Locus Coeruleus Norepinephrine Research Articles

Selective Enhancement of REM Sleep in Male Rats through Activation of MT1 Receptors Located in the Locus Coeruleus Norepinephrine neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMs without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose-response manner, the firing activity of the locus coeruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.Significance Statement Rapid eye movement sleep (REMS) is involved in the processes of memory consolidation and emotional regulation, but drugs selectively enhancing REMS are scant. Herein, we show that the first-in-class selective melatonin MT1 receptor agonist UCM871, by inhibiting the activity of norepinephrine neurons in the locus coeruleus, an important nucleus regulating the sleep/wake cycle, selectively increases the duration of REMS. These findings enhance our current understanding of the neurobiology and pharmacology of REMS and provide a possible novel mechanism and target for disorders associated with REMS dysfunctions.

Locus coeruleus norepinephrine contributes to visual-spatial attention by selectively enhancing perceptual sensitivity.

Selectively focusing on a behaviorally relevant stimulus while ignoring irrelevant stimuli improves perception. Enhanced neuronal response gain is thought to support attention-related improvements in detection and discrimination. However, understanding of the neuronal pathways regulating perceptual sensitivity remains limited. Here, we report that responses of norepinephrine (NE) neurons in the locus coeruleus (LC) of non-human primates to behaviorally relevant sensory stimuli promote visual discrimination in a spatially selective way. LC-NE neurons spike in response to a visual stimulus appearing in the contralateral hemifield only when that stimulus is attended. This spiking is associated with enhanced behavioral sensitivity, is independent of motor control, and is absent on error trials. Furthermore, optogenetically activating LC-NE neurons selectively improves monkeys' contralateral stimulus detection without affecting motor criteria, supporting NE's causal role in granular cognitive control of selective attention at a cellular level, beyond its known diffuse and non-selective functions.

Locus Coeruleus-Norepinephrine System: Spheres of Influence and Contribution to the Development of Neurodegenerative Diseases.

Locus coeruleus is a small bilateral nucleus in the brainstem. It is the main source of norepinephrine (noradrenaline) throughout the central nervous system (about 70% of all norepinephrine in the central nervous system), and, as shown in numerous studies, it is involved in regulating a significant number of functions. The detailed study of the functions of the Locus Coeruleus (LC) and its significance in human life became possible only after the development of histofluorescence methods for monoamines in the 1960s. The widespread locus coeruleus-norepinephrine (LC-NE) projection system regulates the entire central nervous system and modulates sensory processing, motor behavior, arousal, and cognitive processes. Damage to the LC and the associated decrease in norepinephrine levels are involved in a wide range of clinical conditions and pathological processes. Although much about the anatomy and physiology of the LC is currently known, its ultimate role in the regulation of behavior, control of the sleep-wake cycle, stress response, and the development of pathological conditions (such as Alzheimer's disease, dementia, depression, suicidal behavior, chronic traumatic encephalopathy, and Parkinson's disease) is not fully understood. Non-invasive visualization of the LC can be used for differential diagnosis, determining the stage of the disease, and predicting its course. Studying the dysfunction of the LC-norepinephrine system, involved in the pathogenesis of various neurological diseases, may ultimately form the basis for the development of new treatment methods based on the pharmacological elevation of norepinephrine levels. In this review, we will attempt to highlight the key points regarding the structure and function of the Locus Coeruleus, as well as outline the main directions and prospects for its study.

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression.

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here, we combine RNA sequencing with selective pharmacological, chemogenetic, and optogenetic manipulations to isolate the contribution of the locus coeruleus-noradrenaline (LC-NA) system to the acute stress response in mice. We reveal that NA release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, and independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC-mediated hippocampal function and offer new molecular targets for understanding how NA impacts brain function in health and disease.

Evidence for Locus Coeruleus–Norepinephrine System Abnormality in Military Posttraumatic Stress Disorder Revealed by Neuromelanin-Sensitive Magnetic Resonance Imaging

BackgroundThe complex neurobiology of posttraumatic stress disorder (PTSD) calls for the characterization of specific disruptions in brain functions that require targeted treatment. One such alteration could be an overactive locus coeruleus (LC)–norepinephrine system, which may be linked to hyperarousal symptoms, a characteristic and burdensome aspect of the disorder. MethodsStudy participants were Canadian Armed Forces veterans with PTSD related to deployment to combat zones (n = 34) and age- and sex-matched healthy control participants (n = 32). Clinical measures included the Clinician-Administered PTSD Scale for DSM-5, and neuroimaging measures included a neuromelanin-sensitive magnetic resonance imaging scan to measure the LC signal. Robust linear regression analyses related the LC signal to clinical measures. ResultsCompared with control participants, the LC signal was significantly elevated in the PTSD group (t62 = 2.64, p = .010), and this group difference was most pronounced in the caudal LC (t56 = 2.70, Cohen’s d = 0.72). The caudal LC signal was also positively correlated with the severity of Clinician-Administered PTSD Scale for DSM-5 hyperarousal symptoms in the PTSD group (t26 = 2.16, p = .040). ConclusionsThese findings are consistent with a growing body of evidence indicative of elevated LC-norepinephrine system function in PTSD. Furthermore, they indicate the promise of neuromelanin-sensitive magnetic resonance imaging as a noninvasive method to probe the LC-norepinephrine system that has the potential to support subtyping and treatment of PTSD or other neuropsychiatric conditions.

Dysregulated noradrenergic response is associated with symptom severity in individuals with schizophrenia.

The locus coeruleus-noradrenaline (LC-NA) system is involved in a wide range of cognitive functions and may be altered in schizophrenia. A non-invasive method to indirectly measure LC activity is task-evoked pupillary response. Individuals with schizophrenia present reduced pupil dilation compared to healthy subjects, particularly when task demand increases. However, the extent to which alteration in LC activity contributes to schizophrenia symptomatology remains largely unexplored. We aimed to investigate the association between symptomatology, cognition, and noradrenergic response in individuals with schizophrenia. We assessed task-evoked pupil dilation during a pro- and antisaccade task in 23 individuals with schizophrenia and 28 healthy subjects. Both groups showed similar preparatory pupil dilation during prosaccade trials, but individuals with schizophrenia showed significantly lower pupil dilation compared to healthy subjects in antisaccade trials. Importantly, reduced preparatory pupil dilation for antisaccade trials was associated with worse general symptomatology in individuals with schizophrenia. Our findings suggest that changes in LC-NA activity - measured by task-evoked pupil dilation - when task demand increases is associated with schizophrenia symptoms. Interventions targeting the modulation of noradrenergic responses may be suitable candidates to reduce schizophrenia symptomatology.

Linking tonic and phasic pupil responses to P300 amplitude in an emotional face-word Stroop task.

The locus coeruleus-norepinephrine (LC-NE) system, which regulates arousal levels, is important for cognitive control, including emotional conflict resolution. Additionally, the LC-NE system is implicated in P300 generation. If the P300 is mediated by the LC-NE system, and considering the established correlations between LC activity and pupil dilation, P300 amplitude should correlate with task-evoked (phasic) pupil dilation on a trial-by-trial basis. However, prior studies, predominantly utilizing oddball-type paradigms, have not demonstrated correlations between concurrently recorded task-evoked pupil dilation and P300 responses. Using a recently developed emotional face-word Stroop task that links pupil dilation to the LC-NE system, here, we examined both intra- and inter-individual correlations between task-evoked pupil dilation and P300 amplitude. We found that lower accuracy, slower reaction times, and larger task-evoked pupil dilation were obtained in the incongruent compared to the congruent condition. Furthermore, we observed intra-individual correlations between task-evoked pupil dilation and P300 amplitude, with larger pupil dilation correlating with a greater P300 amplitude. In contrast, pupil dilation did not exhibit consistent correlations with N450 and N170 amplitudes. Baseline (tonic) pupil size also showed correlations with P300 and N170 amplitudes, with smaller pupil size corresponding to larger amplitude. Moreover, inter-individual differences in task-evoked pupil dilation between the congruent and incongruent conditions correlated with differences in reaction time and P300 amplitude, though these effects only approached significance. To summarize, our study provides evidence for a connection between task-evoked pupil dilation and P300 amplitude at the single-trial level, suggesting the involvement of the LC-NE system in P300 generation.

Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats.

Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10mg/kg, i. p) or saline was administered to anesthetized WKY rats before in vivo electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.

Partial or Complete Loss of Norepinephrine Differentially Alters Contextual Fear and Catecholamine Release Dynamics in Hippocampal CA1

BackgroundContextual fear learning is heavily dependent on the hippocampus. Despite evidence that catecholamines contribute to contextual encoding and memory retrieval, the precise temporal dynamics of their release in the hippocampus during behavior is unknown. In addition, new animal models are required to probe the effects of altered catecholamine synthesis on release dynamics and contextual learning. MethodsWe generated 2 new mouse models of altered locus coeruleus–norepinephrine (NE) synthesis and utilized them together with GRABNE and GRABDA sensors and in vivo fiber photometry to investigate NE and dopamine (DA) release dynamics in the dorsal hippocampal CA1 during contextual fear conditioning. ResultsAversive foot shock increased both NE and DA release in the dorsal CA1, while freezing behavior associated with recall of fear memory was accompanied by decreased release. Moreover, we found that freezing at the recent time point was sensitive to both partial and complete loss of locus coeruleus–NE synthesis throughout prenatal and postnatal development, similar to previous observations of mice with global loss of NE synthesis beginning postnatally. In contrast, freezing at the remote time point was compromised only by complete loss of locus coeruleus–NE synthesis beginning prenatally. ConclusionsOverall, these findings provide novel insights into the role of NE in contextual fear and the precise temporal dynamics of both NE and DA during freezing behavior and highlight complex relationships between genotype, sex, and NE signaling.

Elevated and accelerated: Locus coeruleus activity and visual search abilities in autistic children

BackgroundAutistic individuals excel at visual search, however, the neural mechanism(s) underlying this advantage remain unclear. The locus coeruleus-norepinephrine (LC-NE) system, which plays a critical role in sensory perception and selective attention, has been shown to function in a persistently elevated state in individuals on the spectrum. However, the relationship between elevated tonic LC-NE activity and accelerated search in autism has not been explored. ObjectiveTo examine the relationship between visual search abilities and resting pupil diameter (an indirect measure of tonic LC-NE activation) in autistic and neurotypical children. MethodsParticipants were 24 school-aged autistic children and 24 age- and IQ-matched neurotypical children aged 8–15 years. Children completed two tasks: a resting eye-tracking task and a visual search paradigm. For the resting eye-tracking task, pupil diameter was monitored while participants fixated a central crosshair. For the visual search paradigm, participants were instructed to find the target (vertical line) embedded within an array of tilted (10°) distractor lines. The target was present on 50% of trials, and displayed within set sizes of 18, 24, and 36 items. ResultsConsistent with previous studies, autistic children had significantly larger resting pupil size and searched faster and more efficiently compared to their neurotypical peers. Eye-tracking findings revealed that accelerated search was associated with fewer, not shorter, fixations in the autism group. Autistic children also showed reduced leftward search bias. Larger resting pupil size, indicative of increased tonic activation of the LC-NE system, was associated with greater search efficiency, longer fixation durations, and reduced leftward bias. Finally, within both groups reduced leftward bias was associated with increased autism symptomatology. DiscussionTogether, these findings add to the existing body of research highlighting superior search in autism, suggest that elevated tonic LC-NE activity may contribute to more efficient search, and link non-social visual-spatial processing strengths to autism symptoms.

Combined α2- and D2-receptor blockade activates noradrenergic and dopaminergic neurons, but extracellular dopamine in the prefrontal cortex is determined by uptake and release from noradrenergic terminals.

Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α2-adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D2-receptor antagonists. In anesthetized male rats, we investigated how the blockade of α2- and D2-receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis. When administered alone, atipamezole activated LC noradrenaline but not VTA dopamine cell firing. Combined with raclopride, atipamezole activated dopamine cell firing above the level produced by raclopride. Atipamezole increased extracellular dopamine to the same level, whether administered alone or combined with raclopride. In the presence of the noradrenaline transporter (NET) inhibitor, atipamezole combined with raclopride increased extracellular dopamine beyond the level produced by either compound administered alone. The results suggest that a) the D2-autoreceptor blockade is required for LC noradrenaline to activate VTA cell firing; b) the level of dopamine released from dopaminergic terminals is determined by NET; c) the elevation of extracellular dopamine levels in the mPFC is the resultant of dopamine uptake and release from noradrenergic terminals, independent of dopaminergic cell firing and release; and d) LC noradrenergic neurons are an important target for treatments to improve the prefrontal deficit of dopamine in neuropsychiatric pathologies.

Isradipine, an L-type calcium channel inhibitor, attenuates cue-associated methamphetamine-seeking in mice

Methamphetamine (meth) is an addictive psychostimulant and there are no FDA-approved treatment options for patients suffering from meth use disorders. In addition to being addictive, meth is also neurotoxic and chronic administration results in degeneration of substantia nigra pars compacta (SNc) dopamine and locus coeruleus (LC) norepinephrine neurons in mice. Optimal treatment strategies for meth use disorders would attenuate maladaptive meth-seeking behavior as well as provide neuroprotection. The L-type calcium channel inhibitor isradipine and the monoamine oxidase (MAO) inhibitor rasagiline both prevent chronic meth-induced SNc and LC degeneration but effects on meth-seeking are unknown. To test whether these clinically available compounds can mitigate meth-seeking, mice were implanted with chronic indwelling jugular vein catheters and allowed to self-administer meth (0.1 mg/kg/infusion) for 10 consecutive days (2-hrs/day) on a fixed ratio (FR) 1 schedule of reinforcement with meth infusions paired to a cue light. One day after the last self-administration session mice were tested for cue-associated meth-seeking behavior wherein the meth-associated cue light was contingently presented but meth reinforcement withheld. Isradipine (3 mg/kg) attenuated cue-associated meth-seeking in both male and female mice. In contrast, rasagiline (1 mg/kg) had no effect on seeking in either sex. These results suggest that isradipine may have the potential to serve as a dual-purpose pharmacotherapy for meth use disorders by attenuating seeking behavior and providing neuroprotection.

Electroacupuncture attenuates ketamine-induced neuronal injury in the locus coeruleus of rats through modulation of the CAMK II/CREB pathway

BackgroundKetamine, despite its efficacy in treating depression, raises concerns regarding safety due to potential abuse, cognitive impairment, and bladder toxicity. Ketamine can affect the locus coeruleus (LC) norepinephrine and attention networks. This study explored the protective effects of electroacupuncture (EA) on the LC of rats exposed to repeated administration of ketamine while investigating the potential role of the Calcium CaM-dependent protein kinase II (CAMK II)/ cAMP response element binding protein (CREB) pathway in mediating EA's impact on ketamine-induced neuronal injury in LC. MethodsRats were repeatedly injected intraperitoneally with ketamine hydrochloride (50 mg/kg) once daily for seven days. Subsequently, EA was performed at the acupoints “Zusanli” (ST36) and “Sanyinjiao” (SP-6) once daily following ketamine administration. The Morris water maze test was employed to assess behavioral changes in the rats. Neuronal injury was examined using Nissl staining, and the expression of CAMK II, CREB, and phospho-CREB (p-CREB) was evaluated through immunohistochemistry and western blotting. ResultsEA mitigated the cognitive and exploratory impairments and attenuated neuronal injury in the LC induced by repeated administration of ketamine. The expression of CAMK II and p-CREB proteins in the LC increased following 7 days of ketamine administration. However, EA treatment led to a downregulation of CAMK II and p-CREB expression. ConclusionRepeated administration of ketamine in male rats can lead to neuronal injury and neurobehavioral dysfunction. However, EA was found to ameliorate neurodegeneration in the LC and enhance neurobehavioral symptoms. This therapeutic effect of EA may be attributed to its modulation of the CAMKII/CREB pathway, thereby mitigating the aforementioned adverse effects.

The intrinsic locus coeruleus functional connectivity change in older adults with subjective memory complaint

AbstractBackgroundThe locus coeruleus (LC) is critical for late‐lift cognitive processing by modulating the norepinephrine system, which is often the first place Alzheimer’s pathology appears. Previous researches have identified that the LC was associated with late‐life cognitive ability. This study aims to investigate whether the intrinsic LC functional connectivity (LC‐FC) is altered in older adults with subjective memory complaints (SMC).MethodA total of 199 participants were selected from the Alzheimer’s Disease Neuroimaging Initiative database, including 95 SMC older adults and 104 cognitively normal individuals (CN). Bilateral LCs were selected to construct the LC functional connectivity based on resting‐state fMRI data. The cognitive function was evaluated by using the ADNI composite executive function (ADNI‐EF) and memory (ADNI‐Mem) scores at baseline and 24 months later. Data were analyzed using the voxel‐wise two‐sample t‐test and partial correlation analysis, we utilized permutation testing with threshold‐free cluster enhancement (TFCE) to multiple comparison correction.ResultThere were no significant differences in demographic information and cognitive function between the two groups. In the left LC‐FC network, compared to CN group, the SMC group showed increased LC‐FC in the left salient network (anterior insula, and frontal operculum cortex), hippocampus, and right default mode network(DMN, inferior temporal gyrus), while they had decreased LC‐FC in left inferior temporal gyrus. No significant difference in the right LC‐FC network between the two groups. The altered FC between left LC and right inferior temporal gyrus (DMN) was significantly associated with ADNI‐EF performance in the SMC group, controlled the effect of age, gender, and APOE genotype (r = ‐0.404, p = 0.002), and the FC between LC and right ITG was also associated with executive function performance after 24 months in SMC group.ConclusionThe present study manifested the abnormal intrinsic LC functional connectivity in elder adults with SMC. In addition, the FC between LC and default mode network was associated with the executive function performance in SMC. These findings might suggest an LC norepinephrine system compensatory mechanism in cognitive processing in older individuals with SMC.

Pupillary response is associated with the reset and switching of functional brain networks during salience processing.

The interface between processing internal goals and salient events in the environment involves various top-down processes. Previous studies have identified multiple brain areas for salience processing, including the salience network (SN), dorsal attention network, and the locus coeruleus-norepinephrine (LC-NE) system. However, interactions among these systems in salience processing remain unclear. Here, we simultaneously recorded pupillometry, EEG, and fMRI during an auditory oddball paradigm. The analyses of EEG and fMRI data uncovered spatiotemporally organized target-associated neural correlates. By modeling the target-modulated effective connectivity, we found that the target-evoked pupillary response is associated with the network directional couplings from late to early subsystems in the trial, as well as the network switching initiated by the SN. These findings indicate that the SN might cooperate with the pupil-indexed LC-NE system in the reset and switching of cortical networks, and shed light on their implications in various cognitive processes and neurological diseases.

Convergence of Pro-Stress and Pro-Inflammatory Signaling in the Central Noradrenergic System: Implications for Mood and Anxiety Disorders

Mood and anxiety disorders are heterogeneous psychiatric diagnoses affecting millions. While the disease etiology is complex, various risk factors have been identified, such as stress. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive processes and behavior. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic–pituitary–adrenal (HPA) axis. In addition to its effects on the HPA axis, stress activates the locus coeruleus (LC), a bilateral brainstem nucleus that projects broadly throughout the central nervous system and releases the catecholamine transmitter norepinephrine (NE). The combined activities of the LC–NE system and HPA axis work synergistically to produce timely adaptive physiological and behavioral responses to stress. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of several neuropsychiatric disease states. Notably, recent studies have also implicated neuroinflammation mediated by microglia as a risk factor in mood and anxiety disorders. Despite their combined association with mood and anxiety disorders, the potential links between stress and inflammation, and possible interactions between their respective signaling cascades, have not been well-explored. This brief review aims to summarize how LC is uniquely positioned to respond to both pro-stress and pro-inflammatory cues, and how their convergence in this site may contribute to the development of mood and anxiety disorders.

Testing locus coeruleus-norepinephrine accounts of working memory, attention control, and fluid intelligence.

The current set of studies examined the relationship among workingmemory capacity, attention control, fluid intelligence, and pupillary correlates of tonic arousal regulation and phasic responsiveness in a combined sample of more than 1,000 participants in two different age ranges (young adults and adolescents). Each study was designed to test predictions made by two recent theories regarding the role of the locus coeruleus-norepinephrine (LC-NE) system in determining individual differences in cognitive ability. The first theory, proposed by Unsworth and Robison (2017a), posits two important individual differences: the moment-to-moment regulation of tonic arousal, and the phasic responsiveness of the system to goal-relevant stimuli. The second theory, proposed by Tsukahara and Engle (2021a), argues that people with higher cognitive abilities have greater functional connectivity between the LC-NE system and cortical networks at rest. These two theories are not mutually exclusive, but they make different predictions. Overall, we found no evidence consistent with a resting-state theory. However, phasic responsiveness was consistently correlated with working memory capacity, attention control, and fluid intelligence, supporting a prediction made by Unsworth and Robison (2017a). Tonic arousal regulation was not correlated with working memory or fluid intelligence and was inconsistently correlated with attention control, which offers only partial support for Unsworth and Robison's (2017a) second prediction.

Baseline pupil diameter does not correlate with fluid intelligence.

There has been debate regarding the correlation between baseline/resting state measures of pupil diameter and cognitive abilities such as working memory capacity and fluid intelligence. A positive correlation between baseline pupil diameter and cognitive ability has been cited as evidence for a role of the locus coeruleus-norepinephrine (LC-NE) and its functional connection with cortical networks as a reason for individual differences in fluid intelligence (Tsukahara & Engle, Proceedings of the National Academy of Sciences, 118(46), e2110630118, 2021a). Several recent attempts to replicate this correlation have failed. The current studies make another attempt and find substantial evidence against a positive correlation between pupil diameter and intelligence. Given the data from the current studies in combination with other recent failures to replicate, we conclude that individual differences in baseline pupil diameter should not be used as evidence for a role of the LC-NE system in goal-directed cognitive activity.

Immediate effects and duration of a short and single application of transcutaneous auricular vagus nerve stimulation on P300 event related potential.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neuromodulatory technique that stimulates the auricular branch of the vagus nerve. The modulation of the locus coeruleus-norepinephrine (LC-NE) network is one of the potential working mechanisms of this method. Our aims were 1-to investigate if short and single applications of taVNS can modulate the P300 cognitive event-related potential (ERP) as an indirect marker that reflects NE brain activation under control of the LC, and 2-to evaluate the duration of these changes. 20 healthy volunteers executed an auditory oddball paradigm to obtain P300 and reaction time (RT) values. Then a 7 min active or sham taVNS period was initiated and simultaneously a new P300 paradigm was performed. We successively repeated the paradigm on 4 occasions with different time intervals up to 56 min after the stimulation onset. During active taVNS an immediate and significant effect of increasing the amplitude and reducing the latency of P300, as well as a shortening in the RT was observed. This effect was prolonged in time up to 28 min. The values then returned to pre-stimulation levels. Sham stimulation did not generate changes. Our results, demonstrate differential facilitating effects in a concrete time window after taVNS. Literature about the modulatory effect of taVNS over P300 ERP shows a wide spread of results. There is not a standardized system for taVNS and currently the great heterogeneity of stimulation approaches concerning targets and parameters, make it difficult to obtain conclusions about this relationship. Our study was designed optimizing several stimulation settings, such as a customized earbud stimulator, enlarged stimulating surface, simultaneous stimulation over the cymba and cavum conchae, a Delayed Biphasic Pulse Burst and current controlled stimulation that adjusted the output voltage and guaranteed the administration of a preset electrical dose. Under our stimulation conditions, targeting vagal nerve fibers via taVNS modulates the P300 in healthy participants. The optimal settings of modulatory function of taVNS on P300, and their interdependency is insufficiently studied in the literature, but our data provides several easily optimizable parameters, that will produce more robust results in future.

Sensory salience processing moderates attenuated gazes on faces in autism spectrum disorder: a case–control study

BackgroundAttenuated social attention is a key marker of autism spectrum disorder (ASD). Recent neuroimaging findings also emphasize an altered processing of sensory salience in ASD. The locus coeruleus–norepinephrine system (LC-NE) has been established as a modulator of this sensory salience processing (SSP). We tested the hypothesis that altered LC-NE functioning contributes to different SSP and results in diverging social attention in ASD.MethodsWe analyzed the baseline eye-tracking data of the EU-AIMS Longitudinal European Autism Project (LEAP) for subgroups of autistic participants (n = 166, age = 6–30 years, IQ = 61–138, gender [female/male] = 41/125) or neurotypical development (TD; n = 166, age = 6–30 years, IQ = 63–138, gender [female/male] = 49/117) that were matched for demographic variables and data quality. Participants watched brief movie scenes (k = 85) depicting humans in social situations (human) or without humans (non-human). SSP was estimated by gazes on physical and motion salience and a corresponding pupillary response that indexes phasic activity of the LC-NE. Social attention is estimated by gazes on faces via manual areas of interest definition. SSP is compared between groups and related to social attention by linear mixed models that consider temporal dynamics within scenes. Models are controlled for comorbid psychopathology, gaze behavior, and luminance.ResultsWe found no group differences in gazes on salience, whereas pupillary responses were associated with altered gazes on physical and motion salience. In ASD compared to TD, we observed pupillary responses that were higher for non-human scenes and lower for human scenes. In ASD, we observed lower gazes on faces across the duration of the scenes. Crucially, this different social attention was influenced by gazes on physical salience and moderated by pupillary responses.LimitationsThe naturalistic study design precluded experimental manipulations and stimulus control, while effect sizes were small to moderate. Covariate effects of age and IQ indicate that the findings differ between age and developmental subgroups.ConclusionsPupillary responses as a proxy of LC-NE phasic activity during visual attention are suggested to modulate sensory salience processing and contribute to attenuated social attention in ASD.