G Model

SJPMH-685; No. of Pages 9 ARTICLE IN PRESS

Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx

Available online at www.sciencedirect.com

Spanish Journal of Psychiatry and Mental Health

journal homepage: http://http://www.elsevier.es/sjpmh

Original

Effective connectivity of the locus coeruleus in patients with late-life

Major Depressive Disorder or mild cognitive impairment
Pablo Maturana-Quijada a,b , Pamela Chavarría-Elizondo a,b,c , Inés del Cerro d ,
Ignacio Martínez-Zalacaín a,e , Asier Juaneda-Seguí a , Andrés Guinea-Izquierdo a ,
Jordi Gascón-Bayarri f , Ramón Reñé f , Mikel Urretavizcaya a,b,c , José M. Menchón a,b,c ,
Isidre Ferrer g,h,i , Virginia Soria a,c,j , Carles Soriano-Mas a,c,k,∗
a
Psychiatry and Mental Health Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
b
Department of Clinical Sciences, Bellvitge Campus, University of Barcelona, Barcelona, Spain
c
Network Center for Biomedical Research on Mental Health (CIBERSAM), Carlos III Health Institute (ISCIII), Barcelona, Spain
d
Department of Psychology, Medical School, Catholic University of Murcia, Murcia, Spain
e
Radiology Department, Hospital Universitari de Bellvitge, Barcelona, Spain
f
Dementia Diagnostic and Treatment Unit, Department of Neurology, Bellvitge University Hospital, Barcelona, Spain
g
Department of Pathology and Experimental Therapeutics, Institute of Neurosciences, University of Barcelona, Barcelona, Spain
h
Bellvitge Biomedical Research Institute-IDIBELL, Department of Pathologic Anatomy, Bellvitge University Hospital, Barcelona, Spain
i
Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
j
Department of Mental Health, Parc Taulí Hospital Universitari, Sabadell, Barcelona, Spain
k
Department of Social Psychology and Quantitative Psychology, Institute of Neurosciences, University of Barcelona, Barcelona, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: We compared effective connectivity from the locus coeruleus (LC) during the resting-state
Received 28 December 2023 in patients with late-life Major Depressive Disorder (MDD), individuals with amnestic Mild Cognitive
Accepted 26 February 2024 Impairment (aMCI), and Healthy Controls (HCs).
Available online xxx
Participants: 23 patients with late-life MDD, 22 patients with aMCI, and 28 HCs.
Material and methods: Participants were assessed in two time-points, 2 years apart. They underwent a
Keywords:
resting-state functional magnetic resonance imaging and a high-resolution anatomical acquisition, as
Dynamic causal modeling
well as clinical assessments. Functional imaging data were analyzed with dynamic causal modeling, and
Effective connectivity
Mild cognitive impairment
parametric empirical Bayes model was used to map effective connectivity between 7 distinct nodes: 4
Major Depressive Disorder from the locus coeruleus and 3 regions displaying gray matter decreases during the two-year follow-up
Alzheimer’s disease period.
Results: Longitudinal analysis of structural data identified three clusters of larger over-time gray matter
volume reduction in patients (MDD + aMCI vs. HCs): the right precuneus, and the visual association and
parahippocampal cortices. aMCI patients showed decreased effective connectivity from the left rostral
to caudal portions of the LC, while connectivity from the left rostral LC to the parahippocampal cortex
increased. In MDD, there was a decline in effective connectivity across LC caudal seeds, and increased
connectivity from the left rostral to the left caudal LC seed over time. Connectivity alterations with cortical
regions involved cross-hemisphere increases and same-hemisphere decreases.
Conclusions: Our discoveries provide insight into the dynamic changes in effective connectivity in indi-
viduals with late-life MDD and aMCI, also shedding light on the mechanisms potentially contributing to
the onset of neurodegenerative disorders.
© 2024 The Authors. Published by Elsevier España, S.L.U. on behalf of Sociedad Española de
Psiquiatría y Salud Mental (SEPSM). This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

The locus coeruleus (LC), an elongated structure situated within

the dorsolateral pontine tegmentum, serves as the primary source
∗ Corresponding author. of norepinephrine (NE) within the brain. Notably, the LC has gar-
E-mail address: carles.soriano.mas@ub.edu (C. Soriano-Mas).

https://doi.org/10.1016/j.sjpmh.2024.02.002
2950-2853/© 2024 The Authors. Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Psiquiatría y Salud Mental (SEPSM). This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al., Effective connectivity of the locus coeruleus
in patients with late-life Major Depressive Disorder or mild cognitive impairment, Spanish Journal of Psychiatry and Mental Health,
https://doi.org/10.1016/j.sjpmh.2024.02.002
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al. Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx

Table 1
Sociodemographic and clinical characteristics of the study sample.

MDD patients aMCI patients HC Statistic MDD patients aMCI patients HC Statistic
N = 23 N = 22 N = 28 (p value)* N = 23 N = 22 N = 28 (p value)*

Sociodemographic characteristics at baseline Sociodemographic characteristics at 2-year follow-up

Age, years; mean 67.57 (4.25) 70.14 (3.61) 67.50 (3.90) H = 6.41 (0.040) 69.70 (4.14) 72.18 (3.58) 69.50 (3.97) H = 6.69 (0.035)
(SD) [range] [60–74] [61–76] [60–75] [62–76] [63–77] [62–77]
2
Sex, female; n (%) 17 (73.9) 13 (59.1) 18 (64.3) X = 1.12 (0.570) 17 (73.9) 13 (59.1) 18 (64.3) X2 = 1.12 (0.570)

Clinical characteristics at baseline Clinical characteristics at 2-year follow-up

HDRS; mean (SD) 10.35 (5.83) 6.45 (5.34) 1.29 (2.93) H = 35.18 3.96 (4.65) 4.64 (6.54) 1.86 (1.94) H = 5.38 (0.068)
[range] [1–19] [0–19] [0–15] (<0.001) [0–16] [0–30] [0–7]
GDS; mean (SD) 5.57 (4.29) 2.95 (2.26) 1.32 (2.43) H = 20.81 5.57 (4.28) 3.14 (3.41) 1.89 (2.57) H = 12.89 (0.002)
[range] [0–12] [0–9] [0–12] (<0.001) [0–14] [0–15] [0–9]
MMSE; mean (SD) 26.96 (2.18) 25.64 (2.50) 28.86 (1.41) H = 27.27 25.39 (2.84) 22.09 (4.51) 28.79 (1.26) H = 43.27
[range]** [21–30] [20–29] [24–30] (<0.001) [19–29] [13–27] [25–30] (<0.001)
Long term 6.39 (1.64) 2.05 (1.29) 8.39 (1.75) H = 53.24 5.78 (2.70) 2.09 (2.45) 8.07 (1.76) H = 38.19
memory***; mean [4–10] [0–4] [6–12] (<0.001) [0–11] [0–7] [3–11] (<0.001)
(SD) [range]

aMCI; amnestic Mild Cognitive Impairment, GDS; Geriatric Depression Scale, HC; healthy controls, HDRS; Hamilton Depression Rating Scale, MDD; late-life Major Depression
Disorder, MMSE; Mini-Mental State Examination, SD; standard deviation.
*
Statistic value corresponds to Kruskal–Wallis H test for continuous variables and Chi-square test for categorical variables.
**
The cut-off in the Spanish version of the MMSE is adjusted for age and schooling years. Scores higher than 23 for literate people and higher than 18 for illiterates indicate
preserved general cognitive functioning.
***
Evaluated with the delayed recall test from the Weschler Memory Scale III (WMS-III).

nered considerable attention in research owing to its pivotal role
in the preclinical phases of Alzheimer’s disease (AD).1 This signifi-
cance arises from the identification of abnormal intraneuronal tau,
a hallmark of AD pathology, in the LC even preceding observable
neuronal loss, and potentially initiating as early as young adult-
hood.
Recent investigations have unveiled a distinct pattern of neu-
ronal loss in AD, particularly affecting the rostral and medial–dorsal
projecting neurons within the LC. This loss profoundly impacts dis-
ease severity by reducing NE availability in critical areas like the
forebrain and hippocampus, known for their involvement in atten-
tion, memory, and arousal.2
Given its close association with the aging process, AD pre-
dominantly affects individuals over 65 years, with its prevalence
doubling approximately every five years, culminating in a time-
dependent exponential rise.3 Mild cognitive impairment (MCI),
a common condition among older adults, entails compromised
cognitive function and poses a substantial risk for progression to
dementia, especially the amnestic subtype (aMCI) characterized by
memory dysfunction. Insightfully, the LC emerges as a key player
in this scenario as neurofibrillary tangles, and their precursors,
manifest during normal aging and escalate in visibility during the
transition from MCI to early AD.4
The intricate interplay between mild cognitive impairment and
late-life Major Depressive Disorder (MDD) remains an enigma,
with both conditions frequently co-occurring in the older persons.5
Notably, depression has been implicated as a risk factor for the
MCI-to-dementia trajectory.6 Furthermore, compelling evidence
substantiates the linkage between late-life depression and height-
ened susceptibility for major neurocognitive disorders (MND),
particularly AD.7 Remarkably, patients with MDD demonstrate
LC neuronal loss, exacerbating the deficiency of NE input to the
cerebral cortex. This degenerative process, albeit gradual, triggers
compensatory mechanisms including axonal sprouting in LC nora-
drenergic projections to the hippocampus and the prefrontal cortex
(PFC).8,9 Notably, neuroimaging techniques present a promising
avenue for non-invasive evaluation of the LC and its connectivity
as a biomarker of noradrenergic dysfunction.
In this study, we explored the 2-year evolution of resting-state
effective connectivity (EC) from the LC, using spectral Dynamic
causal modeling, among patients with major late-life depressive
disorder or amnestic mild cognitive impairment, in compari-
son with healthy controls. Our investigation encompasses seven
distinct regions, including four LC nodes stratified into caudal
and rostral divisions, connected with three brain regions that in
our sample exhibited differential volumetric changes across time
points. We hypothesize that functional compensation mechanisms
can occur alongside EC deficits associated with the early stages of
Alzheimer’s disease (AD).
Methods
Participants
The study sample comprised 73 individuals. These participants
were categorized into three distinct groups: 23 patients diagnosed
with late-life Major Depressive Disorder (MDD), 22 individuals
with amnestic Mild Cognitive Impairment (aMCI), and 28 Healthy
Controls (HCs) (Table 1). MDD subjects were recruited consec-
utively from the Psychiatry Department of Bellvitge University
Hospital in Barcelona, Spain. Inclusion criteria specified that major
depression must be the primary diagnosis, and the onset of the
first depressive episode should occur after 40 years of age, fol-
lowing the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV-TR)10 criteria.
Conversely, individuals with aMCI were consecutively recruited
from the Department of Neurology of the same hospital. Diagno-
sis adhered to Petersen11 criteria, which included self-reported
memory complaints corroborated by informants and objectively
established long-term memory impairments (i.e., scores falling 1.5
standard deviations below age- and education-adjusted normative
values in the delayed recall test from the Wechsler Memory Scale
III12 (WMS-III)), along with Clinical Dementia Rating13 (CDR) scores
of 0.5.
All participants underwent comprehensive evaluations, includ-
ing the administration of the Mini-International Neuropsychiatric
Interview (MINI) and the Mini-Mental State Examination (MMSE)
as a cognitive screening measure. Depression severity in both
groups was assessed using the Spanish brief version of the Geriatric
Depression Scale (GDS) and the Hamilton Depression Rating Scale
(HDRS), although not for diagnostic purposes. Importantly, aMCI
participants had no history or present comorbidities with MDD,
whereas seven out of the 23 MDD patients concurrently exhibited
aMCI diagnoses.

2
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al.
Exclusion criteria comprised: (1) ages below 60 or above 76
years, (2) history or current diagnoses of other major psychiatric
disorders, including substance abuse or dependence (excluding
nicotine), (3) intellectual disabilities or neurodevelopmental dis-
orders, (4) neurological disorders, (5) Hachinski Ischemic Score
exceeding 5 to exclude those at high risk for vascular-derived
cognitive deficits, (6) presence of major neurocognitive disorders
(DSM-5 criteria), which corresponds to dementia as per DSM-IV-TR
criteria and/or Clinical Dementia Rating (CDR) score > 1, (7) sig-
nificant medical conditions, (8) electroconvulsive therapy within
the preceding year, (9) conditions impeding neuropsychological
assessments or MRI procedures (e.g., blindness, deafness, claus-
trophobia, presence of pacemakers or cochlear implants), and (10)
gross abnormalities in the MRI scan.
The study received approval from The Clinical Research Ethics
Committee (CEIC) of Bellvitge University Hospital (reference
PR156/15, February 17th, 2016), and adherence to the ethical
standards outlined in the 1975 Declaration of Helsinki and its
subsequent amendments (revised in 2000) was ensured. All par-
ticipants provided written informed consent before participating
in the study.
Neuroimaging data acquisition and preprocessing
All participants underwent identical imaging sessions at two
time-points: baseline and a two-year follow-up. In each session,
a functional magnetic resonance sequence during the resting-
state and a whole-brain T1-weighted anatomical sequence were
acquired. See the Supplementary material for details on image
acquisition and preprocessing.
ROI selection and time series extraction
Our functional analyses encompassed seven distinct nodes, as
depicted in Fig. 1.
We first performed group comparisons of longitudinal volumet-
ric changes between patients and HCs (i.e., MDD + aMCI vs. HCs)
using an exploratory whole-brain and voxel-wise two-sample t-
test comparison. See the Supplementary material for details on the
preprocessing of structural data. Age and gender were included
as confounding covariates in this analysis. Areas of increased and
decreased GM volume were identified with a voxel-level peak
detection threshold of p = 0.001, uncorrected for multiple compar-
isons.
We then selected the three regions displaying longitudinal vol-
ume decrease according to such longitudinal analysis of structural
data. These were the visual association cortex (VAC) (MNI: 27, −80,
36); the precuneus (PCUN) (MNI: 15, −45, 57); and the parahip-
pocampal cortex (PHC) (MNI: 30, −23, −23); all within the right
hemisphere (see results below).
Next, we selected four coordinates of the LC, as outlined in a
published atlas,14 corresponding to the bilateral locations of the
rostral and caudal divisions of the nucleus. Specifically, our regions
were labeled as: the right rostral LC (RroLC) (MNI 2, −35, −17); the
right caudal LC (RcaLC) (MNI 4, −39, −25); the left rostral LC (LroLC)
(MNI −2, −36, −18); and the left caudal LC (LcaLC) (MNI −4, −38,
−25).
The BOLD fMRI time series corresponding to the aforementioned
Regions of Interest (ROIs) were obtained from the pre-processed
data using the residuals of a General Linear Model (GLM) that
included twenty-four head motion parameters15 and global white
matter (WM) and cerebrospinal fluid (CSF) signals as nuisance
regressors. Therefore, we selected the MNI coordinates of each ROI
as the center of an 8-mm sphere to compute the subject-specific
principal eigenvariate, correcting for such confounds.
3
Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx
Neural network modeling: spectral dynamic causal modeling
(spDCM)
Spectral dynamic causal modeling (spDCM) analyses were con-
ducted using functions from DCM12.5 revision 7497, implemented
within SPM12. spDCM serves as a model-based analytical frame-
work, facilitating the inference of intrinsic causal connections
among specific regions through cross-spectral density. Unlike task-
based approaches, spDCM computes endogenous coupling among
regions without requiring explicit experimental input, making it
computationally efficient and sensitive to group differences. Our
primary focus for spDCM analyses was to investigate alterations in
effective connectivity originating from the LC modulated over time
within the MDD and aMCI groups. Fig. 2 presents a visual sum-
mary of the spDCM analysis outcomes. Further description of these
analyses can be found in the Supplementary material.
Results
Clinical characteristics
The sample consisted of 73 individuals between 60 and 76 years:
23 patients with late-life MDD (17 females, mean age ± standard
deviation (SD): 69 ± 4.1 years), 22 individuals with aMCI (13
females, mean age ± SD: 73 ± 3.5 years), and 28 healthy controls
(18 females, mean age ± SD: 69 ± 3.9 years); see Table 1. The clinical
outcomes are also presented in Table 1. Over the 2-year follow-
up period, both patient groups exhibited significant decreases in
the MMSE scores. Additionally, and as expected, the MDD group
displayed notably higher scores both in the HDRS and the GDS
assessments at baseline. Furthermore, it is noteworthy that HDRS
scores exhibited a decrease during the follow-up period, unlike GDS
scores. This trend suggests that quantitative (non-dichotomous)
scoring systems may possess greater sensitivity to longitudinal
symptom changes compared to GDS.
Structural data analyses
The longitudinal whole-brain voxel-based GM analyses compar-
ing MDD + aMCI vs. HCs revealed different regions of GM volume
reduction. Specifically, patients displayed GM volume decreases
over time in the following right hemisphere regions in compari-
son to HCs: the precuneus (PCUN), the occipital lobe, encompassing
visual motor and visual association cortex (VAC), and the parahip-
pocampal cortex (PHC). Detailed results of this analysis can be
found in Fig. 1a.
Spectral dynamic causal modeling and parametric empirical Bayes
Through the application of parametric empirical Bayes (PEB),
we estimated extrinsic connectivity along with associated uncer-
tainties, the influence of time, and the differences between control
and patient groups (Table 2). Our model focused on connections
from the LC to regions displaying significant patient-control dif-
ferences in volume changes over time. Employing Bayesian Model
Reduction (BMR), we streamlined the model by excluding con-
nections lacking substantial evidence, and subsequently applied
Bayesian Model Averaging (BMA) to compute a weighted mean of
parameters derived from BMR. Fig. 3 illustrates the BMA outcome,
depicting group-level estimates of network connection strengths,
their uncertainties, and posterior probabilities for surviving a 95%
threshold.
Fig. 3A presents the comparison of patients with aMCI and
healthy controls. Patients with aMCI present a decreased connec-
tivity within the LC over time, which extends from the left rostral
region to the bilateral caudal region. There is also an increase in
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al. Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx

Fig. 1. Effective connectivity analysis pipeline. (a) Regions that exhibited significant between-group differences in volume, where controls had greater values than patients,
as revealed in the longitudinal structural data analyses. (b) These nodes, serving as the ROIs (region of interest) or seeds of interest, were selected from the peak coordinates
of the structural analyses described in ‘a.’ These nodes include the posterior hippocampus (PHC), in red, the posterior cingulate cortex (PCUN), in light green, and the ventral
anterior cingulate (VAC), in blue, all from the right hemisphere. (c) The LC ROIs were selected from two different divisions of each hemisphere nuclei: the right rostral and
caudal divisions are depicted in orange, while the left rostral and caudal divisions are depicted in yellow. (d) Time series data extracted from each of the ROIs mentioned in
‘b.’ and ‘c.’ were utilized to perform spectral dynamic causal modeling. (e) In our model, we assumed intrinsic connectivity between the different divisions of the LC and the
brain regions that exhibited differential volume decreases between patients and controls over time.

effective connectivity over time from the left rostral LC to the right
parahippocampal cortex.
Fig. 3B shows the difference between subjects with MDD and
healthy subjects, in which we observed a decline in effective con-
nectivity from the bilateral caudal seeds to the left caudal seed, as
well as an increased connectivity from the right rostral to the left
caudal LC seed over time. The analysis of the connectivity from the
LC to cortical regions reveals increases in cross-hemisphere con-
nections and decreases in same-hemisphere connections, originat-
ing predominantly from the rostral LC and extending to the visual
association cortex and the precuneus of the right hemisphere.
Discussion
This study employed spDCM to examine changes in resting-state
effective connectivity over a two-year follow-up period in patients
with aMCI or MDD, conditions associated with an elevated risk of
developing AD. In comparison to a HC group, our findings revealed
distinct effective connectivity patterns. In patients with aMCI, we
observed a progressive decrease in LC connectivity over time, span-
ning from the left rostral to the bilateral caudal regions of the LC.
Simultaneously, there was an increasing effective connectivity over
time, specifically from the left LC to the right parahippocampal cor-

4
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al. Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx

Fig. 2. Design of the parametric empirical Bayes (PEB) analysis. (a) Presentation of the Spectral Dynamic Causal Modeling (spDCM) results encompassing 31 estimated
parameters. (b) These results were then analyzed using parametric empirical Bayes (PEB) analysis to explore group-level effects over time. The analysis employs a general
linear model of connectivity parameters, illustrated by the design matrix 2 , which represents time (PRE-POST), and 2 , accounting for group effects, baseline (PRE), and
two-year follow-up (POST). (c) Display the estimated parameters for PEB, focusing on time effects. (d) Reveals the estimated parameters for PEB of PEBs, emphasizing group
effects. aMCI; amnestic Mild Cognitive Impairment, HC; healthy controls, MDD; late-life Major Depression Disorder.

5
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al. Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx

Table 2
DCM parameter estimates of intrinsic connections in second level PEB.

Intrinsic parameters Mean (Hz) 95% CI

aMCI vs HC
Rostral left locus coeruleus → caudal right locus coeruleus −0.13 −0.06 to −0.19
Rostral left locus coeruleus → caudal left locus coeruleus −0.14 −0.05 to −0.20
Rostral left locus coeruleus → parahippocampal cortex 0.08 0.03 to 0.13

MDD vs HC
Caudal right locus coeruleus → caudal left locus coeruleus −0.12 −0.04 to −0.18
Caudal left locus coeruleus → caudal left locus coeruleus −0.10 −0.02 to −0.16
Rostral left locus coeruleus → caudal left locus coeruleus 0.15 0.08 to 0.21
Rostral left locus coeruleus → visual association cortex 0.10 0.05 to 0.15
Rostral right locus coeruleus → visual association cortex −0.13 −0.07 to −0.18
Caudal left locus coeruleus → precuneus 0.07 0.01 to 0.13
Rostral right locus coeruleus → precuneus −0.13 −0.06 to −0.13

CI; confidence interval, Hz; hertz, aMCI; amnestic Mild Cognitive Impairment, MDD; late-life Major Depression Disorder, HC; healthy controls.

Fig. 3. Summary of the effective connectivity findings from the hierarchical parametric empirical Bayes analysis. In Panels A and B, tables illustrate the estimation of time X
group interactions. Figures provide a simplified visualization of the parameters with a posterior probability exceeding 0.95. In both cases, over time decreases in effective
connectivity are colored in blue, while increases are colored in yellow. LcaLC; the left caudal locus coeruleus, RcaLC; the right caudal locus coeruleus, LroLC; the left rostral
locus coeruleus, RroLC; the right rostral locus coeruleus, PCUN; precuneus, PHC; parahippocampal cortex, VAC; visual association cortex, aMCI; amnestic Mild Cognitive
Impairment, HC; healthy controls, MDD; late-life Major Depression Disorder.

6
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al.
tex within the same group. For individuals with MDD, we noted
a decline in effective connectivity between LC caudal seeds when
compared to the control group. However, there was an increased
connectivity over time from the left rostral to the left caudal LC seed.
Alterations in connectivity patterns with cortical regions were pri-
marily marked by increases in cross-hemisphere connections and
decreases in same-hemisphere connections, originating predomi-
nantly from the rostral LC and extending to the visual association
cortex and the precuneus of the right hemisphere.
Longitudinal effective connectivity changes in aMCI
The observed effective connectivity reductions from the left
rostral to bilateral caudal portions of the LC in aMCI individuals
align with recent findings in the field. These results are consistent
with a study by Galgani16 which conducted a 2.5-year follow-up
in individuals with aMCI or AD. This study identified a substantial
volume reduction in the left LC, particularly in its rostral subre-
gion, at the outset of the study. Notably, this reduction was most
pronounced in subjects with MCI who subsequently transitioned
to MND/dementia, mirroring the volume reduction observed in
the AD group. Our results also corroborate post-mortem evidence
in humans, which suggests a progressive degeneration of the LC
across various stages of AD, including the preclinical stage. They are
also in line with age-dependent changes in LC functional connec-
tivity, as reported by Song.17 These changes could be attributed to
morphological alterations affecting neuromelanin-containing neu-
rons in the rostral part of the nucleus. Such alterations may lead to
a reduction in cell size and potentially result in cell loss, which
could, in turn, be associated with changes in their projections.18
Another possible explanation lies in the accumulation of misfolded
proteins in the aging brain, which may or may not lead to future
neurodegeneration.19 The LC has been identified as an early site
for tau deposition, and the accumulation of pathological proteins
heightens the risk of neurodegenerative diseases such as AD. His-
tological studies have reported that the distribution of pathological
proteins, particularly tau neurofibrillary tangles, is not uniform
across the LC, with a preference for affecting the rostral–dorsal por-
tion, irrespective of Braak stages, which is considered as a gradient
of neuronal loss and dysfunction.20 Early morphological changes in
tau-containing LC neurons include gradual dendritic atrophy and
alterations in axonal morphology, indicative of impaired axonal
transport. These changes may contribute to an early loss of con-
nectivity in the rostral section of the LC during the aging process.
In contrast to the reductions in intra-LC connectivity, we
observed a notable increase in effective connectivity over time,
specifically from the left rostral LC to the right PHP cortex. One
of the essential functions of the LC NE system is facilitating mem-
ory retrieval by activating hippocampal networks.21 The observed
surge in effective connectivity between the left LC and the right
PHP region could be interpreted as compelling evidence of an
adaptive functional reorganization. This adaptive reconfiguration
of connectivity, directing its focus toward episodic encoding pro-
cesses in aMCI patients, may serve as a compensatory mechanism
to counteract early memory alterations in the neurodegenerative
process. Indeed, such compensatory activities, including height-
ened metabolism in surviving neurons or the reorganization of
functional networks, have been documented in the initial stages of
Alzheimer’s disease (AD).22 Interestingly, in HCs resting-state func-
tional connectivity between the LC and the PHC has been found to
correlate with memory function, in particular with better encod-
ing abilities.23 Furthermore, a recent study by Tang et al. (2023)24
suggests a decrease in structural covariance between the left ros-
tral LC and the PHP in aMCI, a finding that is notably correlated
with MMSE scores. Collectively, these findings lend support to
Robertson’s noradrenergic reserve theory.25 However, it is impor-
7
Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx
tant to acknowledge that further research is imperative to uncover
the underlying reasons for the pronounced left lateralization of
LC connectivity findings in aMCI. Notably, similar effects have
been observed in structural MRI studies, even in cognitively intact
subjects.26,27 For instance, in a study focused on visualizing age-
related differences in the LC using structural MRI, Liu et al., 201928
also reported left lateralized findings.
Longitudinal effective connectivity changes in late-life MDD
The role of the LC in depression has been firmly established
by prior research, encompassing investigations into the deple-
tion of noradrenergic neurons18 and alterations in both intra- and
extra-neuronal signaling pathways.29 More specifically, the LC’s
significance in depression predominantly lies in its association with
the development of anxiety, thus contributing to stress-induced
depression.30 In our previous research with the same study sam-
ple, we discerned distinct LC alterations in patients with Major
Depressive Disorder (MDD). Our initial fMRI exploration unveiled a
reduction in functional connectivity of the LC during a visual odd-
ball task.31 Subsequently, employing structural MRI, we revealed
a marked decrease in LC structural integrity among patients with
MDD.32
The dysregulation of the noradrenergic system observed in MDD
holds relevance for the pathogenesis of this disorder. Previous stud-
ies have reported an increased density and sensitivity of central
noradrenergic alpha-2 receptors in individuals with depression.33
It is noteworthy that the LC houses the highest density of alpha-2
receptors in the brain, and these receptors, among other functions,
play a pivotal role in the autoregulation of NE secretion, govern-
ing approximately 80% of NE distribution through the LC. Notably,
this region has been demonstrated to exhibit an elevated alpha-2
receptor binding capacity in MDD.34 The persistent dysregulation
of the LC-NA system has been discussed in the context of chronic
stress and it is associated with hormonal overstimulation.33
A potential explanation for this dysregulation lies in the
observed decreases over time in the afferent connectivity within
the caudal portions of the LC in our study. Particularly noteworthy
is the reduced self-connection identified in the left caudal por-
tion of the LC, which is believed to induce neural disinhibition.
Self-connections exert inhibitory control on each region within the
model, thereby regulating the excitatory and inhibitory connec-
tions between regions. This regulation is essential to prevent the
development of a runaway positive feedback loop in the neuro-
logical model, as estimated by DCM. Consequently, the decrease in
the self-connection parameter’s magnitude may contribute to an
increase in extrinsic connectivity within the left caudal LC.
The heightened external connectivity stemming from the left
caudal LC can account for the observed rise in effective connectivity
over time between this originating point and the contralateral pre-
cuneus. Numerous neuroimaging investigations have designated
the precuneus as a pivotal hub in the human brain, attributed
to its crucial role in supporting intricate cognitive functions and
behaviors. The precuneus serves as a central component of the
default mode network (DMN), which exhibits augmented activa-
tion during periods of rest and specific cognitive tasks, such as
autobiographical memory recall.35 It also engages in distinct inter-
actions within the broader network.36 Moreover, the precuneus
demonstrates extensive connectivity, encompassing higher-order
association regions, signifying its pivotal role in integrating both
internally and externally driven information. In the context of DMN
research, which is associated with introspection and internal atten-
tion, it has been observed that individuals with major depression
exhibit heightened functional connectivity within this network.37
Importantly, this altered connectivity tends to normalize following
treatment with antidepressants.38 Additionally, the left rostral LC
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al.
also displayed heightened effective connectivity over time with the
contralateral visual association cortex. Taken together, these cross-
hemisphere connective increases resemble findings observed in
the aMCI population and can therefore be interpreted in terms of
potential compensatory mechanisms.
Longitudinal changes in intra- and inter-hemispheric effective
connectivity
Examining the evolving patterns of enhanced and diminished
effective connectivity in both patient groups concerning intra-
hemispheric and interhemispheric networks presents an intriguing
perspective. Over time, there is an observed decrease in intra-
hemispheric connectivity originating from the right portion of the
LC, contrasted by an increase in interhemispheric connectivity
between the left portion of the LC and cortical regions on the right
hemisphere.
This rise in interhemispheric connectivity may be associated
with compensatory mechanisms driven by neuronal plasticity.
The brain’s adaptive capacity to environmental changes enables
compensation for declining cognitive functions, potentially mit-
igating the effects of AD symptoms over an extended period.
Interhemispheric communication plays a pivotal role in cognitive
and emotional processing. Coordinated interaction between both
hemispheres becomes especially vital for executing complex tasks,
particularly when task complexity or workload intensifies. During
the initial stages of neurodegenerative processes, patients might
sustain performance levels akin to those of controls by increasing
interhemispheric communication, as observed in previous stud-
ies. For example, magnetoencephalography studies have shown
greater interhemispheric gamma, beta, and alpha synchrony in
individuals with MCI, performing similarly to controls in memory
tasks.39
The escalating interhemispheric connections from the LC to the
cortex in our patient cohorts as the disorder progresses align well
with evidence suggesting that LC projection patterns exhibit a mod-
ular design. These projections indicate segregated output channels
with the potential for diverse release and actions of NA on their
projection fields.40 The distinct projection patterns of individual
LC neurons might enable the differential modulation of various
processes.41 This signals a paradigm shift in understanding LC
operations and the influence of the LC-NA system on behavioral
outcomes in both health and disease.
Strengths and limitations
This study exhibits several strengths, notably the integration
of hypothesis-driven and data-driven methods in defining regions
of interest. Specifically, while we aimed a priori to assess effec-
tive connectivity from the LC, the cortical regions also included in
DCM analyses were derived from longitudinal analyses of volume
change. Moreover, the longitudinal design for effective connectivity
analysis allowed us to track changes in connections, unveiling both
reductions and increases. Notably, the identified increases may be
indicative of compensatory neuronal mechanisms.
Likewise, the study has its share of limitations. Notably, the rel-
atively small size of the LC presents a challenge for researchers
in terms of determining the most suitable approach for process-
ing image data. Spatial smoothing offers several advantages, such
as enhancing the signal-to-noise ratio and mitigating anatomical
and functional variations among subjects. However, the practice
of spatial smoothing, which permits adjacent voxels to contribute
to the estimated signal, can also elevate the risk that the modest
LC activity area might be contaminated by noise stemming from
the neighboring neural tissue. Consequently, the exact impact of
spatial smoothing on the study’s outcomes remains uncertain. To
8
Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx
address this issue, high-field MRI acquisitions are warranted to bol-
ster both resolution and signal acquisition quality. An additional
limitation arises from the inclusion of individuals with concurrent
aMCI diagnoses within our group of patients with MDD, potentially
affecting the specificity of the findings related to individuals with
MDD. While cognitive alterations in MDD are commonly observed
clinically,42 future studies with larger and more robust samples
should aim to explore the specificity of our findings. Furthermore,
we exclusively present comparisons between patient populations
and healthy controls, as the comprehensive examination of both
disorders was beyond the scope of this manuscript. Nonetheless,
it is worth noting that a comparative analysis between the two
patient groups could offer valuable insights into the commonali-
ties and distinctions between these conditions. Such an exploration
could further enrich our understanding of the role played by the LC
and noradrenergic neurotransmission in late-life pathology.
Conclusions
In summary, our study utilizing spDCM uncovered distinc-
tive resting-state effective connectivity patterns in patients with
aMCI and MDD over a two-year follow-up. Our findings offer con-
crete insights into the evolving dynamics of neural connectivity in
late-life MDD and aMCI, and underscore the intricacies of neural
network adaptations. In addition to providing novel insights into
the neurobiology of these late-life pathologies, with the poten-
tial to inform the development of biologically-informed remedies,
our results also illuminate the underlying mechanisms that may
contribute to the development of neurodegenerative disorders,
including Alzheimer’s disease.
Funding
This study was supported by the Agency for Management
of University and Research Grants of the Catalan Govern-
ment (2021SGR01017), the Carlos III Health Institute (Grants
PIE14/00034, PI19/01040 and INT21/00055), the European
Regional Development Fund (ERDF) “A way to build Europe”
and CIBERSAM. The Institute of Neurosciences of the University
of Barcelona is a María de Maeztu Unit of Excellence CEX2021-
001159-M of the Ministry of Science and Innovation of Spain.
We also thank CERCA Program/Generalitat de Catalunya for the
institutional support.
Conflict of interests
The sponsors had no role in the design and conduct of the
study; in the collection, analysis, and interpretation of data; in the
preparation of the manuscript; or in the review or approval of the
manuscript. The authors report no conflicts of interest with any
product mentioned or concept discussed in this article.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.sjpmh.2024.02.002.
References
1. Andrés-Benito P, Fernández-Dueñas V, Carmona M, et al. Locus coeruleus at
asymptomatic early and middle Braak stages of neurofibrillary tangle pathol-
ogy. Neuropathol Appl Neurobiol. 2017;43:373–392.
2. Kelly SC, He B, Perez SE, Ginsberg SD, Mufson EJ, Counts SE. Locus coeruleus
cellular and molecular pathology during the progression of Alzheimer’s disease.
Acta Neuropathol Commun. 2017;5:8.
3. Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci.
2015;18:794–799.
G Model
SJPMH-685; No. of Pages 9 ARTICLE IN PRESS
P. Maturana-Quijada, P. Chavarría-Elizondo, I. del Cerro et al.
4. Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM. Locus
coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and
early Alzheimer’s disease. Neurobiol Aging. 2007;28:327–335.
5. Brailean A, Aartsen MJ, Muniz-Terrera G, et al. Longitudinal associations
between late-life depression dimensions and cognitive functioning: a cross-
domain latent growth curve analysis. Psychol Med. 2017;47:690–702.
6. Rashidi-Ranjbar N, Miranda D, Butters MA, Mulsant BH, Voineskos AN. Evidence
for structural and functional alterations of frontal-executive and corticolimbic
circuits in late-life depression and relationship to mild cognitive impairment
and dementia: a systematic review. Front Neurosci. 2020;14:253.
7. Smagula SF, Aizenstein HJ. Brain structural connectivity in late-life
major depressive disorder. Biol Psychiatry Cogn Neurosci Neuroimaging.
2016;1:271–277.
8. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Raskind MA. Changes in
adrenoreceptors in the prefrontal cortex of subjects with dementia: evidence
of compensatory changes. Neuroscience. 2007;146:471–480.
9. Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Raskind MA. Compen-
satory changes in the noradrenergic nervous system in the locus ceruleus and
hippocampus of postmortem subjects with Alzheimer’s disease and dementia
with Lewy bodies. J Neurosci. 2006;26:467–478.
10. American Psychiatric Association (2000). Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Vol 1. Arlington,
VA: American Psychiatric Association; 2000.
11. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med.
2004;256:183–194.
12. Wechsler D. Wechsler Memory Scale. The Psycho. The Psychological Corporation;
1997.
13. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for
the staging of dementia. Br J Psychiatry. 1982;140:566–572.
14. Ye R, Rua C, O’Callaghan C, et al. An in vivo probabilistic atlas of the human
locus coeruleus at ultra-high field. Neuroimage. 2021;225:117487.
15. Friston KJ, Williams S, Howard R, Frackowiak RSJ, Turner R. Movement-related
effects in fMRI time-series. Magn Reson Med. 1996;35:346–355.
16. Galgani A, Lombardo F, Martini N, et al. Magnetic resonance imaging Locus
Coeruleus abnormality in amnestic Mild Cognitive Impairment is associated
with future progression to dementia. Eur J Neurol. 2023;30:32.
17. Song I, Neal J, Lee TH. Age-related intrinsic functional connectivity changes of
locus coeruleus from childhood to older adults. Brain Sci. 2021;11:1485.
18. Chan-Palay V, Asan E. Quantitation of catecholamine neurons in the locus
coeruleus in human brains of normal young and older adults and in depression.
J Compar Neurol. 1989;287:357–372.
19. Farrell ME, Papp KV, Buckley RF, et al. Association of emerging ␤-amyloid and
tau pathology with early cognitive changes in clinically normal older adults.
Neurology. 2022;98:e1512.
20. Gilvesy A, Husen E, Magloczky Z, et al. Spatiotemporal characterization of cel-
lular tau pathology in the human locus coeruleus–pericoerulear complex by
three-dimensional imaging. Acta Neuropathol. 2022;144:651.
21. Sterpenich V, D’Argembeau A, Desseilles M, et al. The locus ceruleus is involved
in the successful retrieval of emotional memories in humans. J Neurosci.
2006;26:7416–7423.
22. Hoogendijk WJG, Feenstra MGP, Botterblom MHA, et al. Increased activ-
ity of surviving locus ceruleus neurons in Alzheimer’s disease. Ann Neurol.
1999;45:82–91.
Spanish Journal of Psychiatry and Mental Health xxx (xxxx) xxx–xxx
23. Jacobs HIL, Wiese S, van de Ven V, Gronenschild EHBM, Verhey FRJ, Matthews
PM. Relevance of parahippocampal-locus coeruleus connectivity to memory in
early dementia. Neurobiol Aging. 2015;36:618–626.
24. Tang Y, Cao M, Li Y, et al. Altered structural covariance of locus coeruleus in
individuals with significant memory concern and patients with mild cognitive
impairment. Cerebr Cortex. 2023;33:8523–8533.
25. Robertson IH. A noradrenergic theory of cognitive reserve: implications for
Alzheimer’s disease. Neurobiol Aging. 2013;34:298–308.
26. Bachman SL, Dahl MJ, Werkle-Bergner M, et al. Locus coeruleus MRI contrast is
associated with cortical thickness in older adults. Neurobiol Aging. 2021;100:72.
27. Betts MJ, Cardenas-Blanco A, Kanowski M, Jessen F, Düzel E. In vivo MRI assess-
ment of the human locus coeruleus along its rostrocaudal extent in young and
older adults. Neuroimage. 2017;163:150–159.
28. Liu KY, Acosta-Cabronero J, Cardenas-Blanco A, et al. In vivo visualization of
age-related differences in the locus coeruleus. Neurobiol Aging. 2019;74:101.
29. Bernard R, Kerman IA, Thompson RC, et al. Altered expression of glutamate
signaling, growth factor, and glia genes in the locus coeruleus of patients with
major depression. Mol Psychiatry. 2011;16:634–646.
30. Weiss JM, Stout JC, Aaron MF, et al. Depression and anxiety: role of the locus
coeruleus and corticotropin-releasing factor. Brain Res Bull. 1994;35:561–572.
31. del Cerro I, Martínez-Zalacaín I, Guinea-Izquierdo A, et al. Locus coeruleus
connectivity alterations in late-life major depressive disorder during a visual
oddball task. Neuroimage Clin. 2020;28:102482.
32. Guinea-Izquierdo A, Giménez M, Martínez-Zalacaín I, et al. Lower Locus
Coeruleus MRI intensity in patients with late-life major depression. PeerJ.
2021:9.
33. Cottingham C, Wang Q. ␣2 adrenergic receptor dysregulation in depressive
disorders: Implications for the neurobiology of depression and antidepressant
therapy. Neurosci Biobehav Rev. 2012;36:2214–2225.
34. Ordway GA, Schenk J, Stockmeier CA, May W, Klimek V. Elevated agonist
binding to ␣2-adrenoceptors in the locus coeruleus in major depression. Biol
Psychiatry. 2003;53:315–323.
35. Addis DR, McIntosh AR, Moscovitch M, Crawley AP, McAndrews MP. Charac-
terizing spatial and temporal features of autobiographical memory retrieval
networks: a partial least squares approach. Neuroimage. 2004;23:1460–1471.
36. Fransson P. Spontaneous low-frequency BOLD signal fluctuations: an fMRI
investigation of the resting-state default mode of brain function hypothesis.
Hum Brain Mapp. 2005;26:15.
37. Berman MG, Misic B, Buschkuehl M, et al. Does resting-state connec-
tivity reflect depressive rumination? A tale of two analyses. Neuroimage.
2014;103:267–279.
38. Liston C, Chen AC, Zebley BD, et al. Default mode network mechanisms of
transcranial magnetic stimulation in depression. Biol Psychiatry. 2014;76:517.
39. Bajo R, Maestú F, Nevado A, et al. Functional connectivity in mild cognitive
impairment during a memory task: implications for the disconnection hypoth-
esis. J Alzheimer’s Dis. 2010;22:183–193.
40. Poe GR, Foote S, Eschenko O, et al. Locus coeruleus: a new look at the blue spot.
Nat Rev Neurosci. 2020;21:644.
41. Likhtik E, Johansen JP. Neuromodulation in circuits of aversive emotional learn-
ing. Nat Neurosci. 2019;22:1586–1597.
42. Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depres-
sion: a systematic review and meta-analysis. Psychol Med. 2014;44:2029–2040.