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Attentional effects of noradrenaline vary with arousal level: Selective activation of thalamic pulvinar in humans

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Abstract

Subjects sedated by noradrenergic alpha2 agonists can switch rapidly from a state of extremely low to almost full consciousness following phasic increases in arousal or cognitive demand. Such flexibility is not displayed by traditional sedatives, such as the benzodiazepine diazepam. Experimentally, the phasic modulation of alpha2 effect by arousing or distracting stimuli can counteract the deleterious cognitive effects of alpha2 agonists. We used behavioural and fMRI indices of brain function to investigate the phasic modulatory effect that presentation of loud white noise would have on attentional dysfunction induced by administration of dexmedotomidine, an alpha2 agonist. Dexmedotomidine and midazolam were compared to placebo during performance of a target detection task, which was presented in the presence or absence of white noise. Compared to placebo, both dexmedotomidine and midazolam impaired task performance. This impairment was significantly attenuated by presentation of white noise in the dexmedotomidine condition only. This functional improvement corresponded to selective increase in activity of left medial pulvinar nucleus of the thalamus. This regional increase is suggested to index increases in phasic arousal, which counteract dexmedotomidine's detrimental attentional effects. Finally, despite sedating subjects to equivalent degrees, dexmedotomidine and midazolam had strikingly different regional effects on task-induced brain activity. Therefore, for the same level of sedation, the behavioural and anatomical attributes identifying the quality of sedation can vary.

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... Guanifacine, an α2-adrenoceptor agonist, has been approved as an ADHD medication (Bidwell et al. 2011), and blocking the α2-adrenoceptor has produced phenotypes similar to ADHD in monkeys . However, studies are inconsistent in regard to its beneficial effects on attention, as some studies have shown impaired attentional performance after α2-adrenoceptor agonist administration in humans (Smith and Nutt 1996;Coull et al. 2004) and rats (Sirviö et al. 1994;Ruotsalainen et al. 1997;Brown et al. 2012;Fernando et al. 2012), while blocking the α2-adrenoceptor has been reported to improve attention in humans (Mervaala et al. 1993) and rats performing different attention tasks (Sirvio et al. 1993;Koskinen et al. 2003;Lapiz and Morilak 2006;Brown et al. 2012;Bari and Robbins 2013). Previous studies have also indicated a role for the noradrenergic α1-adrenoceptor in attention, for instance by increasing vigilance (Sirviö and MacDonald 1999). ...
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Rationale Attention is compromised in many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). While dopamine and noradrenaline systems have been implicated in ADHD, their exact role in attentional processing is yet unknown. Objectives We applied the theory of visual attention (TVA) model, adapted from human research, to the rat 5-choice serial reaction time task (5CSRTT) to investigate catecholaminergic modulation of visual attentional processing in healthy subjects of high- and low-attention phenotypes. Methods Rats trained on the standard 5CSRTT and tested with variable stimulus durations were treated systemically with noradrenergic and/or dopaminergic agents (atomoxetine, methylphenidate, amphetamine, phenylephrine and atipamezole). TVA modelling was applied to estimate visual processing speed for correct and incorrect visual perceptual categorisations, independent of motor reaction times, as measures of attentional capacity. Results Atomoxetine and phenylephrine decreased response frequencies, including premature responses, increased omissions and slowed responding. In contrast, methylphenidate, amphetamine and atipamezole sped up responding and increased premature responses. Visual processing speed was also affected differentially. Atomoxetine and phenylephrine slowed, whereas methylphenidate and atipamezole sped up, visual processing, both for correct and incorrect categorisations. Amphetamine selectively improved visual processing for correct, though not incorrect, responses in high-attention rats only, possibly reflecting improved attention. Conclusions These data indicate that the application of TVA to the 5CSRTT provides an enhanced sensitivity to capturing attentional effects. Unexpectedly, we found overall slowing effects, including impaired visual processing, following drugs either increasing extracellular noradrenaline (atomoxetine) or activating the α1-adrenoceptor (phenylephrine), while also ameliorating premature responses (impulsivity). In contrast, amphetamine had potential pro-attentional effects by enhancing visual processing, probably due to central dopamine upregulation.
... DEX has not only effects on the hippocampus but also sensory processing, which involves the sensory cortex [30]. Moreover, DEX significantly regulates the thalamus, the pulvinar nucleus in particular [31], which plays a vital role in visual and auditory processing [32,33]. Moreover, accumulating evidence shows that DEX exerts significant neuroprotective effects in neurological diseases [34][35][36]. ...
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Cerebral ischemia/reperfusion (CI/R) injury results in serious brain tissue damage, thereby leading to long-term disability and mortality. It has been reported that dexmedetomidine (DEX) exerted neuroprotective effects in CI/R injury. Herein, we intended to investigate whether and how circular RNA (circRNA) cerebellar degeneration-related protein 1 antisense RNA (circ-CDR1as) was involved in the DEX-mediated protection on hippocampal neurons. In our work, the mouse hippocampal neuronal cells (HT-22) were used to construct a hypoxia/reperfusion (H/R) model for CI/R injury. Cell proliferation and apoptosis were evaluated by CCK-8 and flow cytometry. Gene expressions were detected by RT-qPCR. Levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) were measured by ELISA. The association between miR-28-3p and circ-CDR1as or TRAF3 was verified by dual-luciferase assay. The results indicated that DEX alleviated HT-22 cell dysfunction induced by H/R treatment. In addition, circ-CDR1as was downregulated after DEX treatment and reversed the effects of DEX on the proliferation, apoptosis, and inflammatory responses of H/R-treated HT-22 cells. Circ-CDR1as positively regulated TRAF3 expression via interaction with miR-28-3p in HT-22 cells. Circ-CDR1as aggravated H/R-treated HT-22 cell dysfunction through targeting miR-28-3p. Furthermore, TRAF3 inhibition partly abolished the effect of circ-CDR1as overexpression on cellular activities of H/R-treated HT-22 cells. To sum up, our findings, for the first time, demonstrated that DEX exerted neuroprotective effects on hippocampal neurons against H/R treatment via the circ-CDR1as/miR-28-3p/TRAF3 regulatory network, providing novel therapeutic targets for DEX administration in CI/R treatment.
... 25,26 Dexmedetomidine is a highly selective a 2 adrenergic receptor agonist that exhibits central antisympathetic effects and can induce natural sleep sedation. [27][28][29] Dexmedetomidine is commonly used in patients under ICU sedation. A randomized controlled trial of intraoperative dexmedetomidine, midazolam, or propofol revealed that dexmedetomidine reduced the incidence of postoperative delirium. ...
Article
Objective To investigate the effects of dexmedetomidine on postoperative delirium in elderly patients undergoing total hip arthroplasty. Methods A total of 100 patients, 42 male and 58 female, ages 60 to 85 years, American Society of Anesthesiologists grade I or II, who were undergoing total hip arthroplasty were randomly divided into 2 groups: a dexmedetomidine group (group D; n = 50) and a control group (group C; n = 50). Group D patients were infused with 0.3 μg · kg−1 · h−1 of dexmedetomidine from 5 minutes prior to anesthesia induction until the end of surgery. Group C patients received an equal volume of saline. Heart rate and mean arterial pressure (MAP) were recorded before anesthesia induction (T0), 1 minute before extubation (T1), and 30 minutes after extubation (T2). The Visual Analog Score (VAS) at 1, 2, and 3 days after surgery, the incidence and duration of postoperative delirium, and the length of hospital stay were recorded. Adverse reactions, such as nausea, vomiting, and lethargy, were also recorded. Results The Visual Analog Scores in the 2 groups were similar. In group D, there was no significant difference in heart rate (P = 0.232) and MAP (P = 0.056) between T0 and T1. However, in group C, heart rate significantly increased by 15.3 bpm (P = 0.000) and MAP significantly increased by 10.7 mmHg (P = 0.001) at T1 compared with those at T0. The incidence of postoperative delirium in group D (10%) was significantly lower than that in group C (26%; P = 0.037). The duration of delirium in group D (1.3 ± 0.6 days) was shorter than that in group C (3.0 ± 0.5 days; P = 0.000). The length of hospital stay in group D (13.2 ± 0.9 days) was shorter than that in group C (16.1 ± 0.7 days; P = 0.000). No significant differences were observed in adverse effects between the 2 groups. Conclusion Intravenous infusion of dexmedetomidine can not only reduce the incidence and duration of postoperative delirium, but also shorten the length of hospital stay in elderly patients undergoing total hip arthroplasty.
... 11 Some studies have indicated that dexmedetomidine significantly improves the subjective sleep quality after surgery. 12 Dexmedetomidine produced a natural sleep state that stabilized the recovery time of the central nervous system, thereby reducing the occurrence of agitation, which is more optimal approach compared to the use of sedative-hypnotics (such as benzodiazepines) that may increase the incidence of EA. 13 Dexmedetomidine is a recently developed drug, it has been widely used to prevent postoperative EA in children, and it effectively reduces EA incidence without side effects. [14][15][16] Many recent studies have demonstrated that intraoperative dexmedetomidine infusion also decreases the incidence of EA in adult patients but has side effects including intraoperative hypotension and bradycardia. ...
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Dexmedetomidine can effectively decrease the incidences of emergence agitation (EA) in adult patients, but there are major side effects related to increased dose of dexmedetomidine. The purpose of this study was to determine the median effective dose of dexmedetomidine in the prevention of EA among geriatric patients undergoing major open surgery with general anesthesia. A total of 50 geriatric patients were enrolled in this study. Dexmedetomidine 0.5 μg·kg ⁻¹ ·h ⁻¹ continuous intravenous infusion was administered to the first patient. The next dose was increased or decreased by .05 depending on the response of the previous patient, according to the Dixon up-and-down method. An “effective” or “ineffective” response was determined based on the Riker sedation-agitation score (RSAS), we defined “effective” as RSAS<5, and “ineffective” as RSAS≥5. The ED50 of dexmedetomidine in prevention of EA was .30 μg·kg ⁻¹ ·h ⁻¹ (95% CI, .27–.33) and the predicted ED95 was .42 μg·kg ⁻¹ ·h ⁻¹ (95% CI, .38–.51). The incidence of bradycardia was significantly increased in the group without EA compared to the group with EA (57.1% vs 13.6%, P = .002). The ED50 of dexmedetomidine in prevention of EA was .30 μg·kg ⁻¹ ·h ⁻¹ (95% CI, .27–.33) and the predicted ED95 was .42 μg·kg ⁻¹ ·h ⁻¹ (95% CI, .38–.51). Bradycardia was the main complication.
... Studies on thalamic modulation by NA are limited, particularly in primates. It is relevant, however, that Coull et al. (2004) showed in humans that performance of a target detection task was decreased under dexmedetomidine treatment (an Alpha-2 adrenergic receptor agonist), and that this detrimental effect was reversed by exposure to white noise, involving higher order thalamic nuclei (pulvinar) selective activation. ...
Article
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Noradrenaline (NA) in the thalamus has important roles in physiological, pharmacological, and pathological neuromodulation. In this work, a complete characterization of NA axons and Alpha adrenoceptors distributions is provided. NA axons, revealed by immunohistochemistry against the synthesizing enzyme and the NA transporter, are present in all thalamic nuclei. The most densely innervated ones are the midline nuclei, intralaminar nuclei (paracentral and parafascicular), and the medial sector of the mediodorsal nucleus (MDm). The ventral motor nuclei and most somatosensory relay nuclei receive a moderate NA innervation. The pulvinar complex receives a heterogeneous innervation. The lateral geniculate nucleus (GL) has the lowest NA innervation. Alpha adrenoceptors were analyzed by in vitro quantitative autoradiography. Alpha-1 receptor densities are higher than Alpha-2 densities. Overall, axonal densities and Alpha adrenoceptor densities coincide; although some mismatches were identified. The nuclei with the highest Alpha-1 values are MDm, the parvocellular part of the ventral posterior medial nucleus, medial pulvinar, and midline nuclei. The nucleus with the lowest Alpha-1 receptor density is GL. Alpha-2 receptor densities are highest in the lateral dorsal, centromedian, medial and inferior pulvinar, and midline nuclei. These results suggest a role for NA in modulating thalamic involvement in consciousness, limbic, cognitive, and executive functions.
... Furthermore, pharmacological manipulations typically depend on baseline levels of arousal, suggesting the importance of tonic NE levels in determining the attentional state (Coull et al., 2004;Smith & Nutt, 1996). ...
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Evidence suggests functional brain networks, especially the executive control network (ECN) and default mode network (DMN), to be abnormal in schizophrenia. Dysfunctions within the locus coeruleus (LC)‐noradrenaline (NE) system, which is supposed to be pivotal to modulate neuronal network activation during executive control (e.g., working memory function), are also considered to play a vital role in the occurrence of positive (e.g., hallucinatory) or negative (e.g., inattentive) symptoms in these patients. In the present study, we sought to shed further light on the role of the LC‐NE system in patients with schizophrenia. More specifically, we wanted to improve our understanding of the relationship and possible disturbances of the ECN and DMN during a working memory task in patients. A total of 58 healthy control subjects and 40 medicated patients with schizophrenia were investigated using a working memory 3‐back task during functional magnetic resonance imaging. Main findings of our present study were differential dynamics of ECN and DMN blood oxygenation level‐dependent (BOLD) activations with increasing task demands in both patients and controls. Moreover, we found increased BOLD activation in the LC in patients compared to controls in the interaction contrast between groups and conditions. LC BOLD activation significantly correlated with both, the main hub of the ECN, that is, the dorsolateral prefrontal cortex, and of the DMN, that is, the posterior cingulate cortex. Thus, the LC‐NE system seems to be crucial in modulating neuronal network activity in a 3‐back working memory task and might significantly contribute to cognitive impairments in schizophrenia.
... In addition, while noradrenergic alpha2 agonist (dexmedotomidine) induces sedation and interferes with behavioral success in attentional detection task, the introduction of white noise (making the task more complex perceptually speaking) recovers behavioral performance and this effect coincides with an increased activity in the left pulvinar. This argues in favor of a contribution of the pulvinar, beyond the attentional function, to phasic arousal or alerting process and the noradrenergic neuromodulation system (Coull et al., 2004). ...
Article
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Perception in ambiguous environments relies on the combination of sensory information from various sources. Most associative and primary sensory cortical areas are involved in this multisensory active integration process. As a result, the entire cortex appears as heavily multisensory. In this review, we focus on the contribution of the pulvinar to multisensory integration. This subcortical thalamic nucleus plays a central role in visual detection and selection at a fast time scale, as well as in the regulation of visual processes, at a much slower time scale. However, the pulvinar is also densely connected to cortical areas involved in multisensory integration. In spite of this, little is known about its multisensory properties and its contribution to multisensory perception. Here, we review the anatomical and functional organization of multisensory input to the pulvinar. We describe how visual, auditory, somatosensory, pain, proprioceptive and olfactory projections are differentially organized across the main subdivisions of the pulvinar and we show that topography is central to the organization of this complex nucleus. We propose that the pulvinar combines multiple sources of sensory information to enhance fast responses to the environment, while also playing the role of a general regulation hub for adaptive and flexible cognition.
... Task-related fMRI will help us identify and characterize functionally distinct nodes in the brain and interpret the neural correlates underlying tasks assessing different neural systems which include primary sensory processes (e.g., auditory, motor function) and different cognitive processes (e.g., episodic memory, language processing, and emotion processing) [48]. A number of studies have investigated the effects of midazolam-induced sedation on brain activity during primary sensory stimulation and high-order cognitive processing [49][50][51][52]. Most studies have focused on the limits of auditory processing, anticipation to pain and memory because of its sedative, anxiolytic, and anterograde amnesic properties. ...
Article
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As a commonly used anesthetic agent, midazolam has the properties of water-soluble, rapid onset, and short duration of action. With the rapid development in the field of neuroimaging, numerous studies have investigated how midazolam acts on the human brain to induce the alteration of consciousness. However, the neural bases of midazolam-induced sedation or anesthesia remain beginning to be understood in detail. In this review, we summarize findings from neuroimaging studies that have used midazolam to study altered consciousness at different levels and content. We also compare the results to those of neuroimaging studies using diverse anesthetic agents and describe the common neural correlates of anesthetic-induced alteration of consciousness.
... Although phasic alerting and conflict resolution are considered to be dissociable mechanisms (Posner & Boies, 1971;Posner & Petersen, 1990), there is still a lack of consensus regarding the conditions and the specific processes involved in the interaction between them (Coull, Jones, Egan, Frith & Maze, 2004;Hackley & Valle-Inclàn, 2003;Weinbach & Henik, 2012). In their attempt to clarify the interaction between these two mechanisms, Callejas, Lupiáñez and Tudela (2004) found a detrimental effect of WSs on performance in a flanker task paradigm (Eriksen & Eriksen, 1974), where targets are presented centrally and surrounded by target-like distracters, associated to either the same (congruent condition) or the opposite (incongruent condition) response. ...
Article
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Previous studies have reported increased interference when a task-irrelevant acoustic warning signal preceded the target presentation in cognitive tasks. However, the alerting-congruence interaction was mostly observed for tasks measuring Flanker and Simon interferences but not for Stroop conflict. These findings led to the assumption that warning signals widen the attentional focus and facilitate the processing of irrelevant spatial characteristics. However, it is not clear whether these effects are because of the temporal information provided by the warning signal or because of their alerting effects. Based on these findings, and on the open question about the nature of the warning signal intervention on visuospatial interferences, we decided to test the impact of the warning signal on the processing of irrelevant spatial features, by using a procedure suitable for measuring both Simon and spatial Stroop interferences. We also manipulated the intensity of the warning signal to study the effect of the task-irrelevant characteristics of warning signals in visuospatial interferences. For the Simon conflict, results demonstrated an increased interference provoked by the presence (Experiment 1) and intensity (Experiment 2) of warning signals. In contrast, neither the presence nor the intensity of warning signals affected the spatial Stroop interference. Overall, these findings suggest that the impact of warning signals primarily depends on the processing of irrelevant spatial attributes and on the type of conflict (e.g., spatial stimulus-response interference in Simon vs. stimulus-stimulus interference in spatial Stroop). In general, acoustic warning signals facilitate the automatic response activation, but their modulatory effect depends on the task setting involved.
... This finding was observed both at the single-subject and group level (seeFigures 4and 5). The brain substrates of vigilance mainly encompass frontal, parietal, and thalamic areas(Coull, Jones, Egan, Frith, & Maze, 2004;Shaw et al., 2009). Previous studies have indicated that the increased activity of the FPN with the occurrence of pupil dilation(Schneider et al., 2016) and microsleep(Poudel, Innes, & Jones, 2018) after sleep deprivation, indicating top-down control following a transient decrease in vigilance. ...
Article
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Sleep inertia refers to a distinct physiological state of waking up from sleep accompanied by performance impairments and sleepiness. The neural substrates of sleep inertia are unknown, but growing evidence suggests that this inertia state maintains certain sleep features. To investigate the neurophysiological mechanisms of sleep inertia, a comparison of pre‐sleep and post‐sleep wakefulness with eyes‐open resting‐state was performed using simultaneous EEG‐fMRI, which has the potential to reveal the dynamic details of neuroelectric and hemodynamic responses with high temporal resolution. Our data suggested sleep‐like features of slow EEG power and decreased BOLD activity were persistent during sleep inertia. In the pre‐sleep phase, participants with stronger EEG vigilance showed stronger activity in the fronto‐parietal network (FPN), but this phenomenon disappeared during sleep inertia. A time course analysis confirmed a decreased correlation between EEG vigilance and the FPN activity during sleep inertia. This simultaneous EEG‐fMRI study advanced our understanding of sleep inertia and revealed the importance of the FPN in maintaining awareness. This is the first study to reveal the dynamic brain network changes from multi‐modalities perspective during sleep inertia.
... Norepinephrine is a critical component of the arousal mechanism. [3][4][5] The locus coeruleus contains a majority of the noradrenergic neurons in the central nervous system and sends extensive efferents throughout the brain. 6 The prefrontal cortex, which is believed to be important for various types of cognitive flexibility, [7][8][9][10][11] has afferent projections to the locus coeruleus in primates. ...
Article
Autism spectrum disorder (ASD) is frequently associated with anxiety and hyperarousal. While the pathological changes in the noradrenergic system in ASD are not entirely clear, a number of functional indices of the sympathetic/parasympathetic balance are altered in individuals with ASD, often with a high degree of inter-individual variability. The neuropsychopharmacological effects of α2 agonists and β-adrenergic antagonists make agents targeting these receptors of particular interest. α2 agonists have shown beneficial effects for attention deficit hyperactivity disorder (ADHD) and in other domains in individuals with ASD, but effects on core ASD symptoms are less clear. Case series and single dose psychopharmacological challenges suggest that treatment with β-adrenergic antagonists has beneficial effects on language and social domains. Additionally, psychophysiological markers and premorbid anxiety may predict response to these medications. As a result, β-adrenergic antagonists are currently being utilized in a clinical trial for improving core symptoms as well as anxiety in individuals with ASD.
... Recent studies conducted on rabbits with subarachnoid hemorrhage found that dexmedetomidine exhibited protective effects on hippocampal neurons [72]. Moreover, magnetic resonance imaging found dexmedetomidine provided a natural sleep-like sedation pattern but had a longer duration [73,74]. ...
Article
Study objective: Postoperative delirium (POD) is a common neurological system disorder in surgical patients. Anesthesia providers have a wide choice of sedative agents involving different mechanisms in clinical practice, and the incidence of POD varies regarding which sedative agent administered. This network meta-analysis aimed to comprehensively analyze the safety and efficacy of each choice for patients. Design: A network meta-analysis. Setting: Vanderbilt University Medical Center. Measurements: We searched PubMed, EMBASE, Ovid Medline and Cochrane Central Register of Controlled Trials (CENTRAL) through the end of September 2018 with the registration number CRD42018110585. The randomized controlled trials were identified and extracted by two reviewers independently. Commonly used sedative agents such as placebo, sevoflurane, desflurane, isoflurane, dexmedetomidine, propofol, midazolam, and ketamine were assessed in this network meta-analysis and the primary outcome was the incidence of POD. The data were synthesized by network meta-analysis. Pair-wise meta-analyses were conducted using the random-effects model. Each intervention was ranked according to its corresponding surface under the cumulative ranking curve (SUCRA) values. The GRADE framework was undertaken to evaluate the risk of bias. Main results: We identified 39 RCTs and 5991 patients in this meta-analysis. Dexmedetomidine was found to be the most effective option in reducing POD, compared to midazolam, propofol, desflurane, and sevoflurane. The results revealed that dexmedetomidine was associated with a lower incidence of POD, whereas midazolam was associated with a significantly higher number of patients with delirium. Midazolam and propofol were also associated with a higher incidence of perioperative hypotension and bradycardia. Conclusion: Our study provided meta-analytic evidence and suggested dexmedetomidine could be considered as the most effective sedative agent to reduce POD. However, clinical practitioners still need to weigh the pros and cons before choosing a sedative agent for individual patient.
... In a comprehensive review on the role of the right-hemisphere in cognitive reserve 13 , Robertson suggested that the integrity and functional connectivity of the right fronto-parietal network is decisive for the late-life maintenance of attentional abilities, and especially alertness functions 14 . He summarized evidence for a close, bidirectional relationship of the availability of noradrenaline provided by the locus coeruleus, which is decisive for the ability to increase arousal 15,16 , and the integrity of the right fronto-parietal network in aging individuals. The model is supported by a more recent demonstration that higher activity of the noradrenergic system (induced by a handgrip task) increased functional connectivity between the locus coeruleus and the fronto-parietal network to a bigger extent for older compared to younger women 17,18 . ...
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Phasic alerting cues temporarily increase the brain's arousal state. In younger and older participants, visual processing speed in a whole report task, estimated based on the theory of visual attention (TVA), is increased in cue compared to no-cue conditions. The present study assessed whether older participants' ability to profit from warning cues is related to iFC in the cingulo-opercular and/or right fronto-parietal network. We obtained resting-state functional magnetic resonance imaging (rs-fMRI) data from 31 older participants. By combining an independent component analysis and dual regression, we investigated iFC in both networks. A voxel-wise multiple regression in older participants revealed that higher phasic alerting effects on visual processing speed were significantly associated with lower right fronto-parietal network iFC. We then compared healthy older participants to a previously reported sample of healthy younger participants to assess whether behaviour-iFC relationships are age group specific. The comparison revealed that the association between phasic alerting and cingulo-opercular network iFC is significantly lower in older than in younger adults. Additionally, it yielded a stronger association between phasic alerting and right fronto-parietal network iFC in older versus younger participants. The results support a particular role of the right fronto-parietal network in maintaining phasic alerting capabilities in aging.
... 49,52 We speculated that dexmedetomidine produced a state akin to natural sleep that stabilized the recovery time of the central nervous system, thereby reducing the occurrence of agitation, which is more optimal approach compared to the use of sedative-hypnotics (such as benzodiazepines) that may increase the incidence of emergence delirium. 53 Conventional meta-analysis demonstrated that extubation time in the dexmedetomidine group was delayed, while the sensitivity analysis showed that these results were not robust. A latest published study showed that intravenous dexmedetomidine did not affect postoperative extubation time. ...
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Objective: The aim of the current meta-analysis was to assess the effect of dexmedetomidine on emergence agitation (EA) and the recovery outcomes after general anesthesia in adults. Methods: We searched the PubMed, the Cochrane Central Register of Controlled Trials, Embase, Web of Science and clinicaltrials.gov for relevant randomized controlled trials (RCTs) investigating the effects of dexmedetomidine on the EA in adults after general anesthesia compared with placebo. The primary outcome was the incidence of EA. Secondary outcomes included other recovery outcomes after general anesthesia. Results: Twelve RCTs (842 participants) met the eligibility criteria. A conventional random-effects meta-analysis demonstrated that peri-operative intravenous dexmedetomidine could be effective for the prevention of EA [risk ratio (RR) 0.49, Trial Sequential Analysis (TSA)-adjusted 95% confidence interval (CI) 0.35-0.68, P<0.00001]. In addition, the TSA indicated that the meta-analysis for the incidence of EA reached the required information size (370). Lower number of patients receiving dexmedetomidine required analgesia (P=0.0009). Extubation time was longer (P=0.03) and hypotension (P=0.03) was more common with dexmedetomidine. Moreover, no difference was found in the other outcomes. Conclusion: Dexmedetomidine was shown to effectively decrease the incidence of EA and to reduce postoperative analgesic requirements. Yet, other recovery outcomes including extubation time, length of PACU stay, postoperative residual sedation, hypotension, bradycardia as well as postoperative nausea and vomiting provided no data that could be used to form final conclusions.
... The noradrenergic system is most widely recognized for its role in arousal [1,2]. The locus coerulees contains the majority of noradrenergic neurons, that project throughout the central nervous system [3]. ...
Article
A number of factors affect performance on tasks associated with creativity. Two pharmacological systems in particularly been identified as important for their impact on creativity, the noradrenergic system and the dopaminergic systems. Furthermore, stress is also established as an important factor impacting performance, most likely mediated by its effects on these neurotransmitter systems. Herein, we review the current literature on the relationships between stress, the noradrenergic system, the dopaminergic system, and other pharmacological factors and their effects on performance on tasks associated with creativity.
... For this purpose, the autism cohort was divided into two groups based on individual clinical scores to contrast the network changes within the sample group as function of severity. We acknowledge the use of midazolam and dexmedetomidine can cause cognitive impairment in certain brain domains (Coull et al., 2004) and may cause increased synchrony in very low frequency signals of acoustic processing regions which can be mistaken for resting state connectivity (Kiviniemi et al., 2005). While valid concerns, a previous study on anaesthetized rhesus monkeys have found that sedation does not necessarily prevent the evaluation of functional connectivity in these regions (Rauschecker et al., 1995;Altman and Bernal, 2001). ...
Article
Objective: To examine the differences in whole brain topology and connectivity in 17 children of the ages 3-8 years across severity of ASD, we performed resting state fMRI using a 3T MRI scanner and graph theoretical analysis of networks. Method: Patients were partitioned into two cohorts based on the severity of ASD, determined using the Childhood Autism Rating Scale (CARS) scores (Mild, 30-36; Severe, 37+). Standard preprocessing pipeline was used, followed by independent component analysis (ICA) to identify regions of interest (ROIs) to construct subject-specific Z-correlation matrices representing the whole brain network. Following which, graph theory measures were calculated in the range of sparsity 6%-35% and statistically analyzed, and corrected for significance (FDR corrected, p < 0.05). Regional clustering coefficient that revealed significant between-group (mild vs. severe) differences were correlated against clinical scores (CARS). Results: Children with severe ASD revealed significantly increased clustering coefficient and small-worldness compared to those with mild or moderate ASD. Region of interest analysis revealed altered clustering in the Heschl's gyrus that significantly correlated with CARS scores. Conclusion: The findings from the current study provide early stage evidence of aberrant brain connectivity appearing in severe ASD, prior to the effect of environmental bias and pruning mechanisms. The clustering of the Heschl's gyrus correlated to the severity of ASD symptoms and agrees with current literature on ASD-associated cortical changes, reflecting early changes to language processing regions.
... A recent rodent study establishes the similarity between the hypnotic state produced by dexmedetomidine and during non-rapid eye movement sleep [40]. In a crossover study in human volunteers, it has been shown that there is no difference in blood flow signal between dexmedetomidine infusion & natural sleep state, as evidenced from a functional magnetic resonance imaging [41]. The similarity between dexmedetomidineinduced hypnosis and natural sleep may maintain cognitive and immunologic function that deteriorates in sleep deprived states [42]. ...
... Since GABA, the primary inhibitory neurotransmitter in the central nervous system seems to play a key role in the pathogenesis of delirium, it is plausible that GABAergic agents such as benzodiazepines and propofol are strongly involved in the development and prolongation of delirium [60,61]. The second theory is that dexmedetomidine-induced sedation provides a more natural sleep-like sedation pattern, which might reduce the risk of developing delirium [19,62]. Furthermore, dexmedetomidine has very little effect on the cholinergic system, which is strongly linked to cognitive functions and the development of delirium [63]. ...
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Background: To determine the preventive and therapeutic effect of dexmedetomidine on intensive care unit (ICU) delirium. Methods: The literature search using PubMed and the Cochrane Central Register of Controlled Trials was performed (August 1, 2018) to detect all randomized controlled trials (RCTs) of adult ICU patients receiving dexmedetomidine. Articles were included if they assessed the influence of dexmedetomidine compared to a sedative agent on incidence of ICU delirium or treatment of this syndrome. Accordingly, relevant articles were allocated to the following two groups: (1) articles that assessed the delirium incidence (incidence comparison) or articles that assessed the treatment of delirium (treatment comparison). Incidence of delirium and delirium resolution were the primary outcomes. We combined treatment effects comparing dexmedetomidine versus (1) placebo, (2) standard sedatives, and (3) opioids in random-effects meta-analyses. Risk of bias for each included RCT was assessed following Cochrane standards. Results: The literature search resulted in 28 articles (25 articles/4975 patients for the incidence comparison and three articles/166 patients for the treatment comparison). In the incidence comparison, heterogeneity was present in different subgroups. Administration of dexmedetomidine was associated with significantly lower overall incidence of delirium when compared to placebo (RR 0.52; 95% CI 0.39-0.70; I2 = 37%), standard sedatives (RR 0.63; 95% CI 0.46-0.86; I2 = 69%), as well as to opioids (RR 0.61; 95% CI 0.44-0.83; I2 = 0%). Use of dexmedetomidine significantly increased the risks of bradycardia and hypotension. Limited data were available on circulatory insufficiency and mortality. In the treatment comparison, the comparison drugs in the three RCTs were placebo, midazolam, and haloperidol. The resolution of delirium was measured differently in each study. Two out of the three studies indicated clear favorable effects for dexmedetomidine (i.e., compared to placebo and midazolam). The study comparing dexmedetomidine with haloperidol was a pilot study (n = 20) with high variability in the results. Conclusion: Findings suggest that dexmedetomidine reduces incidence and duration of ICU delirium. Furthermore, our systematic searches show that there is limited evidence if a delirium shall be treated with dexmedetomidine.
... The noradrenergic system is most widely recognized for its role in arousal [1,2]. The locus coerulees contains the majority of noradrenergic neurons, that project throughout the central nervous system [3]. ...
Chapter
Many factors affect performance on tasks associated with creativity. Stress is one of the more established of these factors impacting performance, most likely mediated by effects on neurotransmitter systems. This chapter discusses the literature on the effects of stress, the noradrenergic system, the dopaminergic system, and other pharmacological factors on creativity. This chapter will also discuss the effects of norepinephrine and dopamine on other related aspects of cognition, such as working memory and set shifting. The effects on divergent and convergent task performance will also be discussed, as well as the need for greater understanding of the optimization of creativity performance.
... In addition, as opposed to these studies, here, participants were required to press a button when they are ready to initiate a trial. It has been shown that stimuli that temporarily increase arousal like white noise [62,63] or a target in a rapid serial visual presentation (RSVP) task [64] can compensate for the tonic decrease in alertness caused by clonidine and completely reverse its effects, probably via a phasic NE response. Yet despite the fact that the button press initiating each trial constituted an arousing stimulus, performance was still impaired under clonidine, suggesting that the effects do not likely stem from a general decrease in alertness. ...
Article
An identical sensory stimulus may or may not be incorporated into perceptual experience, depending on the behavioral and cognitive state of the organism. What determines whether a sensory stimulus will be perceived? While different behavioral and cognitive states may share a similar profile of electrophysiology, metabolism, and early sensory responses, neuromodulation is often different and therefore may constitute a key mechanism enabling perceptual awareness. Specifically, noradrenaline improves sensory responses, correlates with orienting toward behaviorally relevant stimuli, and is markedly reduced during sleep, while experience is largely "disconnected" from external events. Despite correlative evidence hinting at a relationship between noradrenaline and perception, causal evidence remains absent. Here, we pharmacologically down- and upregulated noradrenaline signaling in healthy volunteers using clonidine and reboxetine in double-blind placebo-controlled experiments, testing the effects on perceptual abilities and visually evoked electroencephalography (EEG) and fMRI responses. We found that detection sensitivity, discrimination accuracy, and subjective visibility change in accordance with noradrenaline (NE) levels, whereas decision bias (criterion) is not affected. Similarly, noradrenaline increases the consistency of EEG visually evoked potentials, while lower noradrenaline levels delay response components around 200 ms. Furthermore, blood-oxygen-level-dependent (BOLD) fMRI activations in high-order visual cortex selectively vary along with noradrenaline signaling. Taken together, these results point to noradrenaline as a key factor causally linking visual awareness to external world events. VIDEO ABSTRACT.
... Electrophysiology studies demonstrated that the drop of vigilance at night parallels a wake-dependent increase in the power of slow delta (0.75-4 Hz) and theta (4.5-7.5 Hz) frequency bands of the waking EEG, and a decrease in the power of faster alpha frequency band (8-12 Hz) (Aeschbach et al., 2001;Cajochen et al., 2002Cajochen et al., , 1999. The brain substrates of vigilance encompass mainly frontal and parietal areas at the cortical level, and the thalamus at the subcortical level (Corbetta et al., 1993;Coull et al., 2004;Culham et al., 1998). Reduced fronto-parietal response to a vigilance task has been observed following a night of sleep deprivation (Poudel et al., 2013;Tomasi et al., 2009). ...
Article
Lack of sleep has a considerable impact on vigilance: we perform worse, we make more errors, particularly at night, when we should be sleeping. Measures of brain functional connectivity suggest that decrease in vigilance during sleep loss is associated with an impaired cross-talk within the fronto-parietal cortex. However, fronto-parietal effective connectivity, which is more closely related to the causal cross-talk between brain regions, remains unexplored during prolonged wakefulness. In addition, no study has simultaneously investigated brain effective connectivity and wake-related changes in vigilance, preventing the concurrent incorporation of the two aspects. Here, we used electroencephalography (EEG) to record responses evoked by Transcranial Magnetic Stimulation (TMS) applied over the frontal lobe in 23 healthy young men (18-30 yr.), while they simultaneously performed a vigilance task, during 8 sessions spread over 29 h of sustained wakefulness. We assessed Response Scattering (ReSc), an estimate of effective connectivity, as the propagation of TMS-evoked EEG responses over the fronto-parietal cortex. Results disclose a significant change in fronto-parietal ReSc with time spent awake. When focusing on the night-time period, when one should be sleeping, participants with lower fronto-parietal ReSc performed worse on the vigilance task. Conversely, no association was detected during the well-rested, daytime period. Night-time fronto-parietal ReSc also correlated with objective EEG measures of sleepiness and alertness. These changes were not accompanied by variations in fronto-parietal response complexity. These results suggest that decreased brain response propagation within the fronto-parietal cortex is associated to increased vigilance failure during night-time prolonged wakefulness. This study reveals a novel facet of the detrimental effect on brain function of extended night-time waking hours, which is increasingly common in our societies.
... easily aroused and more cognitively intact when aroused), as demonstrated by instrumental investigations, including electroencephalography (EEG) and functional magnetic resonance imaging. 10,11 Currently, dexmedetomidine is approved in Europe for sedation of ICU patients requiring a sedation not deeper than arousal in response to verbal stimulation. ...
Article
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Light sedation, corresponding to a Richmond AgitationSedation Scale between 0 and 1 is a priority of modern critical care practice. Dexmedetomidine, a highly selective, central, 2adrenoceptor agonist, is increasingly administered in the intensive care units (ICUs) as an effective drug to induce light sedation, analgesia and a quasiphysiological sleep in critically ill patients. Although in general dexmedetomidine is well tolerated, side effects as bradycardia, hypertension, and hypotension may occur. Although a general dosing range is suggested, different ICU patients may require different and highly precise titration that may significantly vary due to neurological status, cardiorespiratory function, baseline blood pressure, heart rate, liver efficiency, age and coadministration of other sedatives. This review analyzes the use of dexmedetomidine in different settings including pediatric, adult, medical and surgical patients starting with some considerations on delirium prevention and sleep quality in critically ill patients and how dexmedetomidine may contribute to these crucial aspects. Dexmedetomidine use in specific subpopulations with unique characteristics will be detailed, with a special attention to a safe use.
... The saccade system is also reportedly supported and/ or promoted by the brain activation system [15][16][17][18]. We have previously reported that maintaining a flexed neck position, which constitutes part of the dynamic posture [19], leads to shortening of the pro-saccade reaction time [20,21]. ...
Article
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Background: We investigated developmental changes in shortening of pro-saccade reaction time while maintaining neck flexion. Methods: Subjects comprised 135 children (3-14 years) and 29 young adults (19-23 years). Children were divided into six groups in 2-year age strata. Pro-saccade reaction tasks for 30 s were performed in neck rest and flexion positions. Reaction times under each position were averaged in every 10-s period. Results: Under neck rest position, reaction time in the 0-10 s period was significantly longer in the 3- to 4-year-old group than in the 5- to 6-year-old group and above. No significant age effect was found for reaction time in the 0-10 s period in the 5- to 6-year-old group and above. Although a significant effect of neck flexion was not observed until the 9- to 10-year-old group, significant shortening of reaction time with neck flexion was found in the 11- to 12-year-old group and above. Furthermore, this shortening was maintained until the first 20-s period in the 11- to 12-year-old group and during the entire 30 s in the 13- to 14-year-old and above. Conclusions: These results suggest that brain activation with the maintenance of neck flexion, related to shortening of the pro-saccade reaction time, was found from a later age of approximately 11 years and above, compared with the age at which information-processing function in the pro-saccade was enhanced. In addition, brain activation with the maintenance of neck flexion was sustained longer with age.
... Connected with the somatosensory cortex, the VP processes sensory information and supports alertness and arousal (Diamond et al., 1992;Krause et al., 2012;Nicolelis and Chapin, 1994;Patterson et al., 2002;Rinaldi et al., 1991). Connected with the parietal, occipital, and temporal cortices, the PUL links associative cortical circuits to mediate visual attention and integrate information for executive control (Coull et al., 2004;Li et al., 2006;Petersen et al., 1987). Lesions circumscribed to the PUL compromised attention to the contralesional hemispace (Habekost and Rostrup, 2006;Kraft et al., 2015). ...
Article
As a key structure to relay and integrate information, the thalamus supports multiple cognitive and affective functions via the connectivity between its subnuclei and cortical and subcortical regions. While extant studies have largely described thalamic regional functions in anatomical terms, evidence accumulates to suggest a more complex picture of subareal activities and connectivities of the thalamus. In the current study, we aimed to parcellate the thalamus and examine whole-brain connectivity of its functional clusters. With resting state fMRI data from 96 adults, we used ICA to parcellate the thalamus into ten components. On the basis of the independence assumption, ICA helps to identify how subclusters overlap spatially. Whole brain functional connectivity of each subdivision was computed for independent component time course (ICtc), which is a unique time series to represent an IC. For comparison, we computed seed-region based functional connectivity using the averaged time course across all voxels within a thalamic subdivision. The results showed that, at p < 10-6, corrected, 49% of voxels on average overlapped among subdivisions. Compared to seed region analysis, ICtc analysis revealed patterns of connectivity that were more distinguished between thalamic clusters. ICtc analysis demonstrated thalamic connectivity to the primary motor cortex, which has eluded the analysis as well as previous studies based on average time series, and clarified thalamic connectivity to the hippocampus, caudate nucleus, and precuneus. The new findings elucidate functional organization of the thalamus and suggest that ICA clustering in combination with ICtc rather than seed region analysis better distinguish whole-brain connectivities among functional clusters of a brain region.
... Two possible, not mutually exclusive, interpretations can explain these results. One possibility is that this improvement in the different variants of the task reflects a general arousal effect following ATX injection (Robbins 1997;Coull et al. 2004;. Alternatively, our results also fit with a more recent claim suggesting that the LC-NE system plays a role in mobilizing energy resources (Raizada and Poldrack 2007; Malecek and Poldrack 2013; Kalwani et al. 2014;Bouret and Richmond 2015;Varazzani et al. 2015). ...
Thesis
La neuromodulation apporte une extraordinaire richesse à la dynamique des réseaux de neurones. Parmi les neuromodulateurs du système nerveux central, la noradrénaline permettrait de faciliter l'adaptation du comportement face aux variations des contraintes environnementales en modulant l'attention, cette fonction au coeur de la cognition qui nous permet de sélectionner l'information la plus pertinente en fonction de notre but. Ce processus complexe qui opère à chaque instant à la fois dans l'espace et le temps, constitue une étape essentielle dans cette adaptation comportementale. Cependant, à ce jour, les mécanismes par lesquels ce neuromodulateur exerce ses effets sur le cerveau sain demeurent mal connus. Mon travail de thèse a pour objectif d'examiner les déterminants comportementaux et les marqueurs neuronaux de l'effet stimulant des agonistes noradrénergiques. La question posée était : "Comment la noradrénaline agit-elle pour optimiser l'attention?" Pour répondre à cette question, j'ai choisi de combiner la pharmacologie, l'analyse du comportement, et l'imagerie par résonnance magnétique fonctionnelle chez le singe. Un des principaux résultats de mes travaux est que l'administration d'agents noradrénergiques induit une large réorganisation des réseaux cérébraux, qui pourrait être à l'origine de l'optimisation des réponses comportementales observées parallèlement
... Drugs such as clonidine decrease central NE leading to lowered subjective alertness and decreased performance on measures of working memory and attention control (see Chamberlain & Robbins, 2013, for a review). Furthermore, these pharmacological manipulations typically depend on baseline levels of arousal, suggesting the importance of tonic NE levels in determining attentional state (Coull et al., 2004;Smith & Nutt, 1996). Finally, dysregulation of the LC-NE system has been implicated in a number of disorders including Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, autism, schizophrenia, and post-traumatic stress disorder, among others (e.g., Arnsten, 2009;Aston-Jones et al., 2007;Berridge & Waterhouse, 2003;Frank et al., 2007;Imeraj et al., 2012;Killeen, Russell, & Sergeant, 2013;Ressler & Nemeroff, 2001;Robertson, 2013;Vazey & Aston-Jones, 2012) as well as cognitive decline associated with normal aging (Mather & Harley, 2016). ...
Article
Studies examining individual differences in working memory capacity (WMC) have suggested that low WMC individuals have particular deficits in attention control processes compared to high WMC individuals. In the current article we suggest that part of the WMC-attention control relation is due to variation in the functioning of the locus coeruleus-norepinephrine system (LC-NE). Specifically, we suggest that because of dysregulation of LC-NE functioning, the fronto-parietal control network for low WMC individuals is only weakly activated, resulting in greater default-mode network activity (and greater mind-wandering) for low WMC individuals compared to high WMC individuals. This results in disrupted attention control and overall more erratic performance (more lapses of attention) for low WMC individuals than for high WMC individuals. This framework is used to examine previous studies of individual differences in WMC and attention control, and new evidence is examined on the basis of predictions of the framework to pupillary responses as an indirect marker of LC-NE functioning.
... Another experimental study found the effectiveness of sedation with dexmedetomidine for patients undergoing ventilator assistance or weaning from ventilator support in intensive care units [8][9]. Patients sedated with dexmedetomidine are reported to be easy to arouse but preserve a tranquil, sleep-like state without respiratory depression [10]. ...
Article
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The clinical characteristics of emergence delirium (ED) associated with post-traumatic stress disorder (PTSD) among military veterans encompass transient agitation, restlessness, disorientation, and violent verbal and physical behaviors due to re-experiencing of PTSD-related incidents. Two cases of ED after general anesthesia associated with PTSD are presented. Different anesthesia methods were applied for the two cases. A traditional medical approach appeared not to prevent the incidence of ED. In the second case, dexmedetomidine infusion along with verbal coaching was effective in preventing ED for a veteran known to have “wild wake-ups” with prior anesthetics. Further clinical studies in effectively utilizing dexmedetomidine in this population with PTSD at high risk for ED are warranted.
... In mice, it was found that, when α 2A receptors were blocked, the sedative, anaesthetic and analgesic effects of dexmedetomidine disappeared (12). In humans, it was found that the blood flow signals caused by dexmedetomidine were similar to the signals produced from natural sleep (13). Dexmedetomidine was able to stimulate α 2C receptors to produce anti-anxiety effects, and the mice without α 2C receptors had shortened attack latency and significantly enhanced alarm reactions (14). ...
Article
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The aim of the present study was to analyze the protective and hemodynamic effects of dexmedetomidine in hypertensive cerebral hemorrhage (HCH) patients during perioperative period. In total, 50 HCH patients were selected and randomly divided into two groups, one group was administered with dexmedetomidine and the other groups with midazolam. The mean arterial pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO2) were monitored in the two groups of patients before and during the operation. The MAP, HR, SpO2 and PETCO2 recorded 5 min after admission into the operation room was considered T1, the same parameters recorded 10 min after drug administration were considered T2, just after starting the operation were considered T3 and 30 min after start of operation were considered T4. The preoperative sedation and analgesia were evaluated by the Ramsay scoring method and the neuron‑specific enolase (NSE) and S100 protein (S100β) were estimated using ELISA. The patients of the midazolam group experienced mild respiratory depression during the period of sedation. Levels of, MAP, HR and PETCO2 were significantly increased whereas SPO2 was decreased (P<0.05). The MAP, HR, SPO2 and PETCO2 were stable during the period of sedation (P>0.05). The plasma concentrations of epinephrine and norepinephrine at T1 were similar in the two groups (P>0.05), but decreased after drug administration. This decrease was more prominent in the dexmedetomidine group patients (P<0.05) than midazolam group patients. The epinephrine and norepinephrine concentrations just after starting operation (T3) were higher than the basal level (T1) in the midazolam group, but close to the basal level in the dexmedetomidine group (P<0.05). The serum concentration of NSE and S100β in the two groups showed no difference (P>0.05) at the end of operation (T5), but after 24 h of operation (T7) NSE and S100β in the dexmedetomidine group were significantly lower compared to the midazolam group (P<0.05). In conclusion, the administration of dexmedetomidine for patients with HCH during perioperative period is safe and serves as an effective sedative, without causing respiratory depression and does not influence stable haemodynamics with certain brain protective effect.
... We hypothesized that some of this variability might be related to the behavioral state of the animal. Because pupil size is positively correlated with arousal (Bradshaw, 1967;Coull et al., 2004;Vinck et al., 2015), we performed eye-tracking during neurophysiological recordings ( Figure S3) and found that during trials in which the mouse's pupil size was large, neuronal responses showed a higher variability (SD) across repetitions to the preferred orientation, as well as increased NCs, despite similar levels of mean activity ( Figure 1E; Figure S3). ...
Article
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Sensory neurons are often tuned to particular stimulus features, but their responses to repeated presentation of the same stimulus can vary over subsequent trials. This presents a problem for understanding the functioning of the brain, because downstream neuronal populations ought to construct accurate stimulus representations, even upon singular exposure. To study how trial-by-trial fluctuations (i.e., noise) in activity influence cortical representations of sensory input, we performed chronic calcium imaging of GCaMP6-expressing populations in mouse V1. We observed that high-dimensional response correlations, i.e., dependencies in activation strength among multiple neurons, can be used to predict single-trial, single-neuron noise. These multidimensional correlations are structured such that variability in the response of single neurons is relatively harmless to population representations of visual stimuli. We propose that multidimensional coding may represent a canonical principle of cortical circuits, explaining why the apparent noisiness of neuronal responses is compatible with accurate neural representations of stimulus features.
... We could speculate that the dissociation in pupillary response we report as a function of PGD lies in the operation of this 'fasttrack' stage. This could be reflected in the very early dissociations we observed in pupillary response, compatible with the response latency of this subcortical system, and by the fact that the areas that comprise this fast-track stage are all known to be associated with the noradrenergic system [85][86][87], of which pupil dilation is a known proxy. This account would suggest that activity within this early eye contact processing stage is enhanced in participants who favour longer periods of direct gaze and who presumably feel more comfortable in engaging in a communicative link. ...
Article
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Most animals look at each other to signal threat or interest. In humans, this social interaction is usually punctuated with brief periods of mutual eye contact. Deviations from this pattern of gazing behaviour generally make us feel uncomfortable and are a defining characteristic of clinical conditions such as autism or schizophrenia, yet it is unclear what constitutes normal eye contact. Here, we measured, across a wide range of ages, cultures and personality types, the period of direct gaze that feels comfortable and examined whether autonomic factors linked to arousal were indicative of people’s preferred amount of eye contact. Surprisingly, we find that preferred period of gaze duration is not dependent on fundamental characteristics such as gender, personality traits or attractiveness. However, we do find that subtle pupillary changes, indicative of physiological arousal, correlate with the amount of eye contact people find comfortable. Specifically, people preferring longer durations of eye contact display faster increases in pupil size when viewing another person than those preferring shorter durations. These results reveal that a person’s preferred duration of eye contact is signalled by physiological indices (pupil dilation) beyond volitional control that may play a modulatory role in gaze behaviour.
... There was also a significant difference between the dexmedetomidine and midazolam groups in terms of the number of adverse events reported. Major complications, including hypertension, requirement for mandible support and intubation, were mainly observed in the midazolam group (46,47). Therefore, dexmedetomidine may be advantageous with regard to the prognosis and outcome of endoscopy patients. ...
Article
Patients undergoing endoscopy frequently require sedation, which commonly includes the administration of midazolam or dexmedetomidine. Previous meta-analyses have mainly focused on comparing the effects of these two drugs in intensive care unit patients. In the present study, randomized controlled trials (RCTs) that compared the sedative and clinical effectiveness of these two drugs in patients undergoing endoscopy were searched in a number of databases. The meta-analysis showed that dexmedetomidine demonstrated a significantly lower rate of respiratory depression and adverse events compared with those presented upon midazolam administration. A significant difference was also observed in the sedation potency of the sedatives. The current controlled data suggest that dexmedetomidine may be an alternative to midazolam in the sedation for endoscopy. However, more high-quality and well-designed studies are required to further evaluate this conclusion.
... The noradrenergic system is most widely recognized for its role in arousal [1,2]. The locus coerulees contains the majority of noradrenergic neurons, that project throughout the central nervous system [3]. ...
Chapter
In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is an outstanding therapeutic resource in anesthesia and critical care: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology and toxicology of anesthetic drugs. The new Section 4, Therapeutics of Clinical Practice, provides integrated and comparative pharmacology and the practical application of drugs in daily clinical practice. Edited by three highly acclaimed academic anesthetic pharmacologists, with contributions from an international team of experts, and illustrated in full colour, this is a sophisticated, user-friendly resource for all practitioners providing care in the perioperative period.
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The rodent homolog of the primate pulvinar, the lateral posterior (LP) thalamus, is extensively interconnected with multiple cortical areas. While these cortical interactions can span the entire LP, subdivisions of the LP are characterized by differential connections with specific cortical regions. In particular, the medial LP has reciprocal connections with frontoparietal cortical areas, including the anterior cingulate cortex (ACC). The ACC plays an integral role in top-down sensory processing and attentional regulation, likely exerting some of these functions via the LP. However, little is known about how ACC and LP interact, and about the information potentially integrated in this reciprocal network. Here, we address this gap by employing a projection-specific monosynaptic rabies tracing strategy to delineate brain-wide inputs to bottom-up LP→ACC and top-down ACC→LP neurons. We find that LP→ACC neurons receive inputs from widespread cortical regions, including primary and higher order sensory and motor cortical areas. LP→ACC neurons also receive extensive subcortical inputs, particularly from the intermediate and deep layers of the superior colliculus (SC). Sensory inputs to ACC→LP neurons largely arise from visual cortical areas. In addition, ACC→LP neurons integrate cross-hemispheric prefrontal cortex inputs as well as inputs from higher order medial cortex. Our brain-wide anatomical mapping of inputs to the reciprocal LP-ACC pathways provides a roadmap for understanding how LP and ACC communicate different sources of information to mediate attentional control and visuomotor functions.
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Previous work introduced the [11C]yohimbine as a suitable ligand of central α2-adrenoreceptors (α2-ARs) for PET imaging. However, reproducibility of [11C]yohimbine PET measurements in healthy humans estimated with a simplified modeling method with reference region, as well as sensitivity of [11C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap. Methods: Thirteen healthy humans underwent two [11C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 minutes before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested. Results: We showed high test-retest reproducibility of DVR estimation with LREF and SRTM regardless of reference region (CC, CERWM, FLWM). The best fit was obtained with SRTMCC (r2=0.94). Test-retest showed that the SRTMCC is highly reproducible (mean ICC>0.7), with a slight bias (-1.8%), whereas SRTMCERWM had lower bias (-0.1%), and excellent ICC (mean>0.8). Using SRTMCC, regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis. Conclusion: The results add experimental support for the suitability of [11C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82.
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Phasic alerting cues temporarily increase the brain’s arousal state. In younger and older participants, visual processing speed in a whole report task, estimated based on the theory of visual attention, is higher in cue than no-cue conditions. The present study assessed whether older participants’ ability to profit from warning cues is related to intrinsic functional connectivity (iFC) in the cingulo-opercular and/or right fronto-parietal network. We acquired resting-state functional magnetic resonance imaging data from 31 older participants. By combining an independent component analysis and dual regression, we investigated iFC in both networks. A voxel-wise multiple regression in older participants yielded that higher phasic alerting effects on visual processing speed were significantly related to lower right fronto-parietal network iFC. This result supports a particular role of the right fronto-parietal network in maintaining phasic alerting capabilities in aging. We then compared healthy older participants to a previously reported sample of healthy younger participants to assess whether behaviour-iFC relationships are age group specific. The comparison revealed that the association between phasic alerting and cingulo-opercular network iFC is significantly lower in older than in younger adults.
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Elucidation of how neuromodulators influence motivated behaviors is a major challenge of neuroscience research. It has been proposed that the locus-cœruleus-norepinephrine system promotes behavioral flexibility and provides resources required to face challenges in a wide range of cognitive processes. Both theoretical models and computational models suggest that the locus-cœruleus-norepinephrine system tunes neural gain in brain circuits to optimize behavior. However, to the best of our knowledge, empirical proof demonstrating the role of norepinephrine in performance optimization is scarce. Here, we modulated norepinephrine transmission in monkeys performing a Go/No-Go discrimination task using atomoxetine, a norepinephrine-reuptake inhibitor. We tested the optimization hypothesis by assessing perceptual sensitivity, response bias, and their functional relationship within the framework of the signal detection theory. We also manipulated the contingencies of the task (level of stimulus discriminability, target stimulus frequency, and decision outcome values) to modulate the relationship between sensitivity and response bias. We found that atomoxetine increased the subject’s perceptual sensitivity to discriminate target stimuli regardless of the task contingency. Atomoxetine also improved the functional relationship between sensitivity and response bias, leading to a closer fit with the optimal strategy in different contexts. In addition, atomoxetine tended to reduce reaction time variability. Taken together, these findings support a role of norepinephrine transmission in optimizing response strategy.
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Abstract Posterior thalamic pulvinar nuclei have been implicated in different aspects of spatial attention, but their exact role in humans remain unclear. Most neuropsychological studies of attention deficits after pulvinar lesion have concerned single patients or small samples. Here we examined a group of 13 patients with focal damage to posterior thalamus on a visual search task with faces, allowing us to test several hypotheses concerning pulvinar function in controlling attention to visually salient or emotionally significant stimuli. Our results identified two subgroups of thalamic patients with distinct patterns of attentional responsiveness to emotional and colour features in face targets. One group with lesions located in anterior and ventral portions of thalamus showed intact performance, with a normal facilitation of visual search for faces with emotional (fearful or happy) expressions on both side of space, similar to healthy controls. By contrast, a second group showed a slower and poorer detection of face targets, most severe for neutral faces, but with a paradoxically enhanced facilitation by both colour and emotional features. This second group had lesions centred on the pulvinar, involving mainly the dorso-medial sectors in patients showing enhanced effects of colour features, but extending to more dorso-lateral sectors in those with enhanced effects of emotional features. These findings reveal that pulvinar nuclei are not critical for orienting attention to emotionally or visually salient features, but instead provide new evidence in support of previous hypotheses suggesting an important role in controlling attention in visual scenes with distracting information.
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The effects of different doses of dexmedetomidine on analgesic efficacy and inflammatory cytokines in patients with laparoscopic surgery were investigated. A total of 179 laparoscopic patients from March 2015 to May 2017 were enrolled and randomly divided into the control group (group A) and three experimental groups with different doses of dexmedetomidine (group B: 0.25; group C: 0.5 and group D: 1 µg/kg). Results showed that there was no significant difference between the four groups in the operation time, the amount of surgical bleeding and intraoperative fluid infusion. The VAS score of group A was significantly higher than the other three groups. In addition, the VAS score of group D at each time-point was the lowest. There was no significant difference regarding the agitation score and sedation score between group A and group B. Furthermore, the restlessness score and sedation score in group C were significantly lower than those in group A and group B. Next we found that CRP and TNF-α in group A and group B were significantly higher than those in groups C and D. In addition, IL-10 in group D was significantly higher than that in group C. Moreover, patients in group C had the least adverse reaction effects. In conclusion, medium dosage of dexmedetomidine cannot only effectively relieve the pain of laparoscopic patients but also regulate the secretion of inflammatory cytokines.
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In the discussion of the neural mechanisms involved in creativity, it is important to gain an understanding of the conditions that impact optimal performance on creativity tasks. Stress is an important factor, long known to impair performance on tasks requiring creativity in healthy individuals (Martindale & Greenough, 1973). The effects of stress are mediated by pharmacological systems, and as such, discussion of stress and pharmacological effects are intertwined. Stress is known to increase activity of the noradrenergic system (Kvetnansky, Pacak, Sabban, Kpoin, & Goldstein, 1998; Ward et al., 1983), as well as the hypothalamic-pituitary-adrenal (HPA) axis. Drugs that block the noradrenergic system in the brain, specifically via action on β-adrenergic receptors, have long been used to mitigate stress-induced impairment in performance on tasks including public speaking or test-taking in anxiety-prone individuals (Faigel, 1991; Lader, 1988; Laverdue & Boulenger, 1991). Exploration of these mechanisms will allow a greater understanding of the processing of information involved in creativity. Additionally, as discussed below, understanding the links between stress, pharmacology, and creativity may also allow a greater opportunity for clinical interventions. Most research has focused on the catecholaminergic systems - the dopaminergic system and the noradrenergic system - but evidence is beginning to be explored for other systems as well. A greater volume of literature exists for the pharmacological effects on other executive functions highly interrelated with creativity, such as set-shifting and working memory. However, some evidence suggests that the distinctions between creativity and these other executive functions may also be quite critical, as will be discussed. Stress and the Noradrenergic System While stress is well known to increase activity of the noradrenergic system (Kvetnansky et al., 1998; Ward et al., 1983), it is the effects of performance and test anxiety that have led to the understanding of the role of the noradrenergic system in creativity. Propranolol, a centrally acting β-adrenergic antagonist, has long been used for stress-induced impairment in performance on tasks including public speaking in anxiety-prone individuals (Lader, 1988; Laverdue & Boulenger, 1991). Furthermore, research involving healthy adolescents with a history of stress-induced cognitive impairment during exams has demonstrated that treatment with the beta-adrenergic antagonist propranolol significantly improved scores on the Scholastic Aptitude Test (SAT) (Faigel, 1991).
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Introduction: This narrative review will describe treatment options for patients in the ICU with major extremity injury requiring extracorporeal myoglobin removal and contemporaneous support for systemic complications, such as sepsis, systemic inflammation and coagulation disorders. Evidence acquisition: Peer-reviewed manuscripts indexed in PubMed. A systematic search for articles describing treatment options for patients in the ICU with major extremity injury were included in the analysis. Our group determined by consensus which resources would best inform this review. Evidence synthesis: Acute Renal Replacement Therapy (ARRT) for renal support may be needed for patients with major extremity trauma developing AKI. Contemporary advances allow the physician to perform a tailored treatment that closely match patient's needs. Techniques and equipment for ARRT can be modulated according to the patient's pathophysiological derangements, maximizing the therapeutic effects and minimizing adverse events. Conclusions: Most of the clinical reviews available in the literature on this topic limit their focus to the extracorporeal removal of myoglobin.
Chapter
As demonstrated by the huge number of publications in the last decade, there is a growing interest in delirium in intensive care. This is a common acute brain dysfunction in the critically ill and is associated with unfavorable outcomes, such as longer hospital stay, increased morbidity, and mortality. Nevertheless, it remains largely underdiagnosed. Its etiology is surely multifactorial and many different mechanisms can be implicated in its development, but its pathogenesis is poorly understood. The use of appropriate diagnostic tools, as specific scoring scales, helps in the diagnosis of delirium, which is not always straightforward, particularly in its hypoactive and subsyndromal forms. Individuation of risk factors and non-pharmacological strategies is a fundamental tool in prevention and treatment of delirium. This chapter outlines epidemiology of delirium, its pathophysiology, and the appropriate measures for diagnosis, prevention, and treatment.
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Sleep is a complex process related to biologic and environmental factors essential to maintaining physiological and emotional well-being. Sleep disturbances and deprivation, and abnormal sleep architecture (prolonged sleep latency, sleep fragmentation, continuous arousals, a preponderance of inefficient sleep stages), frequently occur in critically ill patients, leading to adverse outcomes. Survivors of critical illness frequently refer to sleep deprivation as a major stressor associated with their admission. The following environmental (clinical and nonclinical) factors contribute to sleep disturbances in these patients: mechanical ventilation, drainage positioning and maintenance, bronchial aspiration, hygiene, nursing care, pain, light, and noise. Sleep duration in critically ill patients is shortened and fragmented, and sleep is essential for restoring energy and equilibrating the mind. Sleep deprivation hence alters cognition, leading to apathy, confusion, and delirium, all of which may increase morbidity and mortality. Sedatives are commonly given to critically ill patients to promote sleep, although physiological sleep and sedation may be significantly different. While patients may achieve an acceptable amount of sleep over a 24-h period, this sleep is both discontinuous and abnormally structured. Clinical guidelines strongly support and recommend the application of a multimodal approach aimed at promoting sleep that includes both environmental regulations and clinical assistance.
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Objective: To explore the effect of giving sedatives according to the circadian rhythm in prevention of occurrence of delirium and the prognosis of patients undergoing mechanical ventilation in intensive care unit (ICU). Methods: A prospective double-blinded randomized controlled trial (RCT) was conducted. The patients admitted to Department of Critical Care Medicine of the Second Hospital of Lanzhou University from July 2014 to February 2015, undergoing invasive mechanical ventilation over 12 hours were enrolled. All the patients were given fentanyl for analgesia, and they were randomly divided into simulated circadian clock group (study group, n = 35) and non-simulated circadian clock group (control group, n = 35). The patients in each group were subdivided into three subgroups according to the kinds of sedative drugs, namely dexmedetomidine group (n = 8), propofol group (n = 14), and dexmedetomidine combined with propofol group (combination group, n = 13). Visual analogue scale (VAS) standard and Richmond agitation-sedation scale (RASS) were used to control the analgesic and to quantify the depth of sedation by titrating the dose of sedative drugs, the simulated circadian clock was set to control the RASS score at 0-1 during the day, and -1 to -2 at night in study group. The RASS score in the control group was set at -1 to -2 day and night. The urine 6-hydroxy acid melatonin (aMT6s) levels at different time points in the first diurnal rhythm (06:00, 12:00, 18:00, 24:00) were determined by enzyme linked immunosorbent assay (ELISA). The incidence of delirium, severe hypotension, severe bradycardia and other adverse reactions, duration of mechanical ventilation and the time of extubation, length of ICU stay, amount of sedative and analgesic drugs used were recorded. The correlation between delirium and other indexes was analyzed by using Spearman correlation analysis. Results: (1) There were no significant differences in gender, age, acute physiology and chronic health evaluation II (APACHEII) score among groups. (2) Urine aMT6s levels did not show circadian rhythm in both groups, aMT6s level at 06:00 in study group showed an increasing tendency as compared with the control group, but the difference was not statistically significant. (3) Compared with the control group, the incidence of delirium was significantly lowered in the study group (14.3% vs. 37.1%, P = 0.029), but no significant differences were found in the incidence of severe hypotension or severe bradycardia (20.0% vs. 25.7%, 11.4% vs. 20.0%, both P > 0.05). In simulated circadian clock group, the incidence of delirium in dexmedetomidine group was significantly lower than that of the propofol group (6.3% vs. 32.1%, P < 0.05). (4) Compared with control group with the same sedative, the duration of mechanical ventilation, extubation time, length of ICU stay were significantly shortened, and the dosage of sedative drugs used was reduced in study group (all P < 0.05). In simulated circadian clock group, the duration of mechanical ventilation in dexmedetomidine group was significantly shorter than that of propofol group and combination group (hours: 75.75±26.78 vs. 102.00±26.31 and 100.31±25.38, both P < 0.05), and the length of ICU stay was significantly shorter than that of propofol group (days: 5.75±1.04 vs. 7.00±1.52, P < 0.05). (5) The occurrence of delirium was positively correlated with duration of mechanical ventilation (r = 0.705), extubation time (r = 0.704), length of ICU stay (r = 0.666, all P = 0.000), and no correlation was found between the occurrence of delirium and aMT6s level at 06:00, 12:00, 18:00, and 24:00 (r = -0.135, r = 0.163, r = 0.269, r = -0.077, all P > 0.05). Conclusions: Administration of sedatives according to simulating circadian time could decrease the duration of mechanical ventilation, extubation time, and the length of ICU stay, decrease the dosage of sedative drugs, and reduce the incidence of delirium. Dexmedetomidine could reduce the incidence of delirium, and improve the prognosis of patients.
Article
Background: Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery. Methods: We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0·1 μg/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-10000802. Findings: Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0·35, 95% CI 0·22-0·54; p<0·0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0·50, 0·32-0·78; p=0·002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0·44, 0·26-0·75; p=0·002). Occurrence of hypotension and bradycardia did not differ between groups. Interpretation: For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe. Funding: Braun Anaesthesia Scientific Research Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China.
Chapter
In the neurointensive care setting, specific considerations of sedation are required; sedation may act as a therapeutic agent itself, when causing a reduction in cerebral metabolic rate of oxygen, cerebral blood flow, and intracranial pressure and in the incidence of seizures. However, the physician must be aware of the effects of every sedative agent on cerebral physiology, in order to obtain beneficial effects and avoid side effects. In this chapter, the effects of sedative agents on cerebral physiology are described in order to provide knowledge for an adequate sedative strategy.
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Background: Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. Objectives: To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. Data sources: We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. Methods: Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis. Results: Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001). Limitations: Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors. Conclusions: Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine. Study registration: This study is registered as PROSPERO CRD42014014101. Funding: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.
Article
Objective: To investigate the effect of dexmedetomidine on anxiety in infertile patients after general anesthesia. Methods: Ninety infertile patients were selected for laparoscopic surgeries in the reproductive medicine center in our hospital. The patients were randomly divided into 3 groups (30 patients in each group). Patients' anxiety states were evaluated by themselves using STAI form and by one physician before operation. Patients were intravenously given with dexmedetomidine 0.2 or 0.4 μg·kg-1 within 10 min with an infusing pump after anesthesia induction. Bispectral index during anesthesia, operation duration and extubation time were recorded. Before the patients leave PACU, their anxiety status was objectively evaluated again by the same physician. The intensity of pain was evaluated using VAS score (0~10, 0=no pain, 10=worst pain) at 2, 4, 12 and 24 h after operation. The adverse effects, such as nausea, vomit and shivering, were recorded and compared. Results: The level of anxiety was high in infertile patients before operation. The level of anxiety in patients treated with dexmedetomidine 0.4 μg·kg-1 was the least before leaving PACU. In this group, the number of patients who had sob, shivering, sweatiness and trembling was the least (P<0.05). BIS during operation and at the end of operation was lower in patients treated with dexmedetomidine 0.2 and 0.4 μg·kg-1 than that of control group (P<0.05). The extubation time of 0.4 μg·kg-1 group was longer than that of control group (P<0.05). The numbers of nausea, vomit and shivering in dexmedetomidine 0.4 μg·kg-1 group were lower than that in control group (P<0.05). The needs of postoperative analgesic drugs were significantly reduced in dexmedetomidine 0.2 and 0.4 μg·kg-1 groups than that of control group (P<0.05). The VAS scores of dexmedetomidine 0.4 μg·kg-1 group at 2, 4, 12 and 24 h after operation were lower than that in control group (P<0.05); while at 2 and 4 h, it was lower in dexmedetomidine 0.2 μg·kg-1 group than that in control group (P<0.05). Conclusion: Infertile patients possess high level of anxiety before operation. Intravenous dexmedetomidine can strengthen the effects of analgesic and sedation drugs, reduce the postoperative pain, and reduce the adverse effects and spare the dosage of postoperative analgesic drugs. Intravenous dexmedetomidine 0.4 μg·kg-1 given within 10 min while having laparoscopic surgeries can acquire satisfied anesthesia effects in infertile patients.
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Patients with extensive damage to the right hemisphere of their brain often exhibit unilateral neglect of the left side of space. The spatial attention of these patients is strongly biased towards the right1, so their awareness of visual events on the left is impaired2. Extensive right-hemisphere lesions also impair tonic alertness (the ability to maintain arousal)3, 4, 5. This nonspatial deficit in alertness is often considered to be a different problem from spatial neglect5,6, but the two impairments may be linked7,8. If so, then phasically increasing the patients' alertness should temporarily ameliorate their spatial bias in awareness. Here we provide evidence to support this theory. Right-hemisphere-neglect patients judged whether a visual event on the left preceded or followed a comparable event on the right. They became aware of left events half a second later than right events on average. This spatial imbalance in the time course of visual awareness was corrected when a warning sound alerted the patients phasically. Even a warning sound on the right accelerated the perception of left visual events in this way. Nonspatial phasic alerting can thus overcome disabling spatial biases in perceptual awareness after brain injury.
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Statistical parametric maps (SPMs) are potentially powerful ways of localizing differences in regional cerebral activity. This potential is limited by uncertainties in assessing the significance of these maps. In this report, we describe an approach that may partially resolve this issue. A distinction is made between using SPMs as images of change significance and using them to identify foci of significant change. In the first case, the SPM can be reported nonselectively as a single mathematical object with its omnibus significance. Alternatively, the SPM constitutes a large number of repeated measures over the brain. To reject the null hypothesis, that no change has occurred at a specific location, a threshold adjustment must be made that accounts for the large number of comparisons made. This adjustment is shown to depend on the SPM's smoothness. Smoothness can be determined empirically and be used to calculate a threshold required to identify significant foci. The approach models the SPM as a stationary stochastic process. The theory and applications are illustrated using uniform phantom images and data from a verbal fluency activation study of four normal subjects.
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Positron emission tomographic scans were recorded from human subjects following an object-identification task, one version of which required attentional selection and the other version of which did not. In one experimental session, the attention-demanding displays were presented in the left visual field and the nonattention displays were presented in the right visual field. In a second session, the sides of the displays were reversed. Analysis of the scans indicated that, averaged across the 2 sessions, the pulvinar showed greater glucose uptake when it was contralateral to the display of the selective attention task than when it was contralateral to the display of the nonattention task. The pattern of the data indicated that the degree of the attention task effect on pulvinar glucose uptake may differ between the hemispheres. In view of known connections between the pulvinar and cortical areas that mediate object identification, the present finding suggests that the pulvinar operates interactively with these cortical structures when an identification process demands selective attention.
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1. Single intravenous doses (25, 50 and 100 micrograms) of medetomidine (MPV-785, an imidazole derivative), a selective alpha 2-adrenoceptor agonist, were administered to eight healthy male volunteers in a double-blind, placebo-controlled study. 2. The following dose-related effects, all of which were compatible with an agonistic action of the drug at alpha 2-adrenoceptors, were noted: reductions of systolic and diastolic blood pressure (maximum 18/11 mm Hg), heart rate (maximum 10 beats min-1), saliva secretion (maximum 84%) and noradrenaline levels in plasma (maximum 70%). 3. Dose-dependent sedation or impairment of vigilance was also observed, both by subjective and objective (critical flicker fusion threshold) assessments, with the highest dose actually inducing sleep in five of the subjects. 4. The observed effects were in general agreement with those previously seen after intravenous administration of the centrally acting antihypertensive alpha 2-adrenoceptor activating drug, clonidine, but of a shorter duration. 5. The relative importance of alpha 2-adrenoceptors located in peripheral tissues and in the central nervous system for the drug's cardiovascular effects could not be determined, but the high lipid solubility of the compound and the rapid onset of sedation are in favour of a major central component. 6. Medetomidine may be a useful tool for the investigation of the physiology and pharmacology of alpha 2-adrenoceptors in man. In addition, the therapeutic and diagnostic uses of the compound should be investigated in pathological conditions related to increased sympathetic neuronal activity.
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Space- and object-based attention components were examined in neurologically normal and parietal-lesion subjects, who detected a luminance change at 1 of 4 ends of 2 outline rectangles. One rectangle end was precued (75% valid); on invalid-cue trials, the target appeared at the other end of the cued rectangle or at 1 end of the uncued rectangle. For normals, the cost for invalid cues was greater for targets in the uncued rectangle, indicating an object-based component. Both right- and left-hemisphere patients showed costs that were greater for contralesional targets. For right-hemisphere patients, the object cost was equivalent for contralesional and ipsilesional targets, indicating a spatial deficit, whereas the object cost for left-hemisphere patients was larger for contralesional targets, indicating an object deficit.
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Patients with extensive damage to the right hemisphere of their brain often exhibit unilateral neglect of the left side of space. The spatial attention of these patients is strongly biased towards the right, so their awareness of visual events on the left is impaired. Extensive right-hemisphere lesions also impair tonic alertness (the ability to maintain arousal). This nonspatial deficit in alertness is often considered to be a different problem from spatial neglect, but the two impairments may be linked. If so, then phasically increasing the patients' alertness should temporarily ameliorate their spatial bias in awareness. Here we provide evidence to support this theory. Right-hemisphere-neglect patients judged whether a visual event on the left preceded or followed a comparable event on the right. They became aware of left events half a second later than right events on average. This spatial imbalance in the time course of visual awareness was corrected when a warning sound alerted the patients phasically. Even a warning sound on the right accelerated the perception of left visual events in this way. Nonspatial phasic alerting can thus overcome disabling spatial biases in perceptual awareness after brain injury.
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The physiological basis for the interaction of selective attention and arousal is not clearly understood. Here we present evidence in humans that specifically implicates the thalamus in this interaction. We used functional magnetic resonance imaging to measure brain activity during the performance of an attentional task under different levels of arousal. Activity evoked in the ventrolateral thalamus by the attentional task changed as a function of arousal. The highest level of attention-related thalamic activity is seen under conditions of low arousal (secondary to sleep deprivation) compared with high arousal (secondary to caffeine administration). Other brain regions were also active during the attentional task, but these areas did not change their activity as a function of arousal. Control experiments establish that this pattern of changes in thalamic activity cannot be accounted for by nonspecific effects of arousal on cerebral hemodynamics. We conclude that the thalamus is involved in mediating the interaction of attention and arousal in humans.
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Noradrenergic locus coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.
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Alertness, the most basic intensity aspect of attention, probably is a prerequisite for the more complex and capacity demanding domains of attention selectivity. Behaviorally, intrinsic alertness represents the internal (cognitive) control of wakefulness and arousal; typical tasks to assess optimal levels of intrinsic alertness are simple reaction time measurements without preceding warning stimuli. Up until now only parts of the cerebral network subserving alertness have been revealed in animal, lesion, and functional imaging studies. Here, in a 15O-butanol PET activation study in 15 right-handed young healthy male volunteers for this basic attention function we found an extended right hemisphere network including frontal (anterior cingulate-dorsolateral cortical)-inferior parietal-thalamic (pulvinar and possibly the reticular nucleus) and brainstem (ponto-mesencephalic tegmentum, possibly involving the locus coeruleus) structures, when subjects waited for and rapidly responded to a centrally presented white dot by pressing a response key with the right-hand thumb.
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Objects play an important role in guiding spatial attention through a cluttered visual environment. We used event-related functional magnetic resonance imaging (ER-fMRI) to measure brain activity during cued discrimination tasks requiring subjects to orient attention either to a region bounded by an object (object-based spatial attention) or to an unbounded region of space (location-based spatial attention) in anticipation of an upcoming target. Comparison between the two tasks revealed greater activation when attention selected a region bounded by an object. This activation was strongly lateralized to the left hemisphere and formed a widely distributed network including (a) attentional structures in parietal and temporal cortex and thalamus, (b) ventral-stream object processing structures in occipital, inferior-temporal, and parahippocampal cortex, and (c) control structures in medial- and dorsolateral-prefrontal cortex. These results suggest that object-based spatial selection is achieved by imposing additional constraints over and above those processes already operating to achieve selection of an unbounded region. In addition, ER-fMRI methodology allowed a comparison of validly versus invalidly cued trials, thereby delineating brain structures involved in the reorientation of attention after its initial deployment proved incorrect. All areas of activation that differentiated between these two trial types resulted from greater activity during the invalid trials. This outcome suggests that all brain areas involved in attentional orienting and task performance in response to valid cues are also involved on invalid trials. During invalid trials, additional brain regions are recruited when a perceiver recovers from invalid cueing and reorients attention to a target appearing at an uncued location. Activated brain areas specific to attentional reorientation were strongly right-lateralized and included posterior temporal and inferior parietal regions previously implicated in visual attention processes, as well as prefrontal regions that likely subserve control processes, particularly related to inhibition of inappropriate responding.
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This placebo‐controlled, randomized study evaluated, on separate days, the dose–response relationship for 1 h infusions of clonidine 1, 2 and 4 µg kg–1 h–1, in eight healthy volunteers aged 22–30 yr. Response end‐points included sedation (bispectral index, visual analogue scale and observer assessment of sedation), analgesia to a cold pressor test, memory (recall of word lists), cognitive function (digit symbol substitution test (DSST)), respiratory function (respiratory rate, end‐tidal carbon dioxide, oxygen saturation) and haemodynamic stability (heart rate and mean arterial pressure). Clonidine infusions resulted in significant and progressive sedation, but all subjects were easily awoken to perform tests and evaluations. Statistically significant analgesia, memory impairment and reduced performance on the DSST occurred during 4 µg kg–1 h–1 infusions (resulting in a plasma concentration of 2 ng ml–1. There were no statistically significant changes in cardiorespiratory variables throughout the study. Br J Anaesth 2001; 86: 5–11
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By means of extracellular recordings, individual norepinephrine-containing neurons in the locus coeruleus of unanesthetized behaviorally responsive rats and squirrel monkeys were found to respond to specific sensory and behavioral conditions. In rats, distinct clusters of action potentials followed the presentation of various nonnoxious auditory, visual, or somatosensory stimuli at latencies of 15-60 msec. Increased discharge rates were also seen during periods of spontaneous electroencephalogram arousal in both species. In monkeys, these cells responded most vigorously to complex arousing stimuli such as a preferred food. Because the noradrenergic innervation of most forebrain regions arises from the locus coeruleus, these results allow prediction of situations under which this massive projection system would be active and suggest a physiological role for this chemically identified network in specific behavioral processes.
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Vigilance behavior, or watch keeping, involves the focusing of attention on the detection of subtle changes in the environment that occur over a long period of time. We investigated the time course of changes in brain activity during the continuous performance of a 60-min auditory vigilance task. The task required the detection of an intensity drop that occurred in 5% of the auditory stimuli. Six 1-min samples of cerebral blood flow (CBF) and electroencephalographic (EEG) activity were obtained at l0-min intervals during the vigilance performance. Changes in CBF were measured by means of positron emission tomography (PET). Performance data (hits, false alarms, reaction time) were analyzed across six 10-min blocks. Eight healthy male volunteers participated in the study. During the 60-min test, the number of correct detections (hits) did not change, but both the reaction time and EEG activity in the theta (4 to 7 Hz) range progressively increased across testing. CBF in several subcortical structures (thalamus, substantia innominata, and putamen) and cortical areas (ventrolateral, dorsolateral, and orbital frontal cortex; parietal cortex; and temporal cortex) decreased as a function of time-on-task; changes in the cortical regions were limited to the right hemisphere. Blood flow also decreased in the temporalis muscles. At the same time, CBF increased in several visual cortical areas including the left and right fusiform gyri. Furthermore, the thalamic blood-flow response co-varied with that in the substantia innominata, the ponto-mesencephalic tegmentum, and the anterior cingulate cortex. The right ventrolateral-frontal blood-flow response covaried with that in the right parietal, orbitofrontal, and dorsolateral frontal cortex. 'Iko main conclusions are drawn from the obtained data. First, we suggest that the observed time-related changes in reaction time, EEG activity, and blood flow in the temporalis muscles are related to changes in the level of arousal (alertness) and that CBF changes in the thalamus-related neural circuitry represent a brain correlate of such changes. Second, we speculate that time-related CBF decreases in cortical regions of the right hemisphere underlie a shift from controlled to automatic attentional processing of the auditory stimuli.
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This paper concerns the spatial and intensity transformations that map one image onto another. We present a general technique that facilitates nonlinear spatial (stereotactic) normalization and image realignment. This technique minimizes the sum of squares between two images following nonlinear spatial deformations and transformations of the voxel (intensity) values. The spatial and intensity transformations are obtained simultaneously, and explicitly, using a least squares solution and a series of linearising devices. The approach is completely noninteractive (automatic), nonlinear, and noniterative. It can be applied in any number of dimensions. Various applications are considered, including the realignment of functional magnetic resonance imaging (MRI) time-series, the linear (affine) and nonlinear spatial normalization of positron emission tomography (PET) and structural MRI images, the coregistration of PET to structural MRI, and, implicitly, the conjoining of PET and MRI to obtain high resolution functional images.
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Part 1 Introduction: a multidisciplinary approach the goals of attention the manifestations of attention the expression of attention plan of the book. Part 2 Selective attention: early theories of selective attention selection of what, where and which six properties of the attended area metaphors of selective attention selection of an object in a cluttered field experimental tasks selective attention to actions summary. Part 3 Preparatory attention and maintenance attention: preparatory attention attentional preparation or cognitive expectation? perceptual preparations for objects and their attributes perceptual preparation for locations of objects the "peaked distribution" of attentional activity shifting visual attention through space the resource view of preparatory attention maintenance attention summary. Part 4 Attentional processing in cortical areas: areas of specialized (modular) processing attention to object information in ventral cortical streams attention to spatial information in dorsal cortical streams attentional control versus attentional expression summary. Part 5 Attentional processing in two subcortical areas the superior colliculus the thalamus thalamic circuitry. Part 6 A cognitive-neuroscience model of attention processes in shape identification an experimental trial containing a warning signal and a target summary - the expression, mechanism and control of attention in shape identification. Part 7 Synopsis: a cognitive-neuroscience theory of attention.
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The Observer's Assessment of Alertness/Sedation (OAA/S) Scale was developed to measure the level of alertness in subjects who are sedated. This scale was tested in 18 subjects in a three-period crossover study to assess its reliability and its criterion, behavioral, and construct validity. After receiving either placebo or a titrated dose of midazolam to produce light or heavy sedation, each subject was administered two sedation scales (OAA/S Scale and a Visual Analogue Scale) and two performances tests (Digit Symbol Substitution Test and Serial Sevens Subtraction). Two raters individually evaluated the subject's level of alertness on each of the two sedation scales. The results obtained on the OAA/S Scale were reliable and valid as measured by high correlations between the two raters and high correlations between the OAA/S Scale and two of the three standard tests used in this study. The OAA/S Scale was sensitive to the level of midazolam administered; all pairwise comparisons were significant (p < 0.05) for all three treatment levels at both test periods. (C) Williams & Wilkins 1990. All Rights Reserved.
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Statistical parametric maps are spatially extended statistical processes that are used to test hypotheses about regionally specific effects in neuroimaging data. The most established sorts of statistical parametric maps (e.g., Friston et al. [1991]: J Cereb Blood Flow Metab 11:690–699; Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900–918) are based on linear models, for example ANCOVA, correlation coefficients and t tests. In the sense that these examples are all special cases of the general linear model it should be possible to implement them (and many others) within a unified framework. We present here a general approach that accomodates most forms of experimental layout and ensuing analysis (designed experiments with fixed effects for factors, covariates and interaction of factors). This approach brings together two well established bodies of theory (the general linear model and the theory of Gaussian fields) to provide a complete and simple framework for the analysis of imaging data. The importance of this framework is twofold: (i) Conceptual and mathematical simplicity, in that the same small number of operational equations is used irrespective of the complexity of the experiment or nature of the statistical model and (ii) the generality of the framework provides for great latitude in experimental design and analysis.
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The α2 agonist dexmedetomidine is a new sedative and analgesic agent which is licensed in the USA for post‐operative intensive care sedation. We compared dexmedetomidine with propofol in patients requiring sedation in intensive care. Twenty adult patients expected to require a minimum of 8 h artificial ventilation after surgery were randomized to receive sedation with either dexmedetomidine or propofol infusions. Additional analgesia, if required, was provided by an alfentanil infusion. Depth of sedation was monitored using both the Ramsay sedation score (RSS) and the bispectral index (BIS). Cardiovascular, respiratory, biochemical and haematological data were obtained. Patients’ perceptions of their intensive care stay were assessed using the Hewitt questionnaire. Sedation was equivalent in the two groups [median (interquartile range): RSS, propofol group 5 (4–5), dexmedetomidine group 5 (4–6) (P=0.68); BIS, propofol group 53 (41–64), dexmedetomidine group 46 (36–58); P=0.32], but the propofol group received three times more alfentanil compared with patients sedated with dexmedetomidine [2.5 (2.2–2.9) mg h–1 versus 0.8 (0.65–1.2) mg h–1 (P=0.004)]. No differences were found in arterial pressures between the groups, but heart rate was significantly lower in the dexmedetomidine group [mean (sd) 75 (6) vs 90 (4) beats min–1]. Extubation times were similar and rapid with the use of both sedative agents [median (range) 28 (20–50) and 29 (15–50) min (P=0.63) respectively for the propofol and dexmedetomidine groups]. No adverse events related to the sedative infusions occurred in either group. Despite ventilation and intubation, patients sedated with dexmedetomidine could be easily roused to cooperate with procedures (e.g. physiotherapy, radiology) without showing irritation. From the clinician’s and patient’s perspectives, dexmedetomidine is a safe and acceptable sedative agent for those requiring intensive care. The rate pressure product is reduced in patients receiving dexmedetomidine, which may protect against myocardial ischaemia. Dexmedetomidine reduces the requirement for opioid analgesia. Br J Anaesth 2001; 87; 684–90
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With advancing age, monkeys become impaired on a test of spatial working memory, the delayed response task, and show increased susceptibility to interference from irrelevant stimuli (Bartus and Dean 1979). Alpha-2 adrenergic agonists such as clonidine and guanfacine have been shown to improve the delayed response performance of aged monkeys under standard testing conditions (e.g. Arnsten et al. 1988). The current study examined whether these drugs could protect the delayed response performance of aged monkeys when irrelevant stimuli were presented during the delay intervals. Aged monkeys were tested on the variable delayed response task with short delays to minimize memory demands and optimize performance on control (no interference) sessions. During interference sessions, distractors were presented during the delays on 9 of the 30 trials ("distractor" trials). If the aged monkeys had been pretreated with saline, performance was significantly disrupted by the irrelevant stimuli compared to matched saline control sessions. This impairment was not only evident on the 9 distractor trials, but on the 21 remaining "nondistractor" trials as well. However, if the aged monkeys had been pretreated with clonidine or guanfacine, performance was not impaired on the interference sessions. This beneficial effect of the alpha-2 agonists was most apparent on the nondistractor trials. Guanfacine was able to decrease the harmful effects of distraction without any apparent sedative side effects. Co-administration of the alpha-2 antagonists idazoxan or SKF104078 with clonidine blocked the protective effects of the agonist on delayed response performance, consistent with actions at alpha-2 adrenergic receptors. These findings suggest that alpha-2 agonists improve delayed response performance, at least in part, by helping to protect memory from irrelevant stimulation. Clonidine is already used in the treatment of Attention Deficit Disorder, and the current data suggest that guanfacine may also be useful in this regard.
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One of the major problems of living in a rich visual environment is deciding which particular object or location should be chosen for complete processing or attention; that is, deciding which object is most salient at any particular time. The pulvinar has enlarged substantially during evolution, although little has previously been known about its function. Recent studies suggest that the pulvinar contains neurons that generate signals related to the salience of visual objects. This evidence includes: (1) anatomical and physiological observations of visual function; (2) augmented responses in the pulvinar for visual stimuli presented in important contexts; (3) suppression of activity for stimuli presented in irrelevant conditions; (4) thalamic modulation producing behavioral changes in cued attention paradigms; and (5) similar changes with visual distracter tasks.
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Medetomidine (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole) was tested for alpha 2-adrenoceptor agonist activity and compared to several reference agents. In binding studies carried out with rat brain membrane preparations, medetomidine showed high affinity for alpha 2-adrenoceptors, as measured by the displacement of [3H]clonidine (Ki 1.08 nM compared to 1.62, 3.20, 6.22 and 194 nM for detomidine, clonidine, UK 14,304 and xylazine, respectively). The affinity of medetomidine for alpha 1-adrenoceptors, as measured by [3H]prazosin displacement, was much weaker, yielding a relative alpha 2/alpha 1 selectivity ratio of 1620 which is 5-10 times higher than that of the reference compounds. Medetomidine caused a concentration-dependent inhibition of the twitch response in electrically stimulated mouse vas deferens with a pD2 value of 9.0 compared to that of 8.6, 8.5, 8.2 and 7.1 for detomidine, clonidine, UK 14,304 and xylazine, respectively. The effect of medetomidine was antagonized by idazoxan. In anaesthetized rats, medetomidine caused a dose-dependent mydriasis which could be reversed by alpha 2-adrenoceptor blockade. In receptor binding experiments and isolated organs medetomidine had no affinity or effects on beta 1-, beta 2-, H1, H2, 5-HT1, 5-HT2, muscarine, dopamine, tryptamine, GABA, opiate and benzodiazepine receptors. Based on these results, medetomidine can be classified as a potent, selective and specific alpha 2-adrenoceptor agonist.
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By means of extracellular recordings, individual norepinephrine-containing neurons in the locus coeruleus of unanesthetized behaviorally responsive rats and squirrel monkeys were found to respond to specific sensory and behavioral conditions. In rats, distinct clusters of action potentials followed the presentation of various nonnoxious auditory, visual, or somatosensory stimuli at latencies of 15-60 msec. Increased discharge rates were also seen during periods of spontaneous electroencephalogram arousal in both species. In monkeys, these cells responded most vigorously to complex arousing stimuli such as a preferred food. Because the noradrenergic innervation of most forebrain regions arises from the locus coeruleus, these results allow prediction of situations under which this massive projection system would be active and suggest a physiological role for this chemically identified network in specific behavioral processes.
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Spontaneous discharge of norepinephrine-containing locus coeruleus (NE-LC) neurons was examined during the sleep-walking cycle (S-WC) in behaving rats. Single unit and multiple unit extracellular recordings yielded a consistent set of characteristic discharge properties. (1) Tonic discharge co-varied with stages of the S-WC, being highest during waking, lower during slow wave sleep, and virtually absent during paradoxical sleep. (2) Discharge anticipated S-WC stages as well as phasic cortical activity, such as spindles, during slow wave sleep. (3) Discharge decreased within active waking during grooming and sweet water consumption. (4) Bursts of impulses accompanied spontaneous or sensory-evoked interruptions of sleep, grooming, consumption, or other such ongoing behavior. (5) These characteristic discharge properties were topographically homogeneous for recordings throughout the NE-LC. (6) Phasic robust activity was synchronized markedly among neurons in multiple unit populations. (7) Field potentials occurred spontaneously in the NE-LC and were synchronized with bursts of unit activity from the same electrodes. (8) Field potentials became dissociated from unit activity during paradoxical sleep, exhibiting their highest rates in the virtual absence of impulses. These results are generally consistent with previous proposals that the NE-LC system is involved in regulating cortical and behavioral arousal. On the basis of the present data and those described in the following report (Aston-Jones, G., and F. E. Bloom (1981) J. Neurosci.1: 887-900), we conclude that these neurons may mediate a specific function within the general arousal framework. In brief, the NE-LC system may globally bias the responsiveness of target neurons and thereby influence overall behavioral orientation.
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We present a biologically plausible model of an attentional mechanism for forming position- and scale-invariant representations of objects in the visual world. The model relies on a set of control neurons to dynamically modify the synaptic strengths of intracortical connections so that information from a windowed region of primary visual cortex (V1) is selectively routed to higher cortical areas. Local spatial relationships (i.e., topography) within the attentional window are preserved as information is routed through the cortex. This enables attended objects to be represented in higher cortical areas within an object-centered reference frame that is position and scale invariant. We hypothesize that the pulvinar may provide the control signals for routing information through the cortex. The dynamics of the control neurons are governed by simple differential equations that could be realized by neurobiologically plausible circuits. In preattentive mode, the control neurons receive their input from a low-level "saliency map" representing potentially interesting regions of a scene. During the pattern recognition phase, control neurons are driven by the interaction between top-down (memory) and bottom-up (retinal input) sources. The model respects key neurophysiological, neuroanatomical, and psychophysical data relating to attention, and it makes a variety of experimentally testable predictions.