Sparse Asymmetry in Locus Coeruleus Pathology in Alzheimer's Disease.

 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.

Locus coeruleus features are linked to vagus nerve stimulation response in drug-resistant epilepsy.

The locus coeruleus-norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation.

Impact of light on task-evoked pupil responses during cognitive tasks.

Light has many non-image-forming functions including modulation of pupil size and stimulation of alertness and cognition. Part of these non-image-forming effects may be mediated by the brainstem locus coeruleus. The processing of sensory inputs can be associated with a transient pupil dilation that is likely driven in part by the phasic activity of the locus coeruleus. In the present study, we aimed to characterise the task-evoked pupil response associated with auditory inputs under different light levels and across two cognitive tasks. We continuously monitored the pupil of 20 young healthy participants (mean [SD] 24.05 [4.0] years; 14 women) whilst they completed an attentional and an emotional auditory task whilst exposed to repeated 30-40-s blocks of light interleaved with darkness periods. Blocks could either consist of monochromatic orange light (0.16 melanopic equivalent daylight illuminance (EDI) lux) or blue-enriched white light of three different levels [37, 92, 190 melanopic EDI lux; 6500 K]. For the analysis, 15 and then 14 participants were included in the attentional and emotional tasks, respectively. Generalised linear mixed models showed a significant main effect of light level on the task-evoked pupil responses triggered by the attentional and emotional tasks (p ≤ 0.0001). The impact of light was different for the target versus non-target stimulus of the attentional task but was not different for the emotional and neutral stimulus of the emotional task. There is a smaller sustained pupil size during brighter light blocks but, a higher light level triggers a stronger task-evoked pupil response to auditory stimulation, presumably through the recruitment of the locus coeruleus.

Impact of repeated short light exposures on sustained pupil responses in an fMRI environment.

Light triggers numerous non-image-forming, or non-visual, biological effects. The brain correlates of these non-image-forming effects have been investigated, notably using magnetic resonance imaging and short light exposures varying in irradiance and spectral quality. However, it is not clear whether non-image-forming responses estimation may be biased by having light in sequential blocks, for example, through a potential carryover effect of one light onto the next. We reasoned that pupil light reflex was an easy readout of one of the non-image-forming effects of light that could be used to address this issue. We characterised the sustained pupil light reflex in 13-16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light (0.16 melanopic equivalent daylight illuminance lux) and polychromatic blue-enriched white light of three different levels (37, 92, 190 melanopic equivalent daylight illuminance lux). As expected, higher melanopic irradiance was associated with larger sustained pupil light reflex in each cognitive domain. This result was stable over the light sequence under higher melanopic irradiance levels compared with lower ones. Exploratory frequency-domain analyses further revealed that sustained pupil light reflex was more variable under lower melanopic irradiance levels. Importantly, sustained pupil light reflex varied across tasks independently of the light condition, pointing to a potential impact of light history and/or cognitive context on sustained pupil light reflex. Together, our results emphasise that the distinct contribution and adaptation of the different retinal photoreceptors influence the non-image-forming effects of light and therefore potentially their brain correlates.

Light modulates task-dependent thalamo-cortical connectivity during an auditory attentional task.

Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. Here we record the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they complete an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We test if light modulates the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We find that only the blue-enriched light strengthens the connection from the posterior thalamus to the IPS. To the best of our knowledge, our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.

Locus coeruleus activity while awake is associated with REM sleep quality in older individuals.

BACKGROUNDThe locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans.METHODSWe used 7-Tesla functional MRI, sleep electroencephalography (EEG), and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22 years old; 28 women, 5 men) and 19 older (~61 years old; 14 women, 5 men) individuals.RESULTSWe found that, in older but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC.CONCLUSIONThese findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and we found that the LC may be an important target in the treatment of sleep- and age-related diseases.FUNDINGThis work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20), Action de Recherche Concertée - Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), ULiège, and European Regional Development Fund (Radiomed & Biomed-Hub).

Structural and functional characterization of the locus coeruleus in young and late middle-aged individuals.

Introduction: The brainstem locus coeruleus (LC) influences a broad range of brain processes, including cognition. The so-called LC contrast is an accepted marker of the integrity of the LC that consists of a local hyperintensity on specific Magnetic Resonance Imaging (MRI) structural images. The small size of the LC has, however, rendered its functional characterization difficult in humans, including in aging. A full characterization of the structural and functional characteristics of the LC in healthy young and late middle-aged individuals is needed to determine the potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast. Methods: We used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) to record brain response during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals. Results: Whole-brain analyses confirmed brain responses in the typical cortical and subcortical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC probability mask generated based on individual LC images. Although bilateral, the activation was more extensive in the left LC. Individual LC activity was not significantly different between young and late middle-aged individuals. Importantly, while the LC contrast was higher in older individuals, the functional response of the LC was not significantly associated with its contrast. Discussion: These findings may suggest that the age-related alterations of the LC structural integrity may not be related to changes in its functional response. The results further suggest that LC responses may remain stable in healthy individuals aged 20 to 70.

In vivo Locus Coeruleus activity while awake is associated with REM sleep quality in healthy older individuals.

The locus coeruleus (LC) is the primary source of norepinephrine (NE) in the brain, and the LC-NE system is involved in regulating arousal and sleep. It plays key roles in the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS). However, it is not clear whether the LC activity during the day predicts sleep quality and sleep properties during the night, and how this varies as a function of age. Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI), sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 52 healthy younger (N=33; ~22y; 28 women) and older (N=19; ~61y; 14 women) individuals. We find that, in older, but not in younger participants, higher LC activity, as probed during an auditory mismatch negativity task, is associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS (4-8Hz), which are two sleep parameters significantly correlated in our sample of older individuals. The results remain robust even when accounting for the age-related changes in the integrity of the LC. These findings suggest that the activity of the LC may contribute to the perception of the sleep quality and to an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep disorders and age-related diseases.