Locus Coeruleus-norepinephrine System Research Articles

Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice

BackgroundThe role of microglia in Alzheimer’s disease (AD) pathogenesis is becoming increasingly important, as activation of these cell types likely contributes to both pathological and protective processes associated with all phases of the disease. During early AD pathogenesis, one of the first areas of degeneration is the locus coeruleus (LC), which provides broad innervation of the central nervous system and facilitates norepinephrine (NE) transmission. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging.MethodsIn this study, we evaluated the dynamic changes of neuroinflammation and neurodegeneration in the LC-NE system in the brain and spinal cord of APP/PS1 mice and aged WT mice using immunofluorescence and ELISA.ResultsOur results demonstrated increased expression of inflammatory cytokines and microglial activation observed in the cortex, hippocampus, and spinal cord of APP/PS1 compared to WT mice. LC-NE neuron and fiber loss as well as reduced norepinephrine transporter (NET) expression was more evident in APP/PS1 mice, although NE levels were similar between 12-month-old APP/PS1 and WT mice. Notably, the degree of microglial activation, LC-NE nerve fiber loss, and NET reduction in the brain and spinal cord were more severe in 12-month-old APP/PS1 compared to 12- and 24-month-old WT mice.ConclusionThese results suggest that elevated neuroinflammation and microglial activation in the brain and spinal cord of APP/PS1 mice correlate with significant degeneration of the LC-NE system.

Immediate extinction deficit: Causes and neurobiological mechanisms

<p id="C2">Extinction training that occurs shortly after fear conditioning fails to yield long-term extinction memory, a phenomenon that is known as the immediate extinction deficit (IED). The IED may be linked to levels of stress at the onset of extinction training and event segmentation. Under high levels of stress, the consolidation of extinction memory is impaired, resulting in the IED. Under moderate or low levels of stress, immediate extinction would be effective but susceptible to event segmentation. The neurobiological mechanisms of IED may involve stress-induced activation of the locus coeruleus norepinephrine system, which leads to hyperexcitability of the basolateral amygdala and the subsequent inhibition of activity of the medial prefrontal cortex (i.e., a region that plays a central role in fear extinction) through synaptic projections. Future studies should consider long-term outcomes of the IED and optimization of the clinical application of immediate extinction.

Inter- and intra-individual coupling between pupillary, electrophysiological, and behavioral responses in a visual oddball task.

Although the P3b component of the event-related brain potential is one of the most widely studied components, its underlying generators are not currently well understood. Recent theories have suggested that the P3b is triggered by phasic activation of the locus-coeruleus norepinephrine (LC-NE) system, an important control center implicated in facilitating optimal task-relevant behavior. Previous research has reported strong correlations between pupil dilation and LC activity, suggesting that pupil diameter is a useful indicator for ongoing LC-NE activity. Given the strong relationship between LC activity and pupil dilation, if the P3b is driven by phasic LC activity, there should be a robust trial-to-trial relationship with the phasic pupillary dilation response (PDR). However, previous work examining relationships between concurrently recorded pupillary and P3b responses has not supported this. One possibility is that the relationship between the measures might be carried primarily by either inter-individual (i.e., between-participant) or intra-individual (i.e., within-participant) contributions to coupling, and prior work has not systematically delineated these relationships. Doing so in the current study, we do not find evidence for either inter-individual or intra-individual relationships between the PDR and P3b responses. However, baseline pupil dilation did predict the P3b. Interestingly, both the PDR and P3b independently predicted inter-individual and intra-individual variability in decision response time. Implications for the LC-P3b hypothesis are discussed.

Factors Influencing Saccadic Reaction Time: Effect of Task Modality, Stimulus Saliency, Spatial Congruency of Stimuli, and Pupil Size.

It is often assumed that the reaction time of a saccade toward visual and/or auditory stimuli reflects the sensitivities of our oculomotor-orienting system to stimulus saliency. Endogenous factors, as well as stimulus-related factors, would also affect the saccadic reaction time (SRT). However, it was not clear how these factors interact and to what extent visual and auditory-targeting saccades are accounted for by common mechanisms. The present study examined the effect of, and the interaction between, stimulus saliency and audiovisual spatial congruency on the SRT for visual- and for auditory-target conditions. We also analyzed pre-target pupil size to examine the relationship between saccade preparation and pupil size. Pupil size is considered to reflect arousal states coupling with locus-coeruleus (LC) activity during a cognitive task. The main findings were that (1) the pattern of the examined effects on the SRT varied between visual- and auditory-auditory target conditions, (2) the effect of stimulus saliency was significant for the visual-target condition, but not significant for the auditory-target condition, (3) Pupil velocity, not absolute pupil size, was sensitive to task set (i.e., visual-targeting saccade vs. auditory-targeting saccade), and (4) there was a significant correlation between the pre-saccade absolute pupil size and the SRTs for the visual-target condition but not for the auditory-target condition. The discrepancy between target modalities for the effect of pupil velocity and between the absolute pupil size and pupil velocity for the correlation with SRT may imply that the pupil effect for the visual-target condition was caused by a modality-specific link between pupil size modulation and the SC rather than by the LC-NE (locus coeruleus-norepinephrine) system. These results support the idea that different threshold mechanisms in the SC may be involved in the initiation of saccades toward visual and auditory targets.

Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons.

The ability of animals to retrieve memories stored in response to the environment is essential for behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. Here, we developed a novel chemogenetic activation strategy exploiting insect olfactory ionotropic receptors (IRs), termed "IR-mediated neuronal activation," and used it for selective stimulation of NE neurons in the locus coeruleus (LC). Drosophila melanogaster IR84a and IR8a subunits were expressed in LC NE neurons in transgenic mice. Application of phenylacetic acid (a specific ligand for the IR84a/IR8a complex) at appropriate doses induced excitatory responses of NE neurons expressing the receptors in both slice preparations and in vivo electrophysiological conditions, resulting in a marked increase of NE release in the LC nerve terminal regions (male and female). Ligand-induced activation of LC NE neurons enhanced the retrieval process of conditioned taste aversion without affecting taste sensitivity, general arousal state, and locomotor activity. This enhancing effect on taste memory retrieval was mediated, in part, through α1- and β-adrenergic receptors in the basolateral nucleus of the amygdala (BLA; male). Pharmacological inhibition of LC NE neurons confirmed the facilitative role of these neurons in memory retrieval via adrenergic receptors in the BLA (male). Our findings indicate that the LC NE system, through projections to the BLA, controls the retrieval process of taste associative memory.SIGNIFICANCE STATEMENT Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation, but the role of the NE system in memory retrieval remains unclear. We developed a chemogenetic activation system based on insect olfactory ionotropic receptors and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons enhanced the retrieval of conditioned taste aversion, which was mediated, in part, through adrenoceptors in the basolateral amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdala pathway plays an important role in the recall of taste associative memory.

Drowsiness or mind-wandering? Fluctuations in ocular parameters during attentional lapses

Two independent lines of evidence suggest that drowsiness and mind-wandering share common neurocognitive processes indexed by ocular parameters (e.g., eyeblink frequency and pupil dynamics). Mind-wandering and drowsiness frequently co-occur, however, such that it remains unclear whether observed oculometric variations are related to mind-wandering, drowsiness, or a mix of both. To address this issue, we assessed fluctuations in mind-wandering and sleepiness during a sustained attention task while ocular parameters were recorded. Results showed that oculometric variations during mind-wandering were fully explained by increased sleepiness. However, mind-wandering and sleepiness had additive deleterious effects on performance that were not fully explained by ocular parameters. These findings suggest that oculometric variations during task performance reflect increased drowsiness rather than processes specifically involved in mind-wandering, and that the neurocognitive processes indexed by oculometric parameters (e.g., regulatory processes of the locus coeruleus norepinephrine system) do not fully explain how mind-wandering and sleepiness cause attentional lapses.

Transient Effects Of Acute Aerobic Physical Activity On The Pupillary Response And Inhibitory Control

PURPOSE: Acute bouts of aerobic exercise have been found to transiently improve executive function and its neural underpinnings. Moderate activation of the locus coeruleus-norepinephrine (LC-NE) system increases attention toward goal-directed behaviors, yet non-optimal activation may promote distractibility. Pupillary responses are believed to be a marker of the LC-NE system, and tasks requiring greater amounts of inhibitory control modulate baseline (tonic) and task-evoked (phasic) pupil dilation. The purpose of this study was to examine the pupillary response as a LC-NE biomarker to understand the mechanisms underlying the effect of acute exercise on inhibitory control. METHODS: Twenty-six participants (19.7 ± 1.8 yr, 17 female) performed 20 min interventions (seated rest/moderate intensity exercise) followed by Simon and modified flanker tasks. Participants’ eyes were tracked during the tasks using a tabletop eye imaging camera at a 500hz sampling rate. RESULTS: RM-ANOVAs assessed intervention and inhibitory control (congruency/compatibility) effects on behavior and pupillary outcomes. Incongruent flanker trials resulted in longer reaction times and lower response accuracy, p’s ≤ 0.001. While incompatible Simon trials also resulted in longer reaction times, p = 0.01, there was no difference in response accuracy across compatibility conditions, p = 0.11. Peak phasic pupil dilation was also greater in incongruent flanker trials as well as incompatible Simon trials, p=0.003. While behavior and phasic pupil dilation in both tasks did not differ across the exercise vs. rest interventions, p’s ≥ 0.18, Tonic pupil diameter was larger for the exercise intervention in the flanker task, p = 0.04, and at trend level in the Simon task , p = 0.09. CONCLUSION: The tonic pupillary response may be a sensitive biomarker for examining transient changes in LC-NE activity as a function of acute exercise bouts. Moderate intensity exercise did not significantly affect phasic pupillary response. These findings indicate that the pupillary response can be manipulated by aspects of inhibitory control and physical activity, which suggests it may be a sensitive biomarker for examining changes in LC-NE activity.

How do Stress and Craving Lead to Relapse in Opioid Use Disorder? Determining Sensitization Effects in the Locus Coeruleus Norepinephrine System in Humans

Craving and stress promote opioid reuse during opioid use disorder (OUD) treatment, but a complete understanding of this relationship is lacking. The locus coeruleus norepinephrine (LC-NE) system is a key preclinical pathway linking stress and craving to opioid reuse. The LC-NE can be imaged in humans using high-resolution neuromelanin-sensitive MRI, a noninvasive proxy of LC-NE function and integrity. Inter-individual differences in this measure may reveal sensitization of LC which contributes to stress and craving, leading to opioid reuse. Aims: 1) Examine within-person relationships between stress, craving, and opioid use patterns serially and longitudinally in OUD; 2) Test for moderation of these patterns by LC-NE neuromelanin (between-person).

Incentive motivation improves numerosity discrimination: Insights from pupillometry combined with drift-diffusion modelling

Recent studies show that training the approximate number system (ANS) holds promise for improving symbolic math abilities. Extending this line of research, the present study aims to shed light on incentive motivation of numerosity discrimination and the underlying mechanisms. Thirty-two young adults performed a novel incentivized dot comparison task, that we developed, to discern the larger of two numerosities. An EZ-diffusion model was applied to decompose motivational effects on component processes of perceptual decision-making. Furthermore, phasic pupil dilation served as an indicator of the involvement of the salience network. The results of improved accuracy and a higher information accumulation rate under the reward condition suggest that incentive motivation boosts the precision of the ANS. These novel findings extend earlier evidence on reward-related enhancements of perceptual discrimination to the domain of numerosity perception. In light of the Adaptive Gain Theory, we interpret the results in terms of two processes of gain modulation driven by the locus coeruleus-norepinephrine system. Specifically, the reward-induced increase in pupil dilation may reflect incentive modulation of (i) salience attention during reward anticipation towards incentivized stimuli to upregulate stimulus processing that results in a larger drift rate; and (ii) response caution that leads to an increased decision threshold.

The impact of novelty and emotion on attention-related neuronal and pupil responses in children

Focusing on relevant and ignoring irrelevant information is essential for many learning processes. The present study investigated attention-related brain activity and pupil dilation responses, evoked by task-irrelevant emotional novel sounds. In the framework of current theories about the relation between attention and the locus coeruleus-norepinephrine (LC-NE) system, we simultaneously registered event-related potentials (ERPs) in the EEG and changes in pupil diameter (PDR).Unexpected emotional negative and neutral environmental novel sounds were presented within a sequence of repeated standard sounds to 7–10-year-old children and to adults, while participants focused on a visual task.Novel sounds evoked distinctive ERP components, reflecting attention processes and a biphasic PDR in both age groups. Amplitudes of the novel-minus-standard ERPs were increased in children compared to adults, indicating immature neuronal basis of auditory attention in middle childhood. Emotional versus neutral novel sounds evoked increased responses in the ERPs and in the PDR in both age groups. This demonstrates the increased impact of emotional sounds on attention mechanisms and indicates an advanced level of emotional information processing in children. The similar pattern of novel-related PDR and ERPs is conforming to recent theories, emphasizing the role of the LC-NE system in attention processes adding a developmental perspective.

Delta phase reset predicts conflict-related changes in P3 amplitude and behavior

When multiple competing responses are activated, we respond more slowly than if only one response is activated (response conflict). Conflict-induced slowing is reduced for consecutive high-conflict stimuli, an effect known as conflict adaptation. Verguts and Notebaert’s (2009) adaptation by binding theory suggests this is due to Hebbian learning of cognitive control, potentiated by the response of the locus coeruleus norepinephrine (NE) system. Phasic activity of the NE system can potentially be measured non-invasively in humans by recording the P3 component of the event-related potential (ERP), and the P3 is sensitive to conflict adaptation. Bouret and Sara’s (2005) network reset theory suggests that phasic NE might functionally reset ongoing large-scale network activity, generating synchronous neural population activity like the P3. To examine the possibility that network reset contributes to conflict effects in the P3, we recorded high-density EEG data while subjects performed a flanker task. As expected, conflict and conflict adaptation modulated P3 amplitudes. Brain-behavior correlation analyses indicated that activity during the rise of the P3 was related to RT and predicted RT differences due to conflict. More importantly, phase of delta oscillations not only predicted reaction time differences between low-conflict and high-conflict conditions, but delta phase reset also predicted the amplitude of the P3. Delta oscillations exhibited dominant peaks both pre and post-stimulus, and delta at stimulus onset predicted the post-stimulus ERP, in particular the N2 and P3. This result bridges human EEG with basic mechanisms suggested by computational neural models and invasive patient recordings, namely that salient cognitive events might reset ongoing oscillations leading to the generation of the phase-locked evoked potential. We conclude that partial phase reset is a cortical mechanism involved in monitoring the environment for unexpected events, and this response contributes to conflict effects in the ERP. These results are in line with theories that phasic NE release might reset ongoing cortical activity, leading to the generation of ERP components like the P3.

The role of the locus coeruleus in the generation of pathological anxiety.

This review aims to synthesise a large pre-clinical and clinical literature related to a hypothesised role of the locus coeruleus norepinephrine system in responses to acute and chronic threat, as well as the emergence of pathological anxiety. The locus coeruleus has widespread norepinephrine projections throughout the central nervous system, which act to globally modulate arousal states and adaptive behavior, crucially positioned to play a significant role in modulating both ascending visceral and descending cortical neurocognitive information. In response to threat or a stressor, the locus coeruleus–norepinephrine system globally modulates arousal, alerting and orienting functions and can have a powerful effect on the regulation of multiple memory systems. Chronic stress leads to amplification of locus coeruleus reactivity to subsequent stressors, which is coupled with the emergence of pathological anxiety-like behaviors in rodents. While direct in vivo evidence for locus coeruleus dysfunction in humans with pathological anxiety remains limited, recent advances in high-resolution 7-T magnetic resonance imaging and computational modeling approaches are starting to provide new insights into locus coeruleus characteristics.

Pupil dilation during visuospatial orienting differentiates between autism spectrum disorder and attention-deficit/hyperactivity disorder.

Previous research demonstrated atypical attention in children with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Regarding visual orienting, findings suggest a differential impairment: Atypical orienting to relatively unexpected targets in ASD, and atypical processing of alerting cues in ADHD. The locus coeruleus-norepinephrine (LC-NE) system plays an important role in exploiting alerting cues to increase attention and task performance. The present study's aim was to examine differential subcortical processes underlying visual orienting in ASD and ADHD with pupil dilation (PD) as index of LC activity. Pupil dilation (PD) progression metrics during visual orienting were calculated for task-evoked PD locked to cue, stimulus onset, and behavioral response. Group differences in PD and reaction time (RT) were compared between children with ASDwithout ADHD (ASD-) (N=18), ADHDwithout ASD (ADHD-) (N=28), both disorders(ASD+ADHD) (N=14), and typically developing children(TD) (N=31) using linear mixed models (LMM). To further explore the modulatory role of the LC-NE system group differences in theeffect of task-evoked PD metrics on RT were examined exploratively. ASD (+ADHD) showed slower orienting responses to relatively unexpected spatial target stimuli as compared to TD, which was accompanied by higher PD amplitudes relative to ADHD- and TD. In ADHD-, shorter cue-evoked PD latencies relative to ASD-, ASD+ADHD, and TD were found. Group differences in the effect of cue- and stimulus-evoked PD amplitudes on RT were found in ASD- relative to TD. Study findings provide new evidence for a specific role of the LC-NE system in impaired reflexive orienting responses in ASD, and atypical visual processing of alerting cues in ADHD.

Computational noise in reward-guided learning drives behavioral variability in volatile environments.

When learning the value of actions in volatile environments, humans often make seemingly irrational decisions that fail to maximize expected value. We reasoned that these 'non-greedy' decisions, instead of reflecting information seeking during choice, may be caused by computational noise in the learning of action values. Here using reinforcement learning models of behavior and multimodal neurophysiological data, we show that the majority of non-greedy decisions stem from this learning noise. The trial-to-trial variability of sequential learning steps and their impact on behavior could be predicted both by blood oxygen level-dependent responses to obtained rewards in the dorsal anterior cingulate cortex and by phasic pupillary dilation, suggestive of neuromodulatory fluctuations driven by the locus coeruleus-norepinephrine system. Together, these findings indicate that most behavioral variability, rather than reflecting human exploration, is due to the limited computational precision of reward-guided learning.

Rostral locus coeruleus integrity is associated with better memory performance in older adults.

For decades, research into memory decline in human cognitive ageing has focused on neocortical regions, the hippocampus and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in quantification of LC integrity have hindered the study of LC-cognition associations in humans. Using high-resolution, neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in both younger (n = 66) and older adults (n = 228). Moreover, we observed functionally relevant age differences confined to rostral LC. Older adults with a more 'youth-like' rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in ageing and highlight the role of the LC norepinephrine system in the decline of cognition.

Pupil reactivity to emotional faces among convicted violent offenders: The role of psychopathic traits.

Psychopathy is characteristically associated with impairments in recognizing others' facial expressions of emotion, and there is some evidence that these difficulties are specific to the callousness features of the disorder. However, it remains unclear whether these difficulties are accompanied by reductions in autonomic reactivity when viewing others' emotional expressions, and whether these impairments are particular to expressions showing another's distress or are more pervasive across different emotional expressions. In this study, 73 adult male prisoners with histories of serious sexual or violent offenses-who ranged across the psychopathy continuum-completed a facial emotion recognition task. For the first time in a convicted offender sample, we used pupillometry techniques to measure changes in the pupil dilation response, a measure of sympathetic autonomic arousal to affective stimuli. We found that the callousness features of psychopathy were related to impaired recognition of fearful faces. Strikingly, we also showed that increasing callousness was associated with a reduction in the pupil dilation response and that this was pervasive across different emotional expressions. Our results highlight a potential role of the locus coeruleus-noradrenaline system in the pathophysiology of psychopathy and demonstrate the potential of the pupillary response as a technique for understanding attention-emotion interactions in psychopathy. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Pupil Dilation Progression Modulates Aberrant Social Cognition in Autism Spectrum Disorder.

Progression of pupil dilation (PD) in response to visual stimuli may indicate distinct internal processes. No study has been performed on PD progression during a social cognition task. Here, we describe PD progression during the Movie for the Assessment of Social Cognition (MASC) test in n = 23 adolescents with Autism Spectrum Disorder (ASD) and n = 24 age, IQ and sex-matched neurotypical controls (NTC). The MASC consists of 43 video sequences depicting human social interactions, each followed by a multiple-choice question concerning characters' mental states. PD progression data were extracted by eye tracking and controlled for fixation behavior. Segmenting PD progression during video sequences by principal component analysis, three sequential PD components were unveiled. In ASD compared with NTC, a distinct PD progression was observed with increased constriction amplitude, increased dilation latency, and increased dilation amplitude that correlated with PD progression components. These components predicted social cognition performance. The first and second PD components correlated positively with MASC behavioral performance in ASD but negatively in NTC. These PD components may be interpreted as indicators of sensory-perceptual processing and attention function. In ASD, aberrant sensory-perceptual processing and attention function could contribute to attenuated social cognition performance. This needs to be tested by additional studies combining the respective cognitive tests and the outlined PD progression analysis. Phasic activity of the locus coeruleus-norepinephrine system is discussed as putatively shared underlying mechanism. Autism Res2019. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: In adolescents with autism, we found an altered pupil dilation during watching scenes of human interactions. Early pupil dilation correlated positively with the number of correct answers to questions about the shown human interactions. Our findings suggest that aberrant sensory processing and attention function may contribute to altered social cognition in autism.

Pupillometric indices of locus-coeruleus activation are not modulated following single bouts of exercise

Single bouts of exercise have been observed to enhance numerous domains of cognition including inhibitory aspects of cognitive control and neuroelectric indices of attention. Given that the locus-coeruleus norepinephrine system regulates alertness and attention, this system may underlie these exercise-induced enhancements. The present study used pupillometry to examine the extent to which a single bout of exercise induces changes in aspects of locus-coeruleus activation, as well as the extent to which changes in locus-coeruleus activation were associated with changes in inhibition and neuroelectric indices of attention. Using a within-participants crossover design, behavioral, neuroelectric, and pupillometric measures were assessed in response to an inhibitory control task before and after 20-min of either aerobic exercise or an active-control condition during two separate, counterbalanced sessions. The aerobic exercise condition consisted of walking/jogging on a motor driven treadmill at an intensity of approximately 70% of age-predicted maximum heart rate. The active control condition consisted of walking on the treadmill at 0.5 mph and 0% grade. Replicating prior findings, enhancements in both reaction time and neuroelectric indices of attention were observed in response to the exercise condition. However, neither the exercise nor the active control conditions were observed to induce changes in activation of the locus-coeruleus as indexed by pupil size, and changes in activation of the locus-coeruleus were not associated with exercise-induced changes in inhibition and neuroelectric indices of attention. Accordingly, these findings provide evidence to suggest that activation of the locus-coeruleus is not a mechanism underlying exercise-induced enhancements in cognition.

Mild cognitive impairment in de novo Parkinson's disease: A neuromelanin MRI study in locus coeruleus.

We aimed to investigate neuromelanin-sensitive magnetic resonance imaging (NM-MRI) features in the locus coeruleus of de novo Parkinson's disease patients with different cognitive states and to determine whether these features are associated with cognitive impairment. Three groups of subjects were recruited in this study, including patients with de novo PD with mild cognitive impairment (n = 23), patients with de novo PD without cognitive impairment (n = 48), and control subjects (n = 32). All subjects underwent clinical evaluations, as well as MRI scanning. The contrast-to-noise ratio of the locus coeruleus in the neuromelanin-sensitive MRI images and cortical thickness were measured. The contrast-to-noise ratio of the locus coeruleus in PD patients with mild cognitive impairment was significantly lower than that of controls (P = 0.016). The contrast-to-noise ratio of the locus coeruleus for PD patients without cognitive impairment was intermediate between that of controls and PD patients with mild cognitive impairment. Furthermore, multiple linear regression analysis showed that the contrast-to-noise ratio of the locus coeruleus was negatively associated with performance on the Trail Making Test B in all PD patients, controlling for age, sex, years of education, the Unified Parkinson's Disease Rating Scale motor scores from right upper limb, Geriatric Depression Rating Scales scores, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores, and cortical thickness. Dysfunction of the locus coeruleus neurons may partly contribute to the decline in executive function in early de novo PD. In the future, the locus coeruleus-norepinephrine system might be targeted for early-intervention strategies in PD patients. © 2019 International Parkinson and Movement Disorder Society.

Echoes of Emotions Past: How Neuromodulators Determine What We Recollect

We tend to re-live emotional experiences more richly in memory than more mundane experiences. According to one recent neurocognitive model of emotional memory, negative events may be encoded with a larger amount of sensory information than neutral and positive events. As a result, there may be more perceptual information available to reconstruct these events at retrieval, leading to memory reinstatement patterns that correspond with greater memory vividness and sense of recollection for negative events. In this commentary, we offer an alternative perspective on how emotion may influence such sensory cortex reinstatement that focuses on engagement of the noradrenergic (NE) and dopaminergic (DA) systems rather than valence. Specifically, we propose that arousal-related locus coeruleus-norepinephrine (LC-NE) system activation promotes the prioritization of the most salient features of an emotional experience in memory. Thus, a select few details may drive lower-level sensory cortical activity and a stronger sense of recollection for arousing events. By contrast, states of high behavioral activation, including novelty-seeking and exploration, may recruit the DA system to broaden the scope of cognitive processing and integrate multiple event aspects in memory. These more integrated memory representations may be reflected in higher-order cortical reinstatement at retrieval. Thus, the balance between activation in these neuromodulatory systems at encoding, rather than the valence of the event, may ultimately determine the quality of emotional memory recollection and neural reinstatement.