MRI-assessed locus coeruleus contrast and functional response are not associated in young and late middle-aged individuals

Abstract

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 to 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. 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. 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. Critically, while the LC contrast was higher in older individuals, the functional response of the LC was not associated with its contrast. These findings show that the age-related alterations of the LC structural integrity may not necessarily be related to changes in its functional response. The results further indicate that LC responses could remain stable in healthy individuals aged 20 to 70.

In vivoLocus Coeruleus activity while awake is associated with REM sleep quality in healthy older individuals

“…Participants further provided a subjective evaluation of their habitual sleep quality using a validated questionnaire: the Pittsburgh Sleep Quality Index (PSQI, ( 25 As already reported in this sample (27), we found significant activations within the bilateral (though more left lateralized) rostral part of the LC for the detection of the target sound (Figure 1C; p <.05, FWE corrected for multiple comparisons over the group-wise LC-mask), supporting a robust LC activation during the oddball task. Individual estimates of LC activity were then extracted within the entire individual LC masks in the participant brain space, for higher accuracy, and contrasted against the sleep metrics of interest.…”

“…(C) After the baseline night, participants underwent a fMRI session during which they completed an auditory oddball task. Brain responses to the deviant tones are displayed as in (27) over the group average brain structural image [top row; p<.001 uncorrected, right color legend refers to t-values between 3.26 – red - and 8 – yellow] (top) and only over the group-wise of the LC built based on individual LC masks (bottom ro; p<.05 FWE corrected).…”

“…Both with the left and the right LC activity, post-hoc tests yielded a significant correlation in the older (t > 2, p≤ 0.04 ), but not in the younger group (−0.9 < t < 0, p > 0.39). Furthermore, since we previously reported in our sample a significant age group difference in LC integrity – as indexed by its contrast (see methods and (27)) - we added LC contrast as a covariate in the GLMM which yielded the same main effects of LC activity and LC-activity-by-age-group interaction ( Table S1 ). Interestingly, the GLMM yielded a significant main effect of LC contrast (F = 5.34; p=0.025, R 2* = 0.1), with higher LC contrast associated to better sleep quality ( Figure 2B ) and no significant interaction between LC contrast and age group (p > 0.9)…”

“…REMS would therefore be maladaptive to the dissolving of distress leading to a higher level of general anxiety. Here, we probed LC activity using an oddball task known to recruit the salience network (27) and we used a sample of individuals devoid of sleep and anxiety disorders. Hence, our findings could consist of the healthy spectrum of the association between LC activity and REMS that would lead to insomnia disorder if exacerbated or prolonged over extended periods of time.…”

Insomnia and REM sleep instability

“…However, as noted above, Feige et al (2021) found reduced P2 amplitudes during phasic REM sleep in insomnia, interpreted as increased MMN, suggesting increased orienting response and concomitant arousal. MMN may be regarded as a measure of LC activation itself (Berger et al, 2023;Liao et al, 2016). First functional connectivity studies examined LC function in humans (Song et al, 2017;Zhang et al, 2016), and two studies found changed connectivity associated with anxiety or depression scores in insomnia (Gong et al, 2021;.…”