Cerebral autoregulation-based mean arterial pressure targets and delirium in critically ill adults without brain injury: a retrospective cohort study.

PURPOSE: Cerebral autoregulation (CA) is a mechanism that acts to maintain consistent cerebral perfusion across a range of blood pressures, and impaired CA is associated with delirium. Individualized CA-derived blood pressure targets are poorly characterized in critically ill patients and the association with intensive care unit (ICU) delirium is unknown. Our objectives were to characterize optimal mean arterial pressure (MAPopt) ranges in critically ill adults without brain injury and determine whether deviations from these targets contribute to ICU delirium. METHODS: We performed a retrospective cohort analysis of patients with shock of any etiology and/or respiratory failure requiring invasive mechanical ventilation, without a neurologic admitting diagnosis. Patients were screened daily for delirium. Cerebral oximetry and mean arterial pressure data were captured for the first 24 hr from enrolment. RESULTS: Forty-two patients with invasive blood pressure monitoring data were analyzed. Optimal mean arterial pressure targets ranged from 55 to 100 mm Hg. Optimal mean arterial pressure values were not significantly different based on history of hypertension or delirium status, and delirium was not associated with deviations from MAPopt. Nevertheless, the majority (69%) of blood pressure targets exceeded the current 65 mm Hg Surviving Sepsis guidelines. CONCLUSION: We observed that MAPopt targets across patients were highly variable, but did not observe an association with the incidence of delirium. Studies designed to evaluate the impact on neurologic outcomes are needed to understand the association with individualized mean arterial pressure targets in the ICU. STUDY REGISTRATION: ClinicalTrials.gov (NCT02344043); first submitted 22 January 2015.

RéSUMé: OBJECTIF: L'autorégulation cérébrale (AC) est un mécanisme qui agit pour maintenir une perfusion cérébrale constante pour une gamme de tensions artérielles, et une altération de l'AC est associée au delirium. Les cibles de tension artérielle individualisées dérivées de l'AC sont mal caractérisées chez les patient·es gravement malades et l'association avec le delirium à l'unité de soins intensifs (USI) est inconnue. Nos objectifs étaient de caractériser la tension artérielle moyenne optimale (TAMopt) chez les adultes gravement malades sans lésion cérébrale et de déterminer si les écarts par rapport à ces cibles contribuaient au delirium à l'USI. MéTHODE: Nous avons réalisé une analyse de cohorte rétrospective de patient·es présentant un choc de toute étiologie et/ou une insuffisance respiratoire nécessitant une ventilation mécanique invasive, et n'ayant pas reçu de diagnostic d'atteinte neurologique à l'admission. Les patients ont été dépistés quotidiennement pour le delirium. Les données d'oxymétrie cérébrale et de tension artérielle moyenne ont été saisies pendant les 24 premières heures suivant le recrutement. RéSULTATS: Quarante-deux patient·es pour qui des données de monitorage invasif de la tension artérielle étaient disponibles ont été analysé·es. Les cibles optimales de tension artérielle moyenne variaient de 55 à 100 mm Hg. Les valeurs optimales de tension artérielle moyenne n'étaient pas significativement différentes en fonction des antécédents d'hypertension ou de delirium, et le delirium n'était pas associé à des écarts par rapport à la TAMopt. Néanmoins, la majorité (69 %) des cibles de tension artérielle dépassaient celle de 65 mm Hg préconisée par les lignes directrices Surviving Sepsis. CONCLUSION: Nous avons observé que les cibles de TAMopt étaient très variables chez les patient·es, mais nous n'avons pas observé d'association avec l'incidence de delirium. Des études conçues pour évaluer l'impact sur les issues neurologiques sont nécessaires pour comprendre l'association avec les cibles de tension artérielle moyenne individualisées à l'USI. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02344043); soumis pour la première fois le 22 janvier 2015.

Differential subcellular targeting of glutamate receptor subtypes during homeostatic synaptic plasticity.

Homeostatic processes are believed to contribute to the stability of neuronal networks that are perpetually influenced by Hebbian forms of synaptic plasticity. Whereas the rules governing the targeting and trafficking of AMPA and NMDA subtypes of glutamate receptors during rapid Hebbian LTP have been extensively studied, those that are operant during homeostatic forms of synaptic strengthening are less well understood. Here, we used biochemical, biophysical, and pharmacological approaches to investigate glutamate receptor regulation during homeostatic synaptic plasticity. We show in rat organotypic hippocampal slices that prolonged network silencing induced a robust surface upregulation of GluA2-lacking AMPARs, not only at synapses, but also at extrasynaptic dendritic and somatic regions of CA1 pyramidal neurons. We also detected a shift in NMDAR subunit composition that, in contrast to the cell-wide surface delivery of GluA2-lacking AMPARs, occurred exclusively at synapses. The subunit composition and subcellular distribution of AMPARs and NMDARs are therefore distinctly regulated during homeostatic synaptic plasticity. Thus, because subunit composition dictates key channel properties, such as agonist affinity, gating kinetics, and calcium permeability, the homeostatic synaptic process transcends the simple modulation of synaptic strength by also regulating the signaling and integrative properties of central synapses.

LIM domain only 4 (LMO4) regulates calcium-induced calcium release and synaptic plasticity in the hippocampus.

The LIM domain only 4 (LMO4) transcription cofactor activates gene expression in neurons and regulates key aspects of network formation, but the mechanisms are poorly understood. Here, we show that LMO4 positively regulates ryanodine receptor type 2 (RyR2) expression, thereby suggesting that LMO4 regulates calcium-induced calcium release (CICR) in central neurons. We found that CICR modulation of the afterhyperpolarization in CA3 neurons from mice carrying a forebrain-specific deletion of LMO4 (LMO4 KO) was severely compromised but could be restored by single-cell overexpression of LMO4. In line with these findings, two-photon calcium imaging experiments showed that the potentiation of RyR-mediated calcium release from internal stores by caffeine was absent in LMO4 KO neurons. The overall facilitatory effect of CICR on glutamate release induced during trains of action potentials was likewise defective in LMO4 KO, confirming that CICR machinery is severely compromised in these neurons. Moreover, the magnitude of CA3-CA1 long-term potentiation was reduced in LMO4 KO mice, a defect that appears to be secondary to an overall reduced glutamate release probability. These cellular phenotypes in LMO4 KO mice were accompanied with deficits in hippocampus-dependent spatial learning as determined by the Morris water maze test. Thus, our results establish LMO4 as a key regulator of CICR in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.

Calcium influx through N-type channels and activation of SK and TRP-like channels regulates tonic firing of neurons in rat paraventricular thalamus.

The thalamus is a major relay and integration station in the central nervous system. While there is a large body of information on the firing and network properties of neurons contained within sensory thalamic nuclei, less is known about the neurons located in midline thalamic nuclei, which are thought to modulate arousal and homeostasis. One midline nucleus that has been implicated in mediating stress responses is the paraventricular nucleus of the thalamus (PVT). Like other thalamic neurons, these neurons display two distinct firing modes, burst and tonic. In contrast to burst firing, little is known about the ionic mechanisms modulating tonic firing in these cells. Here we performed a series of whole cell recordings to characterize tonic firing in PVT neurons in acute rat brain slices. We found that PVT neurons are able to fire sustained, low-frequency, weakly accommodating trains of action potentials in response to a depolarizing stimulus. Unexpectedly, PVT neurons displayed a very high propensity to enter depolarization block, occurring at stimulus intensities that would elicit tonic firing in other thalamic neurons. The tonic firing behavior of these cells is modulated by a functional interplay between N-type Ca(2+) channels and downstream activation of small-conductance Ca(2+)-dependent K(+) (SK) channels and a transient receptor potential (TRP)-like conductance. Thus these ionic conductances endow PVT neurons with a narrow dynamic range, which may have fundamental implications for the integrative properties of this nucleus.

Examining form and function of dendritic spines.

The majority of fast excitatory synaptic transmission in the central nervous system takes place at protrusions along dendrites called spines. Dendritic spines are highly heterogeneous, both morphologically and functionally. Not surprisingly, there has been much speculation and debate on the relationship between spine structure and function. The advent of multi-photon laser-scanning microscopy has greatly improved our ability to investigate the dynamic interplay between spine form and function. Regulated structural changes occur at spines undergoing plasticity, offering a mechanism to account for the well-described correlation between spine size and synapse strength. In turn, spine structure can influence the degree of biochemical and perhaps electrical compartmentalization at individual synapses. Here, we review the relationship between dendritic spine morphology, features of spine compartmentalization and synaptic plasticity. We highlight emerging molecular mechanisms that link structural and functional changes in spines during plasticity, and also consider circumstances that underscore some divergence from a tight structure-function coupling. Because of the intricate influence of spine structure on biochemical and electrical signalling, activity-dependent changes in spine morphology alone may thus contribute to the metaplastic potential of synapses. This possibility asserts a role for structural dynamics in neuronal information storage and aligns well with current computational models.

Delirium, Cerebral Perfusion, and High-Frequency Vital-Sign Monitoring in the Critically Ill. The CONFOCAL-2 Feasibility Study.

Rationale: Studies suggest that reduced cerebral perfusion may contribute to delirium development in the intensive care unit (ICU). However, evidence is limited because of factors including small sample size and limited inclusion of covariates.Objectives: To assess the feasibility of a multicenter prospective observational study using a multimodal data collection platform. Feasibility was assessed by enrollment, data-capture, and follow-up rates. The full study will aim to assess the association between noninvasively derived surrogate markers of cerebral perfusion, delirium development, and long-term cognitive outcomes in critically ill patients.Methods: Adult patients in the ICU were enrolled if they had shock and/or respiratory failure requiring invasive mechanical ventilation for >24 hours. For the first 72 hours, a near-infrared spectroscopic sensor was placed on the forehead to continuously monitor regional cerebral oxygenation (rSo2) and high-frequency (1 Hz) vital signs were concurrently captured via an arterial line. Cerebral perfusion was estimated using three variables, including mean rSo2, duration of disturbed autoregulation, and time/magnitude away from optimal mean arterial pressure (MAP). Patients were screened for delirium in the ICU and ward daily for up to 30 days. Cognitive function was assessed 3 and 12 months after ICU admission to identify cognitive impairment.Results: Fifty-nine patients were enrolled across four sites in 1 year. Data-capture rates varied across modalities but exceeded 80% for rSo2, blood gas, and delirium data capture. Vital-sign capture and 3-month follow-up rates were lower at 53% and 55%, respectively. Eighty-three percent (49 of 59) of patients experienced delirium, with a median severity of 0.56 in the ICU. Mean physiological (±standard deviation) values were: rSo2 (70.4% ± 7.0%), heart rate (83.9 ± 16.45 beats/min), MAP (76.4 ± 12.8 mm Hg), peripheral oxygenation saturation (96.5% ± 2.1%), proportion of recording time spent with disturbed autoregulation (10.1% ± 7.3%) and proportion of area under the curve outside optimal MAP (39.6% ± 22.4%). Thirty-two (54%) individuals had cerebral autoregulation curves where a targeted optimal MAP was identified. Barriers to data collection included missing vital-sign data and low follow-up rates.Conclusions: Given our current protocol, a multicenter study examining the association between cerebral oxygenation, delirium, and long-term cognitive impairment is not feasible. However, by performing an early assessment of feasibility, we identified strategies to increase capture rates to ensure success as the study begins the next phase of study recruitment.Clinical trial registered with clinicaltrials.gov (NCT03141619).

A Synthetic Likelihood Solution to the Silent Synapse Estimation Problem.

Functional features of synaptic populations are typically inferred from random electrophysiological sampling of small subsets of synapses. Are these samples unbiased? Here, we develop a biophysically constrained statistical framework to address this question and apply it to assess the performance of a widely used method based on a failure-rate analysis to quantify the occurrence of silent (AMPAR-lacking) synapses. We simulate this method in silico and find that it is characterized by strong and systematic biases, poor reliability, and weak statistical power. Key conclusions are validated by whole-cell recordings from hippocampal neurons. To address these shortcomings, we develop a simulator of the experimental protocol and use it to compute a synthetic likelihood. By maximizing the likelihood, we infer silent synapse fraction with no bias, low variance, and superior statistical power over alternatives. Together, this generalizable approach highlights how a simulator of experimental methodologies can substantially improve the estimation of physiological properties.

Assessing the relationship between near-infrared spectroscopy-derived regional cerebral oxygenation and neurological dysfunction in critically ill adults: a prospective observational multicentre protocol, on behalf of the Canadian Critical Care Trials Group.

INTRODUCTION: Survivors of critical illness frequently exhibit acute and chronic neurological complications. The underlying aetiology of this dysfunction remains unknown but may be associated with cerebral ischaemia. This study will use near-infrared spectroscopy to non-invasively quantify regional cerebral oxygenation (rSO2) to assess the association between poor rSO2 during the first 72 hours of critical illness with delirium severity, as well as long-term sensorimotor and cognitive impairment among intensive care unit (ICU) survivors. Further, the physiological determinants of rSO2 will be examined. METHODS AND ANALYSIS: This multicentre prospective observational study will consider adult patients (≥18 years old) eligible for enrolment if within 24 hours of ICU admission, they require mechanical ventilation and/or vasopressor support. For 72 hours, rSO2 will be continuously recorded, while vital signs (eg, heart rate) and peripheral oxygenation saturation will be concurrently captured with data monitoring software. Arterial and central venous gases will be sampled every 12 hours for the 72 hours recording period and will include: pH, PaO2, PaCO2, and haemoglobin concentration. Participants will be screened daily for delirium with the confusion assessment method (CAM)-ICU, whereas the brief-CAM will be used on the ward. At 3 and 12 months post-ICU discharge, neurological function will be assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and KINARM sensorimotor and cognitive robot-based behavioural tasks. ETHICS AND DISSEMINATION: The study protocol has been approved in Ontario by a central research ethics board (Clinical Trials Ontario); non-Ontario sites will obtain local ethics approval. The study will be conducted under the guidance of the Canadian Critical Care Trials Group (CCCTG) and the results of this study will be presented at national meetings of the CCCTG for internal peer review. Results will also be presented at national/international scientific conferences. On completion, the study findings will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03141619.

Metaplasticity at CA1 Synapses by Homeostatic Control of Presynaptic Release Dynamics.

Hebbian and homeostatic forms of plasticity operate on different timescales to regulate synaptic strength. The degree of mechanistic overlap between these processes and their mutual influence are still incompletely understood. Here, we report that homeostatic synaptic strengthening induced by prolonged network inactivity compromised the ability of CA1 synapses to exhibit LTP. This effect could not be accounted for by an obvious deficit in the postsynaptic capacity for LTP expression, since neither the fraction of silent synapses nor the ability to induce LTP by two-photon glutamate uncaging were reduced by the homeostatic process. Rather, optical quantal analysis reveals that homeostatically strengthened synapses display a reduced capacity to maintain glutamate release fidelity during repetitive stimulation, ultimately impeding the induction, and thus expression, of LTP. By regulating the short-term dynamics of glutamate release, the homeostatic process thus influences key aspects of dynamic network function and exhibits features of metaplasticity.

Correlated Synaptic Inputs Drive Dendritic Calcium Amplification and Cooperative Plasticity during Clustered Synapse Development.

The mechanisms that instruct the assembly of fine-scale features of synaptic connectivity in neural circuits are only beginning to be understood. Using whole-cell electrophysiology, two-photon calcium imaging, and glutamate uncaging in hippocampal slices, we discovered a functional coupling between NMDA receptor activation and ryanodine-sensitive intracellular calcium release that dominates the spatiotemporal dynamics of activity-dependent calcium signals during synaptogenesis. This developmentally regulated calcium amplification mechanism was tuned to detect and bind spatially clustered and temporally correlated synaptic inputs and enacted a local cooperative plasticity rule between coactive neighboring synapses. Consistent with the hypothesis that synapse maturation is spatially regulated, we observed clustering of synaptic weights in developing dendritic arbors. These results reveal developmental features of NMDA receptor-dependent calcium dynamics and local plasticity rules that are suited to spatially guide synaptic connectivity patterns in emerging neural networks.

Tuning into diversity of homeostatic synaptic plasticity.

Neurons are endowed with the remarkable ability to integrate activity levels over time and tune their excitability such that action potential firing is maintained within a computationally optimal range. These feedback mechanisms, collectively referred to as "homeostatic plasticity", enable neurons to respond and adapt to prolonged alterations in neuronal activity by regulating several determinants of cellular excitability. Perhaps the best-characterized of these homeostatic responses involves the regulation of excitatory glutamatergic transmission. This homeostatic synaptic plasticity (HSP) operates bidirectionally, thus providing a means for neurons to tune cellular excitability in response to either elevations or reductions in net activity. The last decade has seen rapid growth in interest and efforts to understand the mechanistic underpinnings of HSP in part because of the theoretical stabilization that HSP confers to neural network function. Since the initial reports describing HSP in central neurons, innovations in experimental approaches have permitted the mechanistic dissection of this cellular adaptive response and, as a result, key advances have been made in our understanding of the cellular and molecular basis of HSP. Here, we review recent evidence that outline the presence of distinct forms of HSP at excitatory glutamatergic synapses which operate at different sub-cellular levels. We further present theoretical considerations on the potential computational roles afforded by local, synapse-specific homeostatic regulation. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'.

A cost-effective method for preparing, maintaining, and transfecting neurons in organotypic slices.

The cellular and molecular mechanisms that underlie brain function are challenging to study in the living brain. The development of organotypic slices has provided a welcomed addition to our arsenal of experimental brain preparations by allowing both genetic and prolonged pharmacological manipulations in a system that, much like the acute slice preparation, retains several core features of the cellular and network architecture found in situ. Neurons in organotypic slices can survive in culture for several weeks, can be molecularly manipulated by transfection procedures and their function can be interrogated by traditional cellular electrophysiological or imaging techniques. Here, we describe a cost-effective protocol for the preparation and maintenance of organotypic slices and also describe a protocol for biolistic transfection that can be used to introduce plasmids in a small subset of neurons living in an otherwise molecularly unperturbed network. The implementation of these techniques offers a flexible experimental paradigm that can be used to study a multitude of neuronal mechanisms.