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Schematic outline of descending projections to the locus coeruleus and autonomic nervous system (ANS). Although
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This chapter discusses recent progress made in the development and validation of noninvasive measures and methods for investigating noradrenergic function in humans. These methods include functional imaging, scalp electrophysiology, the application of computational models of the monkey noradrenergic system to the study of human attention phenomena,...
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... important question is how the LC−this tiny brainstem nucleus−knows whether a stimulus is motivationally significant. To date, the best available answer is that some of the most prominent descending cortical projections to the LC come from two frontal brain structures that are thought to play a critical role in evaluating costs and rewards: the anterior cingulate cortex and the orbitofrontal cortex (Figure 2; Arnsten & Goldman-Rakic, 1984;Lee, Kim, & Waterhouse, 2005). ...
Context 2
... most of these cortical and limbic signals are relayed by the rostral part of the ventrolateral medulla, the area that provides the largest input to the LC (Figure 2; Aston-Jones, Ennis, Pieribone, Nickell, & Shipley, 1986). Importantly, this same area of the medulla is also a key region for the regulation of the symphathetic branch of the autonomic nervous system. ...
Citations
... Non-invasive, in vivo assessments of human LC integrity are notoriously difficult, given the nucleus' small size and location deep in the brainstem 30,40,41 . Fortunately, however, a by-product of catecholamine synthesis, the dark, insoluble pigment neuromelanin, accumulates in the LC across the lifespan 42 . ...
... Animal and post-mortem human studies suggest a link between memory performance in ageing and the integrity of the central noradrenergic system 7,10 . To date, however, in vivo research on humans has been stymied by methodological difficulties in the reliable assessment of LC integrity 30,40,41 (but see ref. 15 ). Here, we took advantage of the paramagnetic properties of neuromelanin, a by-product of NE synthesis, in T 1 -weighted MRI to image the LC in vivo 46,48 . ...
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.
... Cells giving rise to dense hippocampal projections tend to be located in more rostral segments while those that innervate the cerebellum and spinal cord are located more caudally [17][18][19] . NE release by the LC modulates cognitive functions such as perception, attention, learning and memory 17,[20][21][22][23][24][25][26][27][28] . In particular, via its action on ß-adrenoceptors in the hippocampus, the LC modulates long-term potentiation (LTP) and long term-depression (LTD), key determinants of synaptic plasticity and memory 29,30 . ...
... Non-invasive, in vivo assessments of human LC integrity are notoriously difficult, given the nucleus' small size and location deep in the brainstem 26,38,39 . Fortunately, however, a byproduct of catecholamine synthesis, the dark, insoluble pigment neuromelanin, accumulates in the LC across the life span 40 . ...
... Animal and post-mortem human studies suggest a link between memory performance in aging and the integrity of the central noradrenergic system 7,10 . So far, in vivo research on humans, however, has been stymied by methodological difficulties in the reliable assessment of LC integrity 26,38,39 (but see Hämmerer and colleagues 11 ). Here, we took advantage of the paramagnetic properties of neuromelanin, a byproduct of NE synthesis, in T 1 -weighted MRI to image the LC in vivo 44,46 . ...
For decades, the search for drivers of memory decline in human cognitive aging 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 non-invasive monitoring of LC integrity have hindered the study of LC-cognition associations in humans so far. 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 large samples of younger (n = 66), and older adults (n = 233). Moreover, we observed spatially confined and functionally relevant age differences in rostral LC. Older adults who showed 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 human aging and extend our knowledge about the role of the LC norepinephrine system in senescent decline in human cognition.
... Dopamine has since long been considered important (Braver & Cohen, 2000;Cools & D'Esposito, 2011;Montague, Dayan, & Sejnowski, 1996;Schultz, 1998). However, recent years have witnessed an increasing interest in a possible role of norepinephrine (NE) in cognitive control , a neuromodulator originating from the brainstem locus coeruleus (LC) (Arnsten, 1998;Aston-Jones & Cohen, 2005;Eldar, Cohen, & Niv, 2013;Nieuwenhuis & Jepma, 2011;Sara, 2009;Verguts & Notebaert, 2008, 2009). ...
Suppressing irrelevant information in decision making is an essential everyday skill. We studied whether this ability could be improved in epileptic patients during vagus nerve stimulation (VNS). VNS is known to increase norepinephrine (NE) in the brain. NE is thought to improve several aspects of cognitive control, including the suppression of irrelevant information. Nineteen epileptic VNS patients executed the Eriksen flanker task twice, both during on and off stimulation. Distractor interference was indexed by the congruency effect, a standard empirical marker of cognitive control. We found a reduced congruency effect during stimulation, which indicates an improved ability to suppress distractor interference. This effect was only found in patients that are clinically determined VNS-responders (n = 10). As VNS increases NE in VNS-responders, our finding suggests a beneficial role of NE in cognitive control. At the same time, it suggests that VNS does not only reduce seizure frequency in epileptic patients, but also improves cognitive control.
... A limitation of the current study is that most depressed participants used antidepressant medication that can affect norepinephrine levels, and thereby influence pupil size (Gould et al., 2006;Nieuwenhuis and Jepma, 2011;Gabay et al., 2011). We tested whether medication normalized the deviant investment pattern observed in patients; although that does seem to be the case, we cannot rule out alternative explanations (see Supplement S3 for a detailed overview). ...
... It should be noted that inhibitory control and the underlying cortical–striatal–thalamic pathway is not only modulated by dopamine. Evidently, other neurotransmitters such as norepinephrine and acetylcholine also regulate activation in this network and consequently are associated with inhibitory control capacity (Nieuwenhuis and Jepma, 2011; Sarter et al., 2009). Recent work has examined whether improving norepinephrine and dopamine levels by medication such as modafinil may concurrently increase inhibitory control (Brady et al., 2011). ...
Contemporary theoretical models of substance dependence posit that deficits in inhibitory control play an important role in substance dependence. The neural network underlying inhibitory control and its association with substance dependence have been widely investigated. However, the pharmacology of inhibitory control is still insufficiently clear. The aims of the current study were twofold. First, we investigated the role of dopamine in inhibitory control and associated brain activation. Second, the proposed link between dopamine and impaired inhibitory control in nicotine dependence was investigated by comparing smokers and non-smoking controls. Haloperidol (2mg), a dopamine D2/D3 receptor antagonist, and placebo were administered to 25 smokers and 25 non-smoking controls in a double-blind randomized cross-over design while performing a Go/NoGo task during fMRI scanning. Haloperidol reduced NoGo accuracy and associated brain activation in the ACC, right SFG and left IFG, showing that optimal dopamine levels are crucial to effectively implement inhibitory control. In addition, smokers showed behavioral deficits on the Go/NoGo task as well as hypoactivity in the left IFG, right MFG and ACC after placebo, supporting the hypothesis of a hypoactive prefrontal system in smokers. Haloperidol had a stronger impact on prefrontal brain activation in non-smoking controls compared to smokers, which is in line with the inverted 'U' curve theory of dopamine and cognitive control. The current findings suggest that altered baseline dopamine levels in addicted individuals may contribute to the often observed reduction in inhibitory control in these populations.
... Nieuwenhuis and colleagues provide alternative explanations for these apparent discrepancies within the LC-P3 account (see Nieuwenhuis et al., 2005b;Nieuwenhuis and Jepma, 2010). However, the assumption that the dN2 (rather than the P3) reflects the LC-induced enhancement of cortical processing eliminates these issues outright. ...
We applied the event-related brain potential (ERP) technique to investigate the involvement of two neuromodulatory systems in learning and decision making: The locus coeruleus–norepinephrine system (NE system) and the mesencephalic dopamine system (DA system). We have previously presented evidence that the N2, a negative deflection in the ERP elicited by task-relevant events that begins approximately 200 ms after onset of the eliciting stimulus and that is sensitive to low-probability events, is a manifestation of cortex-wide noradrenergic modulation recruited to facilitate the processing of unexpected stimuli. Further, we hold that the impact of DA reinforcement learning signals on the anterior cingulate cortex (ACC) produces a component of the ERP called the feedback-related negativity (FRN). The N2 and the FRN share a similar time range, a similar topography, and similar antecedent conditions. We varied factors related to the degree of cognitive deliberation across a series of experiments to dissociate these two ERP components. Across four experiments we varied the demand for a deliberative strategy, from passively watching feedback, to more complex/challenging decision tasks. Consistent with our predictions, the FRN was largest in the experiment involving active learning and smallest in the experiment involving passive learning whereas the N2 exhibited the opposite effect. Within each experiment, when subjects attended to color, the N2 was maximal at frontal–central sites, and when they attended to gender it was maximal over lateral-occipital areas, whereas the topology of the FRN was frontal–central in both task conditions. We conclude that both the DA system and the NE system act in concert when learning from rewards that vary in expectedness, but that the DA system is relatively more exercised when subjects are relatively more engaged by the learning task.
... In contrast, phasic LC activity consistently precedes behavioural responding and has been strongly associated with processes that lead to the response (e.g., Clayton, Rajkowski, Cohen, & Aston-Jones, 2004;Rajkowski, Majczynski, Clayton, & Aston-Jones, 2004). Nieuwenhuis and Jepma (2010) suggested two possible explanations of this temporal discrepancy. First, they argued that overt behaviours can occur despite minimal NE prior to the arrival of an LC phasic release, such that the P3 need not be generated before the response. ...
... Nieuwenhuis and colleagues provide alternative explanations for these apparent discrepancies within the LC-P3 account (see Nieuwenhuis et al., 2005b;Nieuwenhuis, & Jepma, 2010). However, the assumption that the dN2 (rather than the P3) reflects the LC-induced enhancement of cortical processing eliminates these issues outright. ...
Several lines of evidence have suggested for decades a role for norepinephrine (NE) in the pathophysiology and treatment of schizophrenia. Recent experimental findings reveal anatomical and physiological properties of the locus coeruleus-norepinephrine (LC-NE) system and its involvement in brain function and cognition. Here, we integrate these two lines of evidence. First, we review the functional and structural properties of the LC-NE system and its impact on functional brain networks, cognition, and stress, with special emphasis on recent experimental and theoretical advances. Subsequently, we present an update about the role of LC-associated functions for the pathophysiology of schizophrenia, focusing on the cognitive and motivational deficits. We propose that SCZ phenomenology, in particular cognitive symptoms, may be explained by an abnormal interaction between the genetic susceptibility and stress-initiated LC-NE dysfunction. This in turn, leads to imbalance between LC activity modes, dysfunctional regulation of brain network integration and neural gain, and deficits in cognitive functions. Finally, we suggest how recent development of experimental approaches can be used to characterize LC function in schizophrenia.
The P3 is a prominent positive large-amplitude event-related potential (ERP) component with a typical peak latency between 300 and 400 msec following presentation of stimuli. This chapter discusses the similarities between the P3 and phasic locus coeruleus-norepinephrine (LC-NE) responses in terms of their relationship with learning. It first provides an overview of the LC-P3 theory and then describes the role of the LC-NE system in optimizing the speed and accuracy of responding in choice reaction-time tasks. The chapter concludes with a discussion on the context-updating hypothesis of the P3.
The noradrenaline (norepinephrine) system exerts profound influences on cognition via ascending projections to the forebrain, mostly originating from the locus coeruleus. This paper provides an overview of available infrahuman and healthy human studies, exploring the effects of specific noradrenergic manipulations on dissociable cognitive functions, including attention, working memory, cognitive flexibility, response inhibition and emotional memory. Remarkable parallels across species have been reported which may account for the mechanisms by which noradrenergic medications exert their beneficial effects in disorders such as depression and attention-deficit hyperactivity disorder (ADHD). The literature is discussed in relation to prevailing models of noradrenergic influences over cognition and novel therapeutic directions, including in relation to investigating the effects of noradrenergic manipulations on other disorders characterized by impulsivity, and dementias. Unanswered questions are also highlighted, along with key avenues for future research, both proof-of-concept and clinical.
