% confidence interval -30.0 to -8.2, P=0.015). Dissipation of slow wave pressure was reduced (P=0.02). Changes in combined durations of N2 and N3 between pre- and post-sedation sleep correlated with total dexmedetomidine dose, (r=-0.61, P=0.03). Conclusions: Daytime dexmedetomidine sedation and closed-loop acoustic stimulation targeting EEG slow waves reduced N3/SWS duration and measures of slow wave pressure dissipation on the post-sedation night in healthy young adults. Thus, the paired intervention induces sleep-like states that fulfil certain homeostatic NREM sleep needs in healthy young adults. Clinical trial registration: ClinicalTrials.gov NCT04206059.

8.
J Cogn Neurosci ; 36(2): 394-413, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37902596

RESUMEN

A critical component of anesthesia is the loss of sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of nonhuman primates before and during propofol-mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-related synchronization between brain areas in the local field potential of Awake animals. By contrast, propofol-mediated unconsciousness eliminated stimulus-related synchrony and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in Awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol's effect on sensory processing is not just because of asynchronous Down states. Rather, both Down states and Up states reflect disrupted dynamics.


Asunto(s)
Corteza Auditiva , Propofol , Animales , Propofol/farmacología , Inconsciencia/inducido químicamente , Encéfalo/fisiología , Anestesia General , Corteza Auditiva/fisiología
9.
PNAS Nexus ; 2(10): pgad293, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37920551

RESUMEN

Research in human volunteers and surgical patients has shown that unconsciousness under general anesthesia can be reliably tracked using real-time electroencephalogram processing. Hence, a closed-loop anesthesia delivery (CLAD) system that maintains precisely specified levels of unconsciousness is feasible and would greatly aid intraoperative patient management. The US Federal Drug Administration has approved no CLAD system for human use due partly to a lack of testing in appropriate animal models. To address this key roadblock, we implement a nonhuman primate (NHP) CLAD system that controls the level of unconsciousness using the anesthetic propofol. The key system components are a local field potential (LFP) recording system; propofol pharmacokinetics and pharmacodynamic models; the control variable (LFP power between 20 and 30 Hz), a programmable infusion system and a linear quadratic integral controller. Our CLAD system accurately controlled the level of unconsciousness along two different 125-min dynamic target trajectories for 18 h and 45 min in nine experiments in two NHPs. System performance measures were comparable or superior to those in previous CLAD reports. We demonstrate that an NHP CLAD system can reliably and accurately control in real-time unconsciousness maintained by anesthesia. Our findings establish critical steps for CLAD systems' design and testing prior to human testing.

10.
Sci Adv ; 9(40): eadh0974, 2023 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-37801492

RESUMEN

Recording and modulating neural activity in vivo enables investigations of the neurophysiology underlying behavior and disease. However, there is a dearth of translational tools for simultaneous recording and localized receptor-specific modulation. We address this limitation by translating multifunctional fiber neurotechnology previously only available for rodent studies to enable cortical and subcortical neural recording and modulation in macaques. We record single-neuron and broader oscillatory activity during intracranial GABA infusions in the premotor cortex and putamen. By applying state-space models to characterize changes in electrophysiology, we uncover that neural activity evoked by a working memory task is reshaped by even a modest local inhibition. The recordings provide detailed insight into the electrophysiological effect of neurotransmitter receptor modulation in both cortical and subcortical structures in an awake macaque. Our results demonstrate a first-time application of multifunctional fibers for causal studies of neuronal activity in behaving nonhuman primates and pave the way for clinical translation of fiber-based neurotechnology.


Asunto(s)
Neurofisiología , Vigilia , Animales , Neurofisiología/métodos , Macaca mulatta , Encéfalo/fisiología , Cognición
11.
bioRxiv ; 2023 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-37732234

RESUMEN

Predictive coding is a fundamental function of the cortex. The predictive routing model proposes a neurophysiological implementation for predictive coding. Predictions are fed back from deep-layer cortex via alpha/beta (8-30Hz) oscillations. They inhibit the gamma (40-100Hz) and spiking that feed sensory inputs forward. Unpredicted inputs arrive in circuits unprepared by alpha/beta, resulting in enhanced gamma and spiking. To test the predictive routing model and its role in consciousness, we collected data from intracranial recordings of macaque monkeys during passive presentation of auditory oddballs (e.g., AAAAB) before and after propofol-mediated loss of consciousness (LOC). In line with the predictive routing model, alpha/beta oscillations in the awake state served to inhibit the processing of predictable stimuli. Propofol-mediated LOC eliminated alpha/beta modulation by a predictable stimulus in sensory cortex and alpha/beta coherence between sensory and frontal areas. As a result, oddball stimuli evoked enhanced gamma power, late (> 200 ms from stimulus onset) period spiking, and superficial layer sinks in sensory cortex. Therefore, auditory cortex was in a disinhibited state during propofol-mediated LOC. However, despite these enhanced feedforward responses in auditory cortex, there was a loss of differential spiking to oddballs in higher order cortex. This may be a consequence of a loss of within-area and inter-area spike-field coupling in the alpha/beta and gamma frequency bands. These results provide strong constraints for current theories of consciousness. Significance statement: Neurophysiology studies have found alpha/beta oscillations (8-30Hz), gamma oscillations (40-100Hz), and spiking activity during cognition. Alpha/beta power has an inverse relationship with gamma power/spiking. This inverse relationship suggests that gamma/spiking are under the inhibitory control of alpha/beta. The predictive routing model hypothesizes that alpha/beta oscillations selectively inhibit (and thereby control) cortical activity that is predictable. We tested whether this inhibitory control is a signature of consciousness. We used multi-area neurophysiology recordings in monkeys presented with tone sequences that varied in predictability. We recorded brain activity as the anesthetic propofol was administered to manipulate consciousness. Compared to conscious processing, propofol-mediated unconsciousness disrupted alpha/beta inhibitory control during predictive processing. This led to a disinhibition of gamma/spiking, consistent with the predictive routing model.

12.
bioRxiv ; 2023 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-37425684

RESUMEN

A critical component of anesthesia is the loss sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential (LFP) and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of non-human primates before and during propofol mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-induced coherence between brain areas in the LFP of awake animals. By contrast, propofol mediated unconsciousness eliminated stimulus-induced coherence and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol's effect on sensory processing is not just due to asynchronous down states. Rather, both Down states and Up states reflect disrupted dynamics.

13.
Proc Natl Acad Sci U S A ; 120(30): e2300058120, 2023 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-37467269

RESUMEN

Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, is characterized by slow-delta oscillations (0.3 to 4 Hz) and alpha oscillations (8 to 14 Hz) that are readily visible in the electroencephalogram. At higher doses, these slow-delta-alpha (SDA) oscillations transition into burst suppression. This is a marker of a state of profound brain inactivation during which isoelectric (flatline) periods alternate with periods of the SDA patterns present at lower doses. While the SDA and burst suppression patterns have been analyzed separately, the transition from one to the other has not. Using state-space methods, we characterize the dynamic evolution of brain activity from SDA to burst suppression and back during unconsciousness maintained with propofol or sevoflurane in volunteer subjects and surgical patients. We uncover two dynamical processes that continuously modulate the SDA oscillations: alpha-wave amplitude and slow-wave frequency modulation. We present an alpha modulation index and a slow modulation index which characterize how these processes track the transition from SDA oscillations to burst suppression and back to SDA oscillations as a function of increasing and decreasing anesthetic doses, respectively. Our biophysical model reveals that these dynamics track the combined evolution of the neurophysiological and metabolic effects of a GABAergic anesthetic on brain circuits. Our characterization of the modulatory dynamics mediated by GABAergic anesthetics offers insights into the mechanisms of these agents and strategies for monitoring and precisely controlling the level of unconsciousness in patients under general anesthesia.


Asunto(s)
Anestésicos , Propofol , Humanos , Propofol/farmacología , Sevoflurano/farmacología , Inconsciencia/inducido químicamente , Anestésicos/farmacología , Encéfalo/fisiología , Electroencefalografía/métodos
14.
bioRxiv ; 2023 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-37502983

RESUMEN

Consciousness is comprised of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that modulate awareness in the human brain, but knowledge about the subcortical networks that sustain arousal is lacking. We integrated data from ex vivo diffusion MRI, immunohistochemistry, and in vivo 7 Tesla functional MRI to map the connectivity of a subcortical arousal network that we postulate sustains wakefulness in the resting, conscious human brain, analogous to the cortical default mode network (DMN) that is believed to sustain self-awareness. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain by correlating ex vivo diffusion MRI with immunohistochemistry in three human brain specimens from neurologically normal individuals scanned at 600-750 µm resolution. We performed deterministic and probabilistic tractography analyses of the diffusion MRI data to map dAAN intra-network connections and dAAN-DMN internetwork connections. Using a newly developed network-based autopsy of the human brain that integrates ex vivo MRI and histopathology, we identified projection, association, and commissural pathways linking dAAN nodes with one another and with cortical DMN nodes, providing a structural architecture for the integration of arousal and awareness in human consciousness. We release the ex vivo diffusion MRI data, corresponding immunohistochemistry data, network-based autopsy methods, and a new brainstem dAAN atlas to support efforts to map the connectivity of human consciousness.

15.
A A Pract ; 17(7): e01698, 2023 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-37409746

RESUMEN

The effects of critical illness on electroencephalographic (EEG) signatures of sedatives have not been described, limiting the use of EEG-guided sedation in the intensive care unit (ICU). We report the case of a 36-year-old man recovering from acute respiratory distress syndrome (ARDS). Severe ARDS was characterized by slow-delta (0.1-4 Hz) and theta (4-8 Hz) oscillations but lacked the alpha (8-14 Hz) power expected during propofol sedation in a patient of this age. The alpha power emerged as ARDS resolved. This case raises the question of whether inflammatory states can alter EEG signatures during sedation.


Asunto(s)
Anestesia , Propofol , Síndrome de Dificultad Respiratoria , Masculino , Humanos , Adulto , Propofol/efectos adversos , Hipnóticos y Sedantes/efectos adversos , Electroencefalografía
16.
J Neurophysiol ; 130(1): 86-103, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37314079

RESUMEN

Propofol-mediated unconsciousness elicits strong alpha/low-beta and slow oscillations in the electroencephalogram (EEG) of patients. As anesthetic dose increases, the EEG signal changes in ways that give clues to the level of unconsciousness; the network mechanisms of these changes are only partially understood. Here, we construct a biophysical thalamocortical network involving brain stem influences that reproduces transitions in dynamics seen in the EEG involving the evolution of the power and frequency of alpha/low-beta and slow rhythm, as well as their interactions. Our model suggests that propofol engages thalamic spindle and cortical sleep mechanisms to elicit persistent alpha/low-beta and slow rhythms, respectively. The thalamocortical network fluctuates between two mutually exclusive states on the timescale of seconds. One state is characterized by continuous alpha/low-beta-frequency spiking in thalamus (C-state), whereas in the other, thalamic alpha spiking is interrupted by periods of co-occurring thalamic and cortical silence (I-state). In the I-state, alpha colocalizes to the peak of the slow oscillation; in the C-state, there is a variable relationship between an alpha/beta rhythm and the slow oscillation. The C-state predominates near loss of consciousness; with increasing dose, the proportion of time spent in the I-state increases, recapitulating EEG phenomenology. Cortical synchrony drives the switch to the I-state by changing the nature of the thalamocortical feedback. Brain stem influence on the strength of thalamocortical feedback mediates the amount of cortical synchrony. Our model implicates loss of low-beta, cortical synchrony, and coordinated thalamocortical silent periods as contributing to the unconscious state.NEW & NOTEWORTHY GABAergic anesthetics induce alpha/low-beta and slow oscillations in the EEG, which interact in dose-dependent ways. We constructed a thalamocortical model to investigate how these interdependent oscillations change with propofol dose. We find two dynamic states of thalamocortical coordination, which change on the timescale of seconds and dose-dependently mirror known changes in EEG. Thalamocortical feedback determines the oscillatory coupling and power seen in each state, and this is primarily driven by cortical synchrony and brain stem neuromodulation.


Asunto(s)
Propofol , Humanos , Propofol/efectos adversos , Sincronización Cortical , Corteza Cerebral , Electroencefalografía , Inconsciencia/inducido químicamente , Tálamo
17.
Nat Commun ; 14(1): 1748, 2023 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-36991011

RESUMEN

Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine's antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine's NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.


Asunto(s)
Ketamina , Propofol , Humanos , Ketamina/farmacología , Ketamina/uso terapéutico , Propofol/farmacología , N-Metilaspartato , Neurofisiología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Corteza Cerebral/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
18.
Br J Anaesth ; 130(5): 557-566, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36967282

RESUMEN

BACKGROUND: Conscious states are typically inferred through responses to auditory tasks and noxious stimulation. We report the use of a stimulus-free behavioural paradigm to track state transitions in responsiveness during dexmedetomidine sedation. We hypothesised that estimated dexmedetomidine effect-site (Ce) concentrations would be higher at loss of responsiveness (LOR) compared with return of responsiveness (ROR), and both would be lower than comparable studies that used stimulus-based assessments. METHODS: Closed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine data were analysed for secondary analysis. Fourteen healthy volunteers were asked to perform the breathe-squeeze task of gripping a dynamometer when inspiring and releasing it when expiring. LOR was defined as five inspirations without accompanied squeezes; ROR was defined as the return of five inspirations accompanied by squeezes. Brain states were monitored using 64-channel EEG. Dexmedetomidine was administered as a target-controlled infusion, with Ce estimated from a pharmacokinetic model. RESULTS: Counter to our hypothesis, mean estimated dexmedetomidine Ce was lower at LOR (0.92 ng ml-1; 95% confidence interval: 0.69-1.15) than at ROR (1.43 ng ml-1; 95% confidence interval: 1.27-1.58) (paired t-test; P=0.002). LOR was characterised by progressively increasing fronto-occipital EEG power in the 0.5-8 Hz band and loss of occipital alpha (8-12 Hz) and global beta (16-30 Hz) power. These EEG changes reverted at ROR. CONCLUSIONS: The breathe-squeeze task can effectively track changes in responsiveness during sedation without external stimuli and might be more sensitive to state changes than stimulus-based tasks. It should be considered when perturbation of brain states is undesirable. CLINICAL TRIAL REGISTRATION: NCT04206059.


Asunto(s)
Dexmedetomidina , Hipnóticos y Sedantes , Humanos , Encéfalo , Sedación Consciente , Estado de Conciencia , Electroencefalografía , Hipnóticos y Sedantes/farmacología
19.
Proc Natl Acad Sci U S A ; 120(11): e2207831120, 2023 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-36897972

RESUMEN

During propofol-induced general anesthesia, alpha rhythms measured using electroencephalography undergo a striking shift from posterior to anterior, termed anteriorization, where the ubiquitous waking alpha is lost and a frontal alpha emerges. The functional significance of alpha anteriorization and the precise brain regions contributing to the phenomenon are a mystery. While posterior alpha is thought to be generated by thalamocortical circuits connecting nuclei of the sensory thalamus with their cortical partners, the thalamic origins of the propofol-induced alpha remain poorly understood. Here, we used human intracranial recordings to identify regions in sensory cortices where propofol attenuates a coherent alpha network, distinct from those in the frontal cortex where it amplifies coherent alpha and beta activities. We then performed diffusion tractography between these identified regions and individual thalamic nuclei to show that the opposing dynamics of anteriorization occur within two distinct thalamocortical networks. We found that propofol disrupted a posterior alpha network structurally connected with nuclei in the sensory and sensory associational regions of the thalamus. At the same time, propofol induced a coherent alpha oscillation within prefrontal cortical areas that were connected with thalamic nuclei involved in cognition, such as the mediodorsal nucleus. The cortical and thalamic anatomy involved, as well as their known functional roles, suggests multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness.


Asunto(s)
Propofol , Humanos , Propofol/farmacología , Estado de Conciencia , Electroencefalografía , Encéfalo , Tálamo , Inconsciencia/inducido químicamente , Vías Nerviosas , Corteza Cerebral
20.
EClinicalMedicine ; 56: 101796, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36590787

RESUMEN

Background: The delirium-sparing effect of nighttime dexmedetomidine has not been studied after surgery. We hypothesised that a nighttime dose of dexmedetomidine would reduce the incidence of postoperative delirium as compared to placebo. Methods: This single-centre, parallel-arm, randomised, placebo-controlled superiority trial evaluated whether a short nighttime dose of intravenous dexmedetomidine (1 µg/kg over 40 min) would reduce the incidence of postoperative delirium in patients 60 years of age or older undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomised to receive dexmedetomidine or placebo in a 1:1 ratio. The primary outcome was delirium on postoperative day one. Secondary outcomes included delirium within three days of surgery, 30-, 90-, and 180-day abbreviated Montreal Cognitive Assessment scores, Patient Reported Outcome Measures Information System quality of life scores, and all-cause mortality. The study was registered as NCT02856594 on ClinicalTrials.gov on August 5, 2016, before the enrolment of any participants. Findings: Of 469 patients that underwent randomisation to placebo (n = 235) or dexmedetomidine (n = 234), 75 met a prespecified drop criterion before the study intervention. Thus, 394 participants (188 dexmedetomidine; 206 placebo) were analysed in the modified intention-to-treat cohort (median age 69 [IQR 64, 74] years; 73.1% male [n = 288]; 26·9% female [n = 106]). Postoperative delirium status on day one was missing for 30 (7.6%) patients. Among those in whom it could be assessed, the primary outcome occurred in 5 of 175 patients (2.9%) in the dexmedetomidine group and 16 of 189 patients (8.5%) in the placebo group (OR 0.32, 95% CI: 0.10-0.83; P = 0.029). A non-significant but higher proportion of participants experienced delirium within three days postoperatively in the placebo group (25/177; 14.1%) compared to the dexmedetomidine group (14/160; 8.8%; OR 0.58; 95% CI, 0.28-1.15). No significant differences between groups were observed in secondary outcomes or safety. Interpretation: Our findings suggested that in elderly cardiac surgery patients with a low baseline risk of postoperative delirium and extubated within 12 h of ICU admission, a short nighttime dose of dexmedetomidine decreased the incidence of delirium on postoperative day one. Although non-statistically significant, our findings also suggested a clinical meaningful difference in the three-day incidence of postoperative delirium. Funding: National Institute on Aging (R01AG053582).

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