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Medial and superior frontal theta oscillations are important for response inhibition. The norepinephrine (NE) system has been shown to modulate these oscillations possibly via gain control mechanisms, which depend on the modulation of neuron membrane potentials. Because the latter are also modulated by tDCS, the interrelation of tDCS and NE effects on superior frontal theta band activity needs investigation. We test the hypothesis that anodal tDCS affects modulatory effects of the NE system on theta band activity during inhibitory control in superior frontal regions. Using EEG beamforming, theta band activity in the superior frontal gyrus (SFG) was integrated (correlated) with the pupil diameter data as an indirect index of NE activity. In a within-subject design, healthy participants completed a response inhibition task in two sessions in which they received 2 mA anodal tDCS over the vertex, or sham stimulation. There were no behavioral effects of anodal tDCS. Yet, tDCS affected correlations between SFG theta band activity time course and the pupil diameter time course. Correlations were evident after sham stimulation (r = .701; p < .004), but absent after anodal tDCS. The observed power of this dissociation was above 95%. The data suggest that anodal tDCS may eliminate neuromodulatory effects, likely of the NE system, on theta band activity during response inhibition in a structure of the response inhibition network. The NE system and tDCS seem to target similar mechanisms important for cognitive control in the prefrontal cortex. The results provide a hint why tDCS often fails to induce overt behavioral effects and shows that neurobiological systems, which may exert similar effects as tDCS on neural processes should closely be monitored in tDCS experiments.

In order to control behavior in an adaptive manner the brain has to learn how some situations and actions predict positive or negative outcomes. During the last decade cognitive neuroscientists have shown that the brain is able to evaluate and learn from outcomes within a few hundred milliseconds of their occurrence. This research has been primarily focused on the feedback-related negativity (FRN) and the P3, two event-related potential (ERP) components that are elicited by outcomes. The FRN is a frontally distributed negative-polarity ERP component that typically reaches its maximal amplitude 250 ms after outcome presentation and tends to be larger for negative than for positive outcomes. The FRN has been associated with activity in the anterior cingulate cortex (ACC). The P3 (~300-600 ms) is a parietally distributed positive-polarity ERP component that tends to be larger for large magnitude than for small magnitude outcomes. The neural sources of the P3 are probably distributed over different regions of the cortex. This paper examines the theories that have been proposed to explain the functional role of these two ERP components during outcome processing. Special attention is paid to extant literature addressing how these ERP components are modulated by outcome valence (negative vs. positive), outcome magnitude (large vs. small), outcome probability (unlikely vs. likely), and behavioral adjustment. The literature offers few generalizable conclusions, but is beset with a number of inconsistencies across studies. This paper discusses the potential reasons for these inconsistencies and points out some challenges that probably will shape the field over the next decade.

Following the development of magnetic resonance imaging (MRI) methods to assay the integrity of catecholamine nuclei, including the locus coeruleus (LC), there has been an effort to develop automated methods that can accurately segment this small structure in an automated manner to promote its widespread use and overcome limitations of manual segmentation. Here we characterize an automated LC segmentation approach (referred to as the funnel‐tip [FT] method) in healthy individuals and individuals with LC degeneration in the context of Alzheimer's disease (AD, confirmed with tau‐PET imaging using [18F]MK6240). The first sample included n = 190 individuals across the AD spectrum from cognitively normal to moderate AD. LC signal assayed with FT segmentation showed excellent agreement with manual segmentation (intraclass correlation coefficient [ICC] = 0.91). Compared to other methods, the FT method showed numerically higher correlation to AD status (defined by presence of tau: Cohen's d = 0.64) and AD severity (Braak stage: Pearson R = −.35, cognitive function: R = .25). In a separate sample of n = 12 control participants, the FT method showed excellent scan–rescan reliability (ICC = 0.82). In another sample of n = 30 control participants, we found that the structure of the LC defined by FT segmentation approximated its expected shape as a contiguous line: <5% of LC voxels strayed >1 voxel (0.69 mm) from this line. The FT LC segmentation shows high agreement with manual segmentation and captures LC degeneration in AD. This practical method may facilitate larger research studies of the human LC‐norepinephrine system and has potential to support future use of neuromelanin‐sensitive MRI as a clinical biomarker. The automated segmentation (funnel tip [FT]) method showed good agreement to manual segmentation in measuring LC signal and LC localization. FT method showed numerically higher correlation to Alzheimer's disease severity measures compared to other segmentation approaches. FT method demonstrated a high scan–rescan reliability and provided a practical method to segment the LC along its full rostrocaudal extent.

Alzheimer's disease (AD) poses a significant global health concern over the next several decades. Multiple hypotheses have been put forth that attempt to explain the underlying pathophysiology of AD. Many of these are briefly reviewed here, but to‐date no disease‐altering therapy has been achieved. Despite this, recent work expanding on the role of noradrenergic system dysfunction in both the pathogenesis and symptomatic exacerbation of AD has shown promise. The role norepinephrine (NE) plays in AD remains complicated but pre‐tangle tau has consistently been shown to arise in the locus coeruleus (LC) of patients with AD decades before symptom onset. The current research reviewed here indicates NE can facilitate neuroprotective and memory‐enhancing effects through β adrenergic receptors, while α2A adrenergic receptors may exacerbate amyloid toxicity through a contribution to tau hyperphosphorylation. AD appears to involve a disruption in the balance between these two receptors and their various subtypes. There is also a poorly characterized interplay between the noradrenergic and cholinergic systems. LC deterioration leads to maladaptation in the remaining LC‐NE system and subsequently inhibits cholinergic neuron function, eventually leading to the classic cholinergic disruption seen in AD. Understanding AD as a dysfunctional noradrenergic system, provides new avenues for the use of advanced neural stimulation techniques to both study and therapeutically target the earliest stages of neuropathology. Direct LC stimulation and non‐invasive vagus nerve stimulation (VNS) have both demonstrated potential use as AD therapeutics. Significant work remains, though, to better understand the role of the noradrenergic system in AD and how electroceuticals can provide disease‐altering treatments. In this review, we provide a brief overview of several of the most thoroughly researched pathogenic hypotheses for Alzheimer's disease (AD) and assess their clinical impact to‐date. We focus specifically on recent research into the role of the locus coeruleus norepinephrine (LC‐NE) system, in both AD pathogenesis and symptom exacerbation, as well as the potential to use advanced neural stimulation techniques as a novel therapeutic option in the earliest stages of neuropathology.

Pupil dynamics can represent an indirect measure of perception; thus, it has been broadly explored in the auditory and visual fields. Although it is crucial for experiencing the outside world, tactile perception is not well-explored. Considering that, we sought to answer the following question via a systematic review: does normal tactile perception processing modulate pupil dilation in mammals (human or not)? The review process was conducted according to PRISMA Statement. We searched on Periódicos CAPES (Brazil) for the following terms: [(touch) OR (cutaneous stimulation) OR (tactile perception) OR (somatosensory) AND (pupil OR pupillary) NOT blind NOT reflex NOT pain NOT fear NOT noxious NOT autism NOT nerve NOT (pupillary block) NOT glaucoma NOT cataract NOT aneurysm NOT syndrome NOT treatment NOT special education]. From the 6,488 papers found, 4,568 were duplicates, and nine fulfilled the inclusion criteria. All papers found a positive relationship between pupil diameter and tactile perception. We found that the pupil is a reliable indirect measure of brain states and can evaluate norepinephrine (NE)/locus coeruleus (LC) action, stimulus inhibition, arousal, cognitive processes, and affection independently of the stimuli category (visual, auditory, or tactile). We also found that the perceptual tactile processing occurs in similar ways as the other perceptual modalities. We verified that more studies should be done, mostly avoiding low sampling rate recording systems, confounders as cue signs, not automated stimulation, and concurrent stimulus and using more reliable equipment.

The ability to process emotionally conflicting information is an important requirement for emotional self-control. While it seems obvious that the impact of interfering emotional information critically depends on how deeply this interfering information is processed, it is still unknown what cognitive subprocesses are most affected by manipulating the depth of processing of emotionally interfering information. We examine these aspects integrating neurophysiological (EEG) and source localization data with pupil diameter data as an indirect index of the norepinephrine (NE) system activity. We show that when processing depth of interfering emotional stimulus dimensions is increased, emotional Stroop effects become stronger. The EEG data show that this was associated with modulations of decision-making processes, as reflected by the P3 event-related potential. Notably, the integration with pupil diameter data suggests that these decision processes were modulated by the NE system, especially when the depth of processing of interfering emotional stimulus dimensions was increased. This likely reflects gain modulation processes to facilitate processing of complex interfering, emotional information. The source localization results suggest that regions in the parietal (BA7) and insular cortex (BA13) are associated with these modulatory effects. The results suggest that overcoming more complex emotional interference triggers engagement of the norepinephrine system (indexed by pupil diameter) to facilitate action control mechanisms in a time-specific manner when deeper processing of emotional stimulus dimensions is required.

Empathy for pain (vicariously felt pain), an ability to feel, recognize, understand and share the painful emotions of others, has been gradually accepted to be a common identity in both humans and rodents, however, the underlying neural and molecular mechanisms are largely unknown. Recently, we have developed a rat model of empathy for pain in which pain can be transferred from a cagemate demonstrator (CD) in pain to a naïve cagemate observer (CO) after 30 min dyadic priming social interaction. The naïve CO rats display both mechanical pain hypersensitivity (hyperalgesia) and enhanced spinal nociception. Chemical lesions of bilateral medial prefrontal cortex (mPFC) abolish the empathic pain response completely, suggesting existence of a top-down facilitation system in production of empathy for pain. However, the social transfer of pain was not observed in non-cagemate observer (NCO) after dyadic social interaction with a non-cagemate demonstrator (NCD) in pain. Here we showed that dyadic social interaction with a painful CD resulted in elevation of circulating norepinephrine (NE) and increased neuronal activity in the locus coeruleus (LC) in the CO rats. Meanwhile, CO rats also had over-expression of P2X3, but not TRPV1, in the dorsal root ganglia (DRG). Chemical lesion of the LC-NE neurons by systemic DSP-4 and pharmacological inhibition of central synaptic release of NE by clonidine completely abolished increase in circulating NE and P2X3 receptor expression, as well as the sympathetically-maintained development of empathic mechanical hyperalgesia. However, in the NCO rats, neither the LC-NE neuronal activity nor the P2X3 receptor expression was altered after dyadic social interaction with a painful NCD although the circulating corticosterone and NE were elevated. Finally, in the periphery, both P2X3 receptor and α1 adrenergic receptor were found to be involved in the development of empathic mechanical hyperalgesia. Taken together with our previous results, empathy for pain observed in the CO rats is likely to be mediated by activation of the top-down mPFC-LC/NE-sympathoadrenomedullary (SAM) system that further up-regulates P2X3 receptors in the periphery, however, social stress observed in the NCO rats is mediated by activation of both hypothalamic-pituitary-adrenocortical axis and SAM axis.

Background/Objectives: Migraine is a complex neurological headache disorder, and transcutaneous auricular vagus nerve stimulation (taVNS) can effectively relieve headache symptoms, but its mechanism of effect is still unclear. This study aimed to explore the regulatory effects of taVNS on the locus coeruleus (LC) and the norepinephrine (NE) system in migraine mice. Methods: C57/BL6 mice were randomly assigned to four experimental groups: the control group, model group, taVNS group, and sham taVNS group. A migraine model was established by administration of nitroglycerin. Headache behaviors were assessed using the orofacial stimulation test (OST) and the mouse grimace scale (MGS). Immunofluorescence staining was conducted to evaluate the expression of NE neurons in the LC, while Western blotting was used to determine the expression levels of α-2A adrenergic receptors in the spinal trigeminal nucleus caudalis (Sp5C). Additionally, fiber-optic recording was employed to monitor the real-time dynamics of NE release in Sp5C. Results: After taVNS intervention, the drinking time of OST in the model mice was significantly prolonged(p < 0.05), and facial expression scores were reduced (p < 0.05). TaVNS increased the number of NE neurons in the LC (p < 0.05), promoted the release of NE in Sp5C (p < 0.05), and upregulated the expression of α-2A adrenergic receptors in Sp5C (p < 0.05). Conclusions: The analgesic effects of taVNS are related to the activation of the LC-NE system and the inhibition of the decrease in Sp5C in migraine mice.

In this article, we present ideas related to three key aspects of mindfulness training: the regulation of attention via noradrenaline, the importance of working memory and its various components (particularly the central executive and episodic buffer), and the relationship of both of these to mind-wandering. These same aspects of mindfulness training are also involved in the preparation and execution of movement and implicated in the pathophysiology of psychosis. We argue that by moving in a mindful way, there may be an additive effect of training as the two elements of the practice (mindfulness and movement) independently, and perhaps synergistically, engage common underlying systems (the default mode network). We discuss how working with mindful movement may be one route to mindfulness training for individuals who would struggle to sit still to complete the more commonly taught mindfulness practices. Drawing on our clinical experience working with individuals with severe and enduring mental health conditions, we show the real world application of these ideas and how they can be used to help those who are suffering and for whom current treatments are still far from adequate.

Neuroeconomics is the study of the neurobiological bases of subjective preferences and choices. We present a novel framework that synthesizes findings from the literatures on neuroeconomics and creativity to provide a neurobiological description of creative cognition. We propose that value-based decision-making processes and activity in the locus ceruleus-norepinephrine (LC-NE) neuromodulatory system underlie creative cognition, as well as the large-scale brain network dynamics shown to be associated with creativity. This reconceptualization leads to several falsifiable hypotheses that can further understanding of creativity, decision making, and brain network dynamics.