Dynamic behavior of the locus coeruleus during arousal-related memory processing in a multi-modal 7T fMRI paradigm

  1. Heidi IL Jacobs  Is a corresponding author
  2. Nikos Priovoulos
  3. Benedikt A Poser
  4. Linda HG Pagen
  5. Dimo Ivanov
  6. Frans RJ Verhey
  7. Kâmil Uludağ
  1. Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, United States
  2. Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Netherlands
  3. Faculty of Psychology and Neuroscience, Department of Cognitive Neuroscience, Maastricht University, Netherlands
  4. Center for Neuroscience Imaging Research, Institute for Basic Science and Department of Biomedical Engineering, Sungkyunkwan University, Republic of Korea
  5. Techna Institute & Koerner Scientist in MR Imaging, University Health Network, Canada
13 figures, 1 table and 9 additional files

Figures

Figure 1 with 2 supplements
Experimental design.

(A) Task procedure. The salivettes indicate the time points of collection of saliva samples. For the 7T fMRI part, anatomical scans and a baseline 6 min resting state with a fixation cross were …

Figure 1—figure supplement 1
Sagittal and axial slices of the T1-weighted and fMRI average in the MNI space at the level of the hippocampus and brainstem.

Note: The first column shows the matched MNI template. The middle column shows the average of individual T1-weighted scans warped to the MNI space. The right column shows the average of the …

Figure 1—figure supplement 2
Comparison of the temporal signal-to-noise ratio (tSNR) per participant across fMRI pipelines.

Note: Compared to the ‘spatially normalized’ pipeline, the ‘FIX’ pipeline provided a sizable gain in tSNR, while including explicit physiological time series provided a modest tSNR increase (median …

Figure 2 with 1 supplement
Behavioral performance (N = 27).

(A) Hit rate for emotional and neutral conditions during recognition (paired Wilcoxon test: Z = −1.17, p=0.244). (B) False alarm rate for emotional and neutral conditions during recognition (paired …

Figure 2—source data 1

Behavioral performance on the face-name association task.

Individual hit rates, false alarms, bias scores for the recognition, recollection scores (raw and bias-adjusted) are provided for the neutral and emotional valence condition.

https://cdn.elifesciences.org/articles/52059/elife-52059-fig2-data1-v2.rdata
Figure 2—figure supplement 1
Schematic representation of the procedure used to calculate bias-free emotional recollection scores.

Note: Recognition – and hence the recognition bias - was based on the correct or incorrect recognition of faces. Recollection involved the identification of the name belonging to the face (see also F…

Associations between autonomic tone measures and memory performance across the task stages.

(A) sAA change during the task (encoding, consolidation and recollection) relative to the baseline resting-state. A significant increase in sAA was observed between consolidation and baseline …

Figure 3—source data 1

Autonomic tone and memory performance across the entire paradigm.

Individual ΔsAA, rMSSD values per task stage. The emotional memory scores provided for panel B show the proportion of adjusted emotional scores versus neutral scores as indicated in the methods.

https://cdn.elifesciences.org/articles/52059/elife-52059-fig3-data1-v2.rdata
Figure 4 with 2 supplements
Associations between LC BOLD and autonomic tone measures using repeated measures correlations.

(A–B) LC component visualization. (A) Group average t-map from the dual-regression showing a robust bilateral LC component, thresholded at p<0.01 FWE, after denoising with FIX (N = 24). (B) LC …

Figure 4—source data 1

Locus coeruleus BOLD and autonomic tone measures across the entire paradigm.

Individual ΔsAA, rMSSD, LC and reference BOLD values per task stage. Individual coherence values between.

https://cdn.elifesciences.org/articles/52059/elife-52059-fig4-data1-v2.rdata
Figure 4—figure supplement 1
Functional template of the locus coeruleus during resting-state.

Note: LC template made from all LC scans. (A) Hyperintense signal can be seen close to the 4thventricle. (B-E) Group average t-maps from dual-regression of LC component, thresholded at significance …

Figure 4—figure supplement 2
Relationship between LC variability and rMSSD across the task stages for each preprocessing pipeline.

Note: (A) spatially normalized pipeline (not significant, p-value=0.312, CI (95%) = [−0.175, 0.483]). (B) FIXed + explicit Resp pipeline (trend-level negative association, Rrm = −0.29, p=0.07, CI …

Figure 5 with 3 supplements
Coherence between LC and HRV across the task stages.

(A) LC coherence magnitude squared plotted against frequency for each task stage for a single participant. The high-frequency HRV band is depicted in a lighter shade. (B) Reference ROI-HRV coherence …

Figure 5—source data 1

Coherence between locus coeruleus BOLD and HRV.

Individual coherence values between locus coeruleus or reference BOLD and HRV per frequency are provided for each task stage in the paradigm. For panel E and F, the individual ΔsAA and median of maximum coherence between locus coeruleus or reference BOLD and HRV are provided.

https://cdn.elifesciences.org/articles/52059/elife-52059-fig5-data1-v2.rdata
Figure 5—figure supplement 1
Coherence between LC and HRV across the task stages for the spatially normalized pipeline.

Note: Coherence between LC and HRV across the task stages. (A) LC coherence magnitude squared plotted against frequency for each task stage for a single participant. The high-frequency HRV band is …

Figure 5—figure supplement 2
Coherence between LC and HRV across the task stages for the FIXed pipeline Note: Coherence between LC and HRV across the task stages.

(A) LC coherence magnitude squared plotted against frequency for each task stage for a single participant. The high-frequency HRV band is depicted in a lighter shade. (B) Reference ROI-HRV coherence …

Figure 5—figure supplement 3
Coherence between LC and HRV across the task stages for the FIXed + Explicit Resp pipeline.

Note: Coherence between LC and HRV across the task stages. (A) LC coherence magnitude squared plotted against frequency for each task stage for a single participant. The high-frequency HRV band is …

Figure 6 with 3 supplements
LC and MTL activity during the task stages (N = 24).

(A) Bilateral hippocampus, bilateral amygdala and entorhinal cortex activation during encoding (Encoding >Not Encoding; thresholded at p<0.05, uncorrected). (B–E) LC activation during encoding …

Figure 6—source data 1

Locus coeruleus and medial temporal lobe activity during the task stages.

Individual beta’s are provided for the amygdala, hippocampus and locus coeruleus for the examined relevant contrasts during encoding.

https://cdn.elifesciences.org/articles/52059/elife-52059-fig6-data1-v2.rdata
Figure 6—figure supplement 1
Mask of regions used in the GLM and functional connectivity analyses.

Note: Sagittal, coronal and axial slices of the mask that was used for volume correction for the functional connectivity and general linear model analysis (white; overlaid over the MNI 1 mm template).

Figure 6—figure supplement 2
Individual brainstem results for the GLM contrasts during encoding.

Note: Individual brainstem results for the GLM contrasts during encoding. Each column shows the brainstem activity at p<0.05 (uncorrected) for several contrasts during encoding and for five randomly …

Figure 6—figure supplement 3
Encoding-related brain activation for recognition contrasts.

Note: (A) Right middle temporal gyrus activation during encoding (Emotional >Neutral, threshold at p<0.05, uncorrected). (B) Right temporal fusiform cortex activation during encoding (Successful >Not…

Figure 7 with 1 supplement
Integration of LC and MTL timeseries across the task (N = 24).

(A) Functional connectivity (FC) from LC component to MTL structures across task stages. Clusters of decreased FC in hippocampus, amygdala and entorhinal cortex were observed comparing consolidation …

Figure 7—source data 1

Coherence and phase between time series of the locus coeruleus and medial temporal lobe clusters.

Individual coherence and phase values between the locus coeruleus and each cluster in the medial temporal lobe (amygdala, hippocampus, entorhinal cortex) are provided per task stage.

https://cdn.elifesciences.org/articles/52059/elife-52059-fig7-data1-v2.rdata
Figure 7—figure supplement 1
Functional connectivity from LC to MTL during consolidation compared to baseline across preprocessing steps.

Note: Functional connectivity (FC) from LC component to medial temporal lobe regions during consolidation compared to baseline across preprocessing steps (t-values threshold at p<0.05, uncorrected …

Figure 8 with 1 supplement
Structural segmentation of the LC and associations with emotional memory performance (N = 24).

(A) 3D visualization of the LC placement in the pons. (B) The LC template, coronal view (hyperintense rod-like shape). (C) Segmentation of the LC in template (green). (D) TFL mean intensity …

Figure 8—source data 1

Structural locus coeruleus intensity and memory performance.

Individual locus coeruleus intensity values (entire locus coeruleus, rostral, middle and caudal) and emotional memory scores are provided. The emotional memory scores are calculated as the proportion of adjusted emotional scores versus neutral scores as indicated in the methods.

https://cdn.elifesciences.org/articles/52059/elife-52059-fig8-data1-v2.rdata
Figure 8—figure supplement 1
Template of the locus coeruleus for structural analyses.

Note: Axial slices of the high-resolution Magnetization-Transfer weighted template (2 mm apart) that was used for structural analysis. Zoomed-in slices at LC level are shown in the middle row. In …

Author response image 1
Mid-sagittal, coronal and axial slices in the MNI-space for every T1-weighted (first 3 columns) and fMRI-dataset (last 3 columns).

Every row represents a participant. The first row shows the relevant MNI slices. Also see Author responses image 2-4.

Author response image 2
Author response image 3
Author response image 4
Author response image 5
Overlap ratio of individual ROI (Freesurfer-segmented hippocampus and brainstem) versus the matched ROI across the group.

The distribution for each individual is shown in the x-axis.

Tables

Table 1
Behavioral results of the memory task for emotional and neutral valence.

Note: numbers provided are median and interquartile range (IQR). Differences between emotional and neutral stimuli were tested with a paired Wilcoxon test. All scores, except for the bias express %.

Emotional
(Median (IQR))
Neutral
(Median (IQR))
Zp-value
Recognition Hit Rate
(Old faces)
53.33
(45.56, 61.11)
53.33
(44.44, 67.78)
−1.170.244
Recognition Miss Rate (Old faces)46.67
(38.89, 54.44)
46.67
(32.22, 55.56)
1.20.229
Recognition Correct Rejection Rate
(New faces)
77.27
(65.91, 81.82)
86.36
(77.27, 90.91)
−3.77<0.001
Recognition False Alarm Rate (New faces)22.73
(18.18, 34.09)
13.64
(9.09, 22.73)
3.81<0.001
Recognition Hit Rate - Recognition False Alarm Rate23.94
(17.02, 32.83)
37.68
(28.23, 50.81)
−3.16<0.001
Recognition Response Bias0.90
(0.81, 0.92)
0.84
(0.74, 0.9)
2.290.02
Recollection Hit Rate Raw24.44
(18.89, 31.11)
26.67
(18.89, 33.33)
0.350.726
Recollection Hit Rate (correct recognition)50
(43.43, 54.01)
44.83
(37.97, 58.77)
0.060.953
Recollection Hit Rate (Old faces) - Recollection False Alarm Rate (Old faces)0.00
(−13.14–8.01)
−10.34
(−24.07–17.54)
0.060.953
Bias-corrected Recollection Hit Rate38.68
(36.68, 39.46)
29.97
(28.01, 33.39)
4.41<0.001

Additional files

Supplementary file 1

Demographics and neuropsychological performance of the group.

https://cdn.elifesciences.org/articles/52059/elife-52059-supp1-v2.docx
Supplementary file 2

Available data per modality and time point.

Note: numbers provided are N and % compared to the total sample size (N = 27); HRV = heart rate variability

https://cdn.elifesciences.org/articles/52059/elife-52059-supp2-v2.docx
Supplementary file 3

Task stages differences in sAA, rMSSD or LC BOLD variance.

Note: Linear mixed effects models with random intercept for each person and task stage as fixed effect. Estimates indicate the unstandardized beta-coefficients. P-values are adjusted for multiple comparisons using the False Discovery rate.

https://cdn.elifesciences.org/articles/52059/elife-52059-supp3-v2.docx
Supplementary file 4

Relationship between frequency and coherence between LC and heart rate variability across the task stages (Spatially normalized pipeline).

Note: Linear mixed effects models with random intercept for each person, task stage, frequency and their interaction as fixed effect. Estimates indicate the unstandardized beta-coefficients. P-values are adjusted for multiple comparisons using the False Discovery rate.

https://cdn.elifesciences.org/articles/52059/elife-52059-supp4-v2.docx
Supplementary file 5

Relationship between frequency and coherence between LC and heart rate variability across the task stages.

Note: Linear mixed effects models with random intercept for each person, task stage, frequency and their interaction as fixed effect. Estimates indicate the unstandardized beta-coefficients. P-values are adjusted for multiple comparisons using the False Discovery rate.

https://cdn.elifesciences.org/articles/52059/elife-52059-supp5-v2.docx
Supplementary file 6

Relationship between frequency and coherence between LC and heart rate variability across the task stages (Fixed + Explicit Resp pipeline).

Note: Linear mixed effects models with random intercept for each person, task stage, frequency and their interaction as fixed effect. Estimates indicate the unstandardized beta-coefficients. P-values are adjusted for multiple comparisons using the False Discovery rate.

https://cdn.elifesciences.org/articles/52059/elife-52059-supp6-v2.docx
Supplementary file 7

Relationship between frequency and coherence between LC and heart rate variability across the task stages (Fixed + Explicit Phys pipeline).

Note: Linear mixed effects models with random intercept for each person, task stage, frequency and their interaction as fixed effect. Estimates indicate the unstandardized beta-coefficients. P-values are adjusted for multiple comparisons using the False Discovery rate.

https://cdn.elifesciences.org/articles/52059/elife-52059-supp7-v2.docx
Supplementary file 8

Task-related activation patterns during encoding and recollection and functional connectivity (FC) alterations across the task stages.

Note: Brain regions activated during encoding, recollection or functional connectivity differences across the conditions (Family-wise error corrected for multiple comparisons using TFCE at p<0.05). Coordinates are provided in 1 mm MNI-space.

https://cdn.elifesciences.org/articles/52059/elife-52059-supp8-v2.docx
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