Locus coeruleus co-activation patterns at rest show higher state persistence in patients with dissociative seizures: A Pilot Study.

OBJECTIVE: Dissociative seizures are paroxysmal disruptions of awareness and behavioral control in the context of affective arousal. Alterations in stress-related endocrine function have been demonstrated, but the timescale of dissociation suggests that the central locus coeruleus (LC) noradrenergic system is likely pivotal. Here, we investigate whether LC activation at rest is associated with altered brain network dynamics. METHODS: A preliminary co-activation pattern (CAP) analysis of resting-state functional magnetic resonance imaging (fMRI) in 14 patients with dissociative seizures and 14 healthy controls was performed by using the LC as a seeding region. The red nucleus served as a control condition. Entry rates, durations, and state transition probabilities of identified CAPs were calculated. Analyses were corrected for demographic, technical, and clinical confounders including depression and anxiety. RESULTS: Three LC-related CAPs were identified, with the dominant two showing inverse activations and deactivations of the default mode network and the attention networks, respectively. Analysis of transition probabilities between and within the three CAPs revealed higher state persistence in patients compared to healthy controls for both CAP2LC (Cohen's d = -0.55; p = 0.01) and CAP3LC (Cohen's d = -0.57; p = 0.01). The control analysis using the red nucleus as a seed yielded similar CAPs, but no significant between-group differences in transition probabilities. SIGNIFICANCE: Higher state persistence of LC-CAPs in patients with dissociative seizures generates the novel hypothesis that arousal-related impairments of network switching might be a candidate neural mechanism of dissociation. PLAIN LANGUAGE SUMMARY: Dissociative seizures often arise during high affective arousal. The locus coeruleus is a brain structure involved in managing such acute arousal states. We investigated whether the activity of the locus coeruleus correlates with activity in other regions of the brain (which we refer to as "brain states"), and whether those brain states were different between patients with dissociative seizures and healthy controls. We found that patients tended to stay in certain locus coeruleus-dependent brain states instead of switching between them. This might be related to the loss of awareness and disruptions of brain functions ("dissociation") that patients experience during seizures.

Task-evoked pupillary responses as potential biomarkers of mild cognitive impairment.

INTRODUCTION: Eye movement alterations are effective biomarkers for Alzheimer's disease (AD). This study examines task-evoked pupillary responses (TEPRs) as potential biomarkers of the mild cognitive impairment (MCI), the symptomatic stage preceding AD. METHODS: The prospective cohort study included 213 MCI patients and 514 cognitively normal controls (CNs). Participants performed a prosaccade (PS) or antisaccade (AS) task while their eye movements were tracked using a Tobii Pro Spectrum system. RESULTS: The CNs showed unique TEPRs linked to better performance, characterized by larger baselines, greater PS target-onset variability, and smaller AS target-onset variability. Conversely, for MCI patients, better performance was linked to larger AS target-onset sizes. Furthermore, MCI patients displayed reduced dilation during the cue and target-onset periods compared to CNs. DISCUSSION: MCI patients showed altered pupillary response patterns associated with cognitive task performance, highlighting the potential of oculomotor changes as a biomarker for early cognitive decline. Highlights: MCI patients displayed markedly smaller pupil dilation than CNs in response to cue and target stimuli.For MCI patients, larger pupil size upon target appearance during antisaccades correlated with better performance.Faster and more consistent prosaccades were linked to better performance in both groups.For MCI patients, the association between longer AS latencies and better performance was more pronounced than in CNs.Combined analysis of TEPRs and saccade performances in a sizeable cohort strengthens the generalizability of our findings to the broader MCI population.

The pivotal role of PACAP/PAC1R signaling from the anterior insular cortex to the locus coeruleus on anxiety-related behaviors of mice.

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific receptor (PAC1R) are widely present in the central nervous system (CNS), and PACAP/PAC1R signaling has been implicated in anxiety-related behaviors. The locus coeruleus (LC), with its extensive noradrenergic (NA) projections throughout the CNS, is also implicated in anxiety. Although the LC exhibits a high expression of PAC1R, the precise role of PACAP/PAC1R signaling in the LC's involvement in anxiety remains unclear. Histochemical analysis confirmed high levels of PAC1R mRNA in the LC and showed that PAC1R gene transcripts were highly localized to NA neurons. Targeted deletion of PAC1R from these cells led to a hyperactive/low anxiety phenotype in the open field and elevated-plus maze tests. Retrograde neurocircuit tracing indicated PACAP neurons from the anterior insular cortex (aIC) and a few other regions projected axons to the LC. The selective activation of PACAP neurons in the aIC led to significantly increased anxiety behavior without a change in overall locomotor activity. Moreover, shRNA PACAP knockdown in the aIC in wild-type mice led to a selective decrease in anxiety. The present results identify an aIC to LC neurocircuit controlling anxiety that critically requires PACAP/PAC1R signaling.

Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson's disease.

Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, the association of reduced LC norepinephrine signaling with brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC = 27) and task-free magnetoencephalography (NPD = 58; NHC = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha (8-12 Hz) activity in patients with decreased LC neuromelanin, with a stronger association in patients with worse attentional impairments. This negative alpha-LC neuromelanin relationship is strongest in fronto-motor cortices, where alpha activity is inversely related to attention scores. Using neurochemical colocalization analyses with normative atlases of neurotransmitter transporters, we also show that this effect is more pronounced in regions with high densities of norepinephrine transporters. These observations support a noradrenergic association between LC integrity and alpha band activity. Our data also show that rhythmic beta (15-29 Hz) activity in the left somato-motor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha activity is related to dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.

The Kir channel in the nucleus tractus solitarius integrates the chemosensory system with REM sleep executive machinery for homeostatic balance.

The locus coeruleus (LC), nucleus tractus solitarius (NTS), and retrotrapezoid nucleus (RTN) are critical chemosensory regions in the brainstem. In the LC, acid-sensing ion channels and proton pumps serve as H+ sensors and facilitate the transition from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep. Interestingly, the potassium inward rectifier (KIR) channels in the LC, NTS, and RTN also act as H+-sensors and are a primary target for improving sleep in obstructive sleep apnea and Rett syndrome patients. However, the role of Kir channels in NREM to REM sleep transition for H+ homeostasis is not known. Male Wistar rats were surgically prepared for chronic sleep-wake recording and drug delivery into the LC, NTS, and RTN. In different animal cohorts, microinjections of the Kir channel inhibitor, barium chloride (BaCl2), at concentrations of 1 mM (low dose) and 2 mM (high dose) in the LC and RTN significantly increased wakefulness and decreased NREM sleep. However, BaCl2 microinjection into the LC notably reduced REM sleep, whereas it didn't change in the RTN-injected group. Interestingly, BaCl2 microinjections into the NTS significantly decreased wakefulness and increased the percent amount of NREM and REM sleep. Additionally, with the infusion of BaCl2 into the NTS, the mean REM sleep episode numbers significantly increased, but the length of the REM sleep episode didn't change. These findings suggest that the Kir channels in the NTS, but not in the LC and RTN, modulate state transition from NREM to REM sleep.

Aging disrupts locus coeruleus-driven norepinephrine transmission in the prefrontal cortex: Implications for cognitive and motor decline.

The locus coeruleus (LC)-prefrontal cortex (PFC) circuitry is crucial for cognition, planning, posture and mobility. This study examines the role of norepinephrine (NE) in elucidating the neurobiological basis of age-related cognitive and motor declines. Aged mice exhibited reduced spatial learning, impaired memory, decreased physical endurance, and notable changes in locomotor behavior. The neurochemical foundations of these deficits were investigated through fast-scan cyclic voltammetry to measure NE release in the PFC and LC, both in vivo and in brain slices. Additionally, oxygen levels were monitored as a proxy for PFC neuronal function, and NE levels were analyzed in the extracellular space via microdialysis and total content in the PFC. Aged mice exhibited a frequency-dependent increase in NE release in the PFC upon LC stimulation, suggesting alterations in neural responsiveness due to aging. We also recorded slower NE reuptake rates and increased NE content and neuronal activity, indicated by higher oxygen levels and facilitated neuron activation due to membrane depolarization recorded via whole-cell patch-clamp. To understand the basis for LC-driven NE surges in the PFC with aging, we examined the expression levels of two proteins critical for presynaptic NE release and NE reuptake: the α2a-adrenergic receptor and the NE transporter. Both showed a significant decrease in the PFC with aging. These findings support the concept that aging significantly alters the structural and functional dynamics within the LC-PFC neural circuit, impacting NE modulation and neuronal activity, which may underlie the observed declines in cognitive and motor functions in aging populations.

The beneficial effects of modafinil administration on repeat mild traumatic brain injury (RmTBI) pathology in adolescent male rats are not dependent upon the orexinergic system.

The sleep-wake cycle plays an influential role in the development and progression of repeat mild traumatic brain injury (RmTBI)-related pathology. Therefore, we first aimed to manipulate the sleep-wake cycle post-RmTBI using modafinil, a wake-promoting substance used for the treatment of narcolepsy. We hypothesized that modafinil would exacerbate RmTBI-induced deficits. Chronic behavioural analyses were completed along with a 27-plex serum cytokine array, metabolomic and proteomic analyses of cerebrospinal fluid (CSF), as well as immunohistochemical staining in structures important for sleep/wake cycles, to examine orexin, melanin-concentrating hormone, tyrosine hydroxylase, and choline acetyltransferase, in the lateral hypothalamus, locus coeruleus, and basal forebrain, respectively. Contrary to expectation, modafinil administration attenuated behavioural deficits, metabolomic changes, and neuropathological modifications. Therefore, the second aim was to determine if the beneficial effects of modafinil treatment were driven by the orexinergic system. The same experimental protocol was used; however, RmTBI rats received chronic orexin-A administration instead of modafinil. Orexin-A administration produced drastically different outcomes, exacerbating anxiety-related and motor deficits, while also significantly disrupting their metabolomic and neuropathological profiles. These results suggest that the beneficial effects of modafinil administration post-RmTBI, work independently of its wake-promoting properties, as activation of the orexinergic wake-promoting system with orexin-A was detrimental. Overall, these findings highlight the complexity of sleep-wake changes in the injured brain and showcase the potential of the arousal and sleep systems in its treatment.

Characteristics of locus coeruleus functional connectivity network in patients with comorbid migraine and insomnia.

BACKGROUND: Migraine and insomnia are prevalent conditions that often co-occur, each exacerbating the other and substantially impacting the quality of life. The locus coeruleus (LC), a brainstem region responsible for norepinephrine synthesis, participates in pain modulation, sleep/wake cycles, and emotional regulation, rendering it a potential nexus in the comorbidity of migraine and insomnia. Disruptions in the LC-noradrenergic system have been hypothesized to contribute to the comorbidities of migraine and insomnia, although neuroimaging evidence in humans remains scarce. In this study, we aimed to investigate the intrinsic functional connectivity (FC) network of the LC in patients with comorbid migraine and subjective chronic insomnia and patients with migraine with no insomnia (MnI) using resting-state functional magnetic resonance imaging (rs-fMRI) and seed-based FC analyses. METHODS: In this cross-sectional study, 30 patients with comorbid migraine and chronic insomnia (MI), 30 patients with MnI, and 30 healthy controls (HCs) were enrolled. Participants underwent neuropsychological testing and rs-fMRI. The LC-FC network was constructed using seed-based voxel-wise FC analysis. To identify group differences in LC-FC networks, voxel-wise covariance analysis was conducted with sex and age as covariates. Subsequently, a partial correlation analysis was conducted to probe the clinical relevance of aberrant LC-FC in patients with MI and MnI. RESULTS: Except for the insomnia score, no other significant difference was detected in demographic characteristics and behavioral performance between the MI and MnI groups. Compared with HCs, patients with MI exhibited altered LC-FC in several brain regions, including the dorsomedial prefrontal cortex (DMPFC), anterior cerebellum, dorsolateral prefrontal cortex (DLPFC), thalamus, and parahippocampal gyrus (PHG). Lower FC between the LC and DLPFC was associated with greater insomnia severity, whereas higher FC between the LC and DMPFC was linked to longer migraine attack duration in the MI group. CONCLUSION: Our findings reveal the presence of aberrant LC-FC networks in patients with MI, providing neuroimaging evidence of the interplay between these conditions. The identified LC-FC alterations may serve as potential targets for therapeutic interventions and highlight the importance of considering the LC-noradrenergic system in the management of MI.

Impact of Stimulation Duration in taVNS-Exploring Multiple Physiological and Cognitive Outcomes.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that modulates the noradrenergic activity of the locus coeruleus (LC). Yet, there is still uncertainty about the most effective stimulation and reliable outcome parameters. In a double blind, sham-controlled study including a sample of healthy young individuals (N = 29), we compared a shorter (3.4 s) and a longer (30 s) stimulation duration and investigated the effects of taVNS (real vs. sham) on saliva samples (alpha amylase and cortisol concentration), pupil (pupillary light reflex and pupil size at rest) and EEG data (alpha and theta activity at rest, ERPs for No-Go signals), and cognitive tasks (Go/No-Go and Stop Signal Tasks). Salivary alpha amylase concentration was significantly increased in the real as compared to sham stimulation for the 30 s stimulation condition. In the 3.4 s stimulation condition, we found prolonged reaction times and increased error rates in the Go/No-Go task and increased maximum acceleration in the pupillary light reflex. For the other outcomes, no significant differences were found. Our results show that prolonged stimulation increases salivary alpha-amylase, which was expected from the functional properties of the LC. The finding of longer response times to short taVNS stimulation was not expected and cannot be explained by an increase in LC activity. We also discuss the difficulties in assessing pupil size as an expression of taVNS-mediated LC functional changes.

Locus coeruleus microstructural integrity is associated with vigilance vulnerability to sleep deprivation.

Insufficient sleep compromises cognitive performance, diminishes vigilance, and disrupts daily functioning in hundreds of millions of people worldwide. Despite extensive research revealing significant variability in vigilance vulnerability to sleep deprivation, the underlying mechanisms of these individual differences remain elusive. Locus coeruleus (LC) plays a crucial role in the regulation of sleep-wake cycles and has emerged as a potential marker for vigilance vulnerability to sleep deprivation. In this study, we investigate whether LC microstructural integrity, assessed by fractional anisotropy (FA) through diffusion tensor imaging (DTI) at baseline before sleep deprivation, can predict impaired psychomotor vigilance test (PVT) performance during sleep deprivation in a cohort of 60 healthy individuals subjected to a rigorously controlled in-laboratory sleep study. The findings indicate that individuals with high LC FA experience less vigilance impairment from sleep deprivation compared with those with low LC FA. LC FA accounts for 10.8% of the variance in sleep-deprived PVT lapses. Importantly, the relationship between LC FA and impaired PVT performance during sleep deprivation is anatomically specific, suggesting that LC microstructural integrity may serve as a biomarker for vigilance vulnerability to sleep loss.

Simulating combined monoaminergic depletions in a PD animal model through a bio-constrained differential equations system.

Introduction: Historically, Parkinson's Disease (PD) research has focused on the dysfunction of dopamine-producing cells in the substantia nigra pars compacta, which is linked to motor regulation in the basal ganglia. Therapies have mainly aimed at restoring dopamine (DA) levels, showing effectiveness but variable outcomes and side effects. Recent evidence indicates that PD complexity implicates disruptions in DA, noradrenaline (NA), and serotonin (5-HT) systems, which may underlie the variations in therapy effects. Methods: We present a system-level bio-constrained computational model that comprehensively investigates the dynamic interactions between these neurotransmitter systems. The model was designed to replicate experimental data demonstrating the impact of NA and 5-HT depletion in a PD animal model, providing insights into the causal relationships between basal ganglia regions and neuromodulator release areas. Results: The model successfully replicates experimental data and generates predictions regarding changes in unexplored brain regions, suggesting avenues for further investigation. It highlights the potential efficacy of alternative treatments targeting the locus coeruleus and dorsal raphe nucleus, though these preliminary findings require further validation. Sensitivity analysis identifies critical model parameters, offering insights into key factors influencing brain area activity. A stability analysis underscores the robustness of our mathematical formulation, bolstering the model validity. Discussion: Our holistic approach emphasizes that PD is a multifactorial disorder and opens promising avenues for early diagnostic tools that harness the intricate interactions among monoaminergic systems. Investigating NA and 5-HT systems alongside the DA system may yield more effective, subtype-specific therapies. The exploration of multisystem dysregulation in PD is poised to revolutionize our understanding and management of this complex neurodegenerative disorder.

Banisteriopsis caapi extract: Implications for neuroinflammatory pathways in Locus coeruleus lesion rodent model.

ETHNOPHARMACOLOGY RELEVANCE: Ayahuasca is a beverage obtained from the decoctions of Banisteriopsis caapi (Spruce ex Griseb.) Morton and Psychotria viridis Ruiz & Pav., used throughout the Amazon as a medicinal beverage for healing and spiritual exploration. The Banisteriopsis caapi extract consists of harmine, harmaline, and tetrahydroharmine (THH); which inhibit the isoforms of monoamine oxidase A and B. In the central nervous system (CNS), it can increase the norepinephrine (NE) concentration, produced in the Locus coeruleus (LC), reducing inflammation that is associated with some neurological disease, such as Parkinson's disease and Alzheimer's disease. AIM OF THE STUDY: evaluate the effects of treatment with B. caapi extract on the neuroinflammatory profile in animals with selective LC lesions. MATERIAL AND METHODS: male Wistar rats with LC lesions induced by 6-hydroxydopamine were treated with B. caapi extract. Subsequently, behavioral tests were conducted, including the elevated plus maze, rotarod, and open field. Tyrosine hydroxylase positive (TH+) neurons and IBA-1 positive microglia were quantified from the LC inflammatory markers and free radical products were assessed. RESULTS: Both 6-Hydroxydopamine hydrochloride and the Banisteriopsis caapi extract causes reduction of LC neurons, at the concentration and frequency used. The LC depletion and the treatment of B. caapi extract interfere with locomotion. B. caapi extract and the LC lesion increased the number and activation of inflammatory cells, such as microglia. B. caapi extract decreases IL-10 in the hippocampus and BDNF gene expression. CONCLUSION: This study suggests that B. caapi extract (at the concentration and frequency used) promotes noradrenergic neuron depletion and creates a proinflammatory environment in the CNS.

Cardiovascular risk of dementia is associated with brain-behaviour changes in cognitively healthy, middle-aged individuals.

Alzheimer's Disease (AD) neuropathology start decades before clinical manifestations, but whether risk factors are associated with early cognitive and brain changes in midlife remains poorly understood. We examined whether AD risk factors were associated with cognition and functional connectivity (FC) between the Locus Coeruleus (LC) and hippocampus - two key brain structures in AD neuropathology - cross-sectionally and longitudinally in cognitively healthy midlife individuals. Neuropsychological assessments and functional Magnetic Resonance Imaging were obtained at baseline (N=210), and two-years follow-up (N=188). Associations of cognition and FC with apolipoprotein ε4 (APOE ε4) genotype, family history of dementia, and the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score were investigated. Cross-sectionally, higher CAIDE scores were associated with worse cognition. Menopausal status interacted with the CAIDE risk on cognition. Furthermore, the CAIDE score significantly moderated the relationship between cognition and LC-Hippocampus FC. Longitudinally, the LC-Hippocampus FC decreased significantly over 2 years. These results suggest that cardiovascular risk of dementia is associated with brain-behaviour changes in cognitively healthy, middle-aged individuals.

Occlusal effects on text reading: an eye-tracker study.

Introduction: Asymmetric electromyographic (EMG) activity during teeth clenching has been linked to cognitive impairment, as evaluated by the Spinnler-Tognoni matrices test, and to asymmetric pupil size (anisocoria). Anisocoria indicates an asymmetric Locus Coeruleus activity, leading to an asymmetric hemispheric excitability worsening cognitive performance. Bite splint wearing corrects EMG asymmetry, reduces anisocoria and improves cognitive performance. This study explores the possible effect of EMG asymmetry on oculomotor behavior during text reading. Methods: In subjects showing different degrees of EMG asymmetry during clenching, the number and duration of fixation periods during a reading task, performed under two different occlusal conditions were analyzed. The first lecture was executed with a dental impression (imprint) interposed between the dental arches (corrected condition) and the second one with the arches in direct contact (habitual condition), without clenching effort. The imprint reduced the EMG asymmetries during clenching. Results: In both occlusal conditions, total reading time correlated with duration of fixations, but not with their number. An inverse relation was observed between the number of fixations and their duration across individuals. Fixation frequency and duration were positively and negatively correlated with the amplitude of EMG asymmetry, respectively. Differently, total reading time was not related to the EMG asymmetry. When switching from the corrected to the habitual condition, an increase in the number of fixations and a reduction in their duration was observed, while total reading time could be either increased or decreased. An increased fixation frequency was observed in most of the subjects, while a reduced duration only among individuals with shorter reading times in habitual condition. Discussion: In the habitual condition, EMG asymmetry influences reading patterns (more saccades/shorter fixations, less saccades/longer fixations) in our sample. The changes in text reading behavior elicited by occlusal correction can be explained by assuming that occlusal disharmony negatively interferes with the reading task by increasing the number of saccades necessary for text scanning. This finding may also indicate an increased difficulty in processing of visual information. The potential involvement of trigeminal pathways in the relation between occlusal factors and oculomotor control is discussed.

The Locus Coeruleus in Chronic Pain.

Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates.

Implication of locus coeruleus dysfunction in Prader-Willi syndrome: Insights from a mouse model.

Prader-Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/-p) animals. Compared to WT mice, Ndn + m/-p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/-p and WT mice, but Ndn + m/-p mice were less anxious. After acute restraint, Ndn + m/-p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/-p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/-p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.

Unique Pathology in the Locus Coeruleus of Individuals with Down Syndrome.

Background: Down syndrome (DS) is one of the most commonly occurring chromosomal conditions. Most individuals with DS develop Alzheimer's disease (AD) by 50 years of age. Recent evidence suggests that AD pathology in the locus coeruleus (LC) is an early event in sporadic AD. It is likely that the widespread axonal network of LC neurons contributes to the spread of tau pathology in the AD brain, although this has not been investigated in DS-AD. Objective: The main purpose of this study was to profile AD pathology and neuroinflammation in the LC, comparing AD and DS-AD in postmortem human tissues. Methods: We utilized immunofluorescence and semi-quantitative analyses of pTau (4 different forms), amyloid-ß (Aß), glial, and neuronal markers in the LC across 36 cases (control, DS-AD, and AD) to compare the different pathological profiles. Results: Oligomeric tau was highly elevated in DS-AD cases compared to LOAD or EOAD cases. The distribution of staining for pT231 was elevated in DS-AD and EOAD compared to the LOAD group. The DS-AD group exhibited increased Aß immunostaining compared to AD cases. The number of tau-bearing neurons was also significantly different between the EOAD and DS-AD cases compared to the LOAD cases. Conclusions: While inflammation, pTau, and Aß are all involved in AD pathology, their contribution to disease progression may differ depending on the diagnosis. Our results suggest that DS-AD and EOAD may be more similar in pathology than LOAD. Our study highlights unique avenues to further our understanding of the mechanisms governing AD neuropathology.

Can transcutaneous auricular vagus nerve stimulation mitigate vigilance loss? Examining the effects of stimulation at individualized versus constant current intensity.

According to the arousal model of vigilance, the locus coeruleus-norepinephrine (LC-NE) system modulates sustained attention over long periods by regulating physiological arousal. Recent research has proposed that transcutaneous auricular vagus nerve stimulation (taVNS) modulates indirect physiological markers of LC-NE activity, although its effects on vigilance have not yet been examined. Aiming to develop a safe and noninvasive procedure to prevent vigilance failures in prolonged tasks, the present study examined whether taVNS can mitigate vigilance loss while modulating indirect markers of LC-NE activity. Following a preregistered protocol (https://osf.io/tu2xy/), 50 participants completed three repeated sessions in a randomized order, in which either active taVNS at individualized intensity set by participant, active taVNS set at 0.5 mA for all participants, or sham taVNS, was delivered while performing an attentional and vigilance task (i.e., ANTI-Vea). Changes in salivary alpha-amylase and cortisol concentrations were measured as markers of LC-NE activity. Self-reports of feelings associated with stimulation and guessing rate of active/sham conditions supported the efficacy of the single-blind procedure. Contrary to our predictions, the observed vigilance decrement was not modulated by active taVNS. Pairwise comparisons showed a mitigation by active taVNS on cortisol reduction across time. Interestingly, Spearman's correlational analyses showed some interindividual effects of taVNS on indirect markers of LC-NE, evidenced by positive associations between changes in salivary alpha-amylase and cortisol in active but not sham taVNS. We highlight the relevance of replicating and extending the present outcomes, investigating further parameters of stimulation and its effects on other indirect markers of LC-NE activity.

Neuropathological findings in essential tremor.

Essential tremor (ET) is one of the most common neurological conditions and the most common movement disorder. The pathophysiological mechanisms that underlie this entity have not yet been described. However, recent post-mortem brain studies have provided useful insight into the underlying pathology of ET. Two brain areas have been consistently found to present neuropathological alterations in patients with ET: the brainstem, for presence of Lewy bodies or neuronal depletion, and the cerebellum, regarding Purkinje cells' morphology and density. In the present study we aim to review the literature on the main neuropathological findings in ET brains.