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Locus coeruleus imaging. (A) Study specific locus coeruleus atlas, also showing the reference region (light blue) in the central pons. (B) CNR for the locus coeruleus subdivisions and whole structure in Parkinson's disease patients (PD) versus controls (note, left and right locus coeruleus are combined).
Source publication
Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition defi...
Contexts in source publication
Context 1
... facilitate accurate extraction of the locus coeruleus signal we created a study-specific unbiased locus coeruleus atlas ( Fig. 2A). To this end, we used an independent sample of 29 age-and education-matched healthy control subjects [13 female; age mean (SD) ¼ 67 (8.2), age range ¼ 52-84] collected under the same neuroimaging protocol. We used a validated pipeline for locus coeruleus atlas construction described in Ye et al. 45 Briefly, for each axial slice on the ...
Context 2
... a measure of locus coeruleus integrity, we quantified contrast by establishing the CNR with respect to a reference region in the central pons (Fig. 2A). A CNR map was computed voxel-by-voxel on the average MT image for each subject using the signal difference between a given voxel (V) and the mean intensity in the reference region (Mean REF ) divided by the standard deviation (SD REF ) of the reference ...
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Background: Stimulants such as methylphenidate and atomoxetine, a nonstimulant norepinephrine reuptake inhibitor, are approved for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Associations between the use of methylphenidate or atomoxetine with suicidal ideation and suicide-related behavior have been reported in the literature....
Citations
... A growing body of research suggests that the prefrontal cortex is a central node in the brain's impulsivity network, playing a crucial role in inhibitory control [3][4][5] . Moreover, several neurotransmitter systems profoundly influence cognitive functions, including inhibitory control [6][7][8][9][10][11][12] . The dopaminergic system has long been implicated in impulse control. ...
... This is due to the dramatic therapeutic efficacy of amphetamine, a dopamine agonist, and methylphenidate, a dopamine and norepinephrine reuptake inhibitor, in treating impulsivity symptoms in ADHD patients. More recently, several lines of evidence from preclinical and clinical studies have indicated the involvement of the noradrenergic and cholinergic systems in inhibitory control [7][8][9][10][11][12] . For example, Robinson et al. 8 found that administering Atomoxetine, a selective norepinephrine reuptake inhibitor, significantly improved the impulse control of rats across various behavioral tasks measuring impulsivity. ...
Inhibitory control is a critical executive function that allows animals to suppress their impulsive behavior in order to achieve certain goals or avoid punishment. We investigated norepinephrine (NE) and acetylcholine (ACh) dynamics and population neuronal activity in the prefrontal cortex during inhibitory control. Using fluorescent sensors to measure extracellular levels of NE and ACh, we simultaneously recorded the dynamics of prefrontal NE and ACh in mice performing an inhibitory control task. The prefrontal NE and ACh signals exhibited strong coherence at 0.4-0.8 Hz. Chemogenetic inhibition of locus coeruleus (LC) neurons that project to the basal forebrain region reduced inhibitory control performance to chance levels. However, this manipulation did not diminish the difference in NE/ACh signals between successful and failed trials; instead, it abolished the difference in NE-ACh phase synchrony between the successful and failed trials, indicating that NE-ACh phase synchrony is a task-relevant neuromodulatory feature. Chemogenetic inhibition of cholinergic neurons that project to the LC region did not impair the inhibitory control performance, nor did it abolish the difference in NE-ACh phase synchrony between successful or failed trials, further confirming the relevance of NE-ACh phase synchrony to inhibitory control. To understand the possible effect of NE-ACh synchrony on prefrontal population activity, we employed Neuropixels to record from the prefrontal cortex with and without inhibiting LC neurons that project to the basal forebrain during inhibitory control. The LC inhibition reduced the number of prefrontal neurons encoding inhibitory control. Demixed principal component analysis (dPCA) further revealed that population firing patterns representing inhibitory control were impaired by the LC inhibition. Disparities in NE-ACh phase synchrony relevant to inhibitory control occurred only in the prefrontal cortex, but not in the parietal cortex, somatosensory cortex, and the somatosensory thalamus. Taken together, these findings suggest that the LC modulates inhibitory control through its collective effect with cholinergic systems on population activity in the prefrontal cortex. Our results further revealed that NE-ACh phase synchrony is a critical neuromodulatory feature with important implications for cognitive control.
... We speculate that as the disease progresses, cells in the caudal section degenerate and become more dispersed. Caudal asymmetry in neuronal degeneration (relative to rostral) may thus signal progression to a more advanced disease stage (above Braak stage IV and Thal stage 3) and possibly correspond to late-stage symptoms including motor-related or autonomic dysfunctions -reflective of its projections to the cerebellum and spinal cord affected earlier in Parkinson's disease [7,26]. This does not preclude potential asymmetry in neuronal degeneration of the rostral part earlier in life. ...
Tau accumulation in and neurodegeneration of locus coeruleus (LC) neurons is observed in Alzheimer’s disease (AD). We investigated whether tangle and neuronal density in the rostral and caudal LC is characterized by an asymmetric pattern in 77 autopsy cases of the Rush Memory and Aging Project. We found left-right equivalence for tangle density across individuals with and without AD pathology. However, neuronal density, particularly in the caudal-rostral axis of the LC, is asymmetric among individuals with AD pathology. Asymmetry in LC neuronal density may signal advanced disease progression and should be considered in AD neuroimaging studies of LC neurodegeneration.
... Li et al., 2020;Tomassini et al., 2022). Recently, one study reported that oral atomoxetine (i.e. a noradrenergic reuptake inhibitor) improved reaction times during inhibition in Parkinson patients with lower LC integrity (O'Callaghan et al., 2021). Consistent with this, taVNS has been found to increase the activation of brainstem regions, including the LC (Frangos, Ellrich & Komisaruk, 2015;Yakunina, Kim & Nam, 2017), suggesting a modulatory role of taVNS in inhibitory control ability via its impact on the LC -NE network. ...
Background
Inhibitory control represents a core executive function that critically facilitates adaptive behavior and survival in an ever-changing environment. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been hypothesized to improve behavioral inhibition performance, however the neurocomputational mechanism of taVNS-induced neuroenhancement remains elusive.
Method
In the current study, we investigated the efficacy of taVNS in a sham-controlled between-subject functional near infrared spectroscopy (fNIRS) experiment with an emotional face Go/No-Go paradigm in ninety healthy young adults.
Results
After a data quality check, eighty-two subjects were included in the final data analysis. Behaviorally, the taVNS improved No-Go response accuracy, together with computational modeling using Hierarchical Bayesian estimation of the Drift Diffusion Model (HDDM) indicating that it specifically reduced the information accumulation rate for Go responses, and this was negatively associated with increased accuracy of No-Go responses. On the neural level, taVNS enhanced engagement of the bilateral inferior frontal gyrus (IFG) during inhibition of angry expression faces and modulated functional couplings (FCs) within the prefrontal inhibitory control network. Mediation models revealed that taVNS-induced facilitation of inhibitory control was critically mediated by a decreased information accumulation for Go responses and concomitantly enhanced neurofunctional coupling between the inferior and orbital frontal cortex.
Discussion
Our findings demonstrate a potential for taVNS to improve emotional inhibitory control via reducing pre-potent responses and enhancing FCs within prefrontal inhibitory control networks, suggesting a promising therapeutic role in treating specific disorders characterized by inhibitory control deficits.
... Non-invasive neuroimaging of the LC using MRI allows for the assessment of LC integrity and its correlation with the functioning of the noradrenergic system and cognitive and behavioral symptoms, which could potentially lead to a better diagnosis of neurodegeneration before the onset of symptoms [11]. In addition, targeting the noradrenergic system represents an additional therapeutic strategy in the treatment of Parkinson's disease, especially for compensating cognitive impairments, as the main dopaminergic therapy used in the treatment of Parkinson's disease does not lead to improvement in cognitive function [59,60]. It is believed that restoring norepinephrine levels may lead to an improvement in patients' condition [59]. ...
... In addition, targeting the noradrenergic system represents an additional therapeutic strategy in the treatment of Parkinson's disease, especially for compensating cognitive impairments, as the main dopaminergic therapy used in the treatment of Parkinson's disease does not lead to improvement in cognitive function [59,60]. It is believed that restoring norepinephrine levels may lead to an improvement in patients' condition [59]. ...
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.
... propranolol is used to treat tremor 124 and control levodopa-induced dyskinesia in PD 125 , desipramine and other norepinephrine reuptake inhibitors are used to treat depression and anxiety in PD 126-129 , and the NE reuptake inhibitor atomoxetine is being examined as a therapy for cognitive decline in PD 130,131 . Given the role of NE signaling in brain health and immunity, the effect of these drugs on neuroin ammation must be considered. ...
Parkinson’s disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD. In this study, we generate a novel two-hit mouse model that captures both features, using dextran sulfate sodium (DSS) to induce gut inflammation and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion the LC. We first confirmed the specificity of DSP-4 for central NE using neurochemical methods and fluorescence light-sheet microscopy of cleared tissue, and established that DSS-induced outcomes in the periphery, including weight loss, gross indices of gut injury and systemic inflammation, the loss of tight junction proteins in the colonic epithelium, and markers of colonic inflammation, were unaffected with DSP-4 pre-administration. We then measured alterations in neuroimmune gene expression in the ventral midbrain in response to DSS treatment alone as well as the extent to which prior LC injury modified this response. In this two-hit model we observed that DSS-induced colitis activates the expression of key cytokines and chemokines in the ventral midbrain only in the presence of LC injury and the typical DSS-associated neuroimmune is blunted by pre-LC lesioning with DSP-4. In all, this study supports the growing appreciation for the LC as neuroprotective against inflammation-induced brain injury and draws attention to the potential for NEergic interventions to exert disease-modifying effects under conditions where peripheral inflammation may compromise ventral midbrain dopaminergic neurons and increase the risk for development of PD.
... For instance, LC-sensitive imaging showed reduced LC signal intensity in both AD and PD patients compared to controls [12][13][14][15][16]. Although the biophysiological interpretation of the LC signals requires further investigation [17,18], assessments of LC integrity have shown potentials for patient stratification and predicting a noradrenergic treatment response in relation to behavioral improvements [19,20]. Another MRI technique, diffusion MRI, is able to assess the microstructural integrity of the white and grey matter with its derivatives, fractional anisotropy (FA) and mean diffusivity (MD) [21][22][23][24][25][26]. ...
... As an alternative, LC-sensitive MRI has a better capacity to segment the LC and differentiate the rostral and caudal LC [12], which are differentially vulnerable in AD and PD [68]. Changes of LC signal intensity on LC-sensitive MRI have been shown to be a potential biomarker for monitoring disease progression and assessing behavioral improvement on noradrenergic treatments [12,15,19,20,[122][123][124]. Future studies are encouraged to combine LC-sensitive MRI and diffusion MRI for LC segmentation and LC tractography. ...
Background
Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.
Methods
Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.
Results
The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity.
Conclusions
In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.
... To overcome these challenges, longer acquisition times and increased slice thickness are often required 18 , resulting in compromised spatial resolution for the small SNpc region, ultimately resulting in variable test-retest reliability [19][20][21][22] . While ultra-high-field MRI at 7T offers several advantages, including higher SNR and spatial resolution [23][24][25][26][27][28] , the higher specific absorption rate (SAR) at 7T, particularly for MT contrast, is a limiting factor that can diminish some of these advantages. There is currently limited evidence for the role of 7T NM imaging to diagnose PD from controls, and no studies comparing PD to essential tremor (ET). ...
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that presents a diagnostic challenge due to symptom overlap with other disorders. Neuromelanin (NM) imaging is a promising biomarker for PD, but adoption has been limited, in part due to subpar performance at standard MRI field strengths. We aimed to evaluate the diagnostic utility of ultra-high field 7T NM-sensitive imaging in the diagnosis of PD versus controls and essential tremor (ET), as well as NM differences among PD subtypes. A retrospective case-control study was conducted including PD patients, ET patients, and controls. 7T NM-sensitive 3D-GRE was acquired, and substantia nigra pars compacta (SNpc) volumes, contrast ratios, and asymmetry indices were calculated. Statistical analyses, including general linear models and ROC curves, were employed. Twenty-one PD patients, 13 ET patients, and 18 controls were assessed. PD patients exhibited significantly lower SNpc volumes compared to non-PD subjects. SNpc total volume showed 100% sensitivity and 96.8% specificity (AUC = 0.998) for differentiating PD from non-PD and 100% sensitivity and 95.2% specificity (AUC = 0.996) in differentiating PD from ET. Contrast ratio was not significantly different between PD and non-PD groups ( p = 0.07). There was also significantly higher asymmetry index in SNpc volume in PD compared to non-PD cohorts ( p < 0.001). NM signal loss in PD predominantly involved the inferior, posterior, and lateral aspects of SNpc. Akinetic-rigid subtype showed more significant NM signal loss compared to tremor dominant subtype ( p < 0.001). 7T NM imaging demonstrates potential as a diagnostic tool for PD, including potential distinction between subtypes, allowing improved understanding of disease progression and subtype-related characteristics.
... Clearly the pathological changes that contribute to sleep disturbance in diseases of ageing will be multifaceted. However, a key focus for future work may be the locus coeruleus-noradrenergic system, given its possibility as a pharmacological target and the availability of noradrenergic drugs that are undergoing a renewed interest for their utility in treating non-motor symptoms across disease of ageing [106][107][108]. ...
Sleep spindles are a hallmark of non-REM sleep and play a fundamental role in memory consolidation. Alterations in these spindles are emerging as sensitive biomarkers for neurodegenerative diseases of ageing. Understanding the clinical presentations associated with spindle alterations may help to elucidate the functional role of these distinct electroencephalographic oscillations and the pathophysiology of sleep and neurodegenerative disorders. Here, we use a data-driven approach to examine the sleep, memory and default mode network connectivity phenotypes associated with sleep spindle architecture in older adults (mean age = 66 years). Participants were recruited from a specialist clinic for early diagnosis and intervention for cognitive decline, with a proportion showing mild cognitive deficits on neuropsychological testing. In a sample of 88 people who underwent memory assessment, overnight polysomnography and resting-state fMRI, a k-means cluster analysis was applied to spindle measures of interest: fast spindle density, spindle duration and spindle amplitude. This resulted in three clusters, characterised by preserved spindle architecture with higher fast spindle density and longer spindle duration (Cluster 1), and alterations in spindle architecture (Clusters 2 and 3). These clusters were further characterised by reduced memory (Clusters 2 and 3) and nocturnal hypoxemia, associated with sleep apnea (Cluster 3). Resting-state fMRI analysis confirmed that default mode connectivity was related to spindle architecture, although directionality of this relationship differed across the cluster groups. Together, these results confirm a diversity in spindle architecture in older adults, associated with clinically meaningful phenotypes, including memory function and sleep apnea. They suggest that resting-state default mode connectivity during the awake state can be associated with sleep spindle architecture; however, this is highly dependent on clinical phenotype. Establishing relationships between clinical and neuroimaging features and sleep spindle alterations will advance our understanding of the bidirectional relationships between sleep changes and neurodegenerative diseases of ageing.
... To facilitate more targeted treatment of impulsivity in PSP and PD, it is necessary to quantify LC structural integrity in vivo and determine its relationship to response inhibition. Specialist MRI sequences for ultrahigh field scanners (7T) have enabled sensitive and welltolerated quantification of LC pathology (Wang et al., 2018;Betts et al., 2019b;O'Callaghan et al., 2021;. The contrast and the resolution (400 Â 400 Â 500 mm) provided by the specialist sequence and the 7T MR scanner are sufficient to examine regional effects of pathology within the LC (Mason and Fibiger, 1979;Loughlin et al., 1986), and an advantage over the contrast and resolution at 3T. ...
... Response inhibition can be measured using performance on a stop signal task, but singular parameters of performance may obscure the complexity of underlying decision mechanisms. A multivariate model of computational parameters of response inhibition overcomes this limitation, to distinguish motor, attentional, and decisional components of inhibition (Zhang et al., 2016;Murley et al., 2020;O'Callaghan et al., 2021). ...
... Ye et al., 2014Z. Ye et al., , 2015Borchert et al., 2016;O'Callaghan et al., 2021). We propose that LC imaging could be used as a heuristic stratification marker in clinical trials, targeting response inhibition deficits with noradrenergic drugs in those most likely to benefit. ...
Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson’s syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetisation-transfer-weighted imaging of the LC. Parameters of ‘race models’ of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer non-decision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioural modelling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioural changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimisation of noradrenergic treatment is likely to benefit from stratification according to LC integrity.
Significance Statement
Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson’s disease and progressive supranuclear palsy. We used cognitive modelling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson’s disease and progressive supranuclear palsy.
... In line with the observed relation between LC changes and future memory performance, a recent meta-analysis demonstrates the efficacy of noradrenergic treatments in improving cognitive symptoms in Alzheimer's disease 118 . Mirroring its clinical potential, MRI-indexed catecholaminergic integrity has been suggested as a useful tool for stratifying patients suffering from neurodegenerative diseases in clinical trials that include noradrenergic treatments 48,119 . Some older participants also showed LC and SN-VTA intensity increases over time, which might indicate higher intracellular proton density 56 , potentially linked to the activity-related volume increase of catecholaminergic cells 9,12,120,121 . ...
Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra–ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger (n = 69) and older (n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.
