4 Discussion
The present study examined RSFC network differences between patients
with a diagnosis of MDD, patients with comorbid MDD and at least one
anxiety disorder and healthy controls within the context of the triple
network model. Comparing MDD+AD to HC, we found significantly reduced
RSFC for the VAN with both the ECN and the DMN, whereas there were no
alterations between the ECN and the DMN. This finding confirms the
triple network model by Menon et al. (2010). In addition, the ECN showed
significantly reduced within-network-connectivity. These effects were
independent of severity of symptoms and medication status. No effects
were found when comparing MDD with HC and MDD with MDD+AD.
Although we did not find any differences between patients with MDD and
HC, aberrations of RSFC within the triple network are well documented
(Kaiser et al., 2015; Mulders et al., 2015; Zheng et al., 2015).
However, results in the RSFC-literature are generally heterogonous
(Kaiser et al., 2016; Lydon-Staley et al., 2019) and with the relatively
small sample size of this study and rigorous correction for multiple
testing (Bonferroni correction is regarded as a comparatively
conservative correction method (Chen et al., 2017)), smaller effects
could have gone undetected. Therefore, we cannot exclude, that the MDD
group does show aberrant RSFC compared to HC, in particular since this
group does not differ to MDD+AD.
In research concerning MDD and the triple network model, the
introspective qualities of the DMN and the more outwards oriented
qualities associated with the ECN have been central to the discussion of
the symptomatic correlates of the commonly found aberrations (Jiang et
al., 2017; Li et al., 2021). Here, alterations in DMN connectivity have
been found to be associated with higher levels of rumination (Brakowski
et al., 2017; Kühn et al., 2012) and negative self-referential thoughts
(Cullen et al., 2014). The ECN, on the other hand, shows a more
outward-directed and stimulus-driven set of tasks, being involved in
decision making and cognitive control (Li et al., 2021; Manoliu et al.,
2013). Within the triple network model, alterations in the RSFC between
these two networks and the VAN as a switch between them are thought to
impair the engagement of the ECN and the disengagement of the DMN (Menon
& Uddin, 2010), leading to maladaptive rumination and impaired
cognitive abilities (Schimmelpfennig et al., 2023).
Similar to the MDD literature, in the much more sparse research
regarding anxiety, the VAN is thought of as an important intermediary
between the DMN and the ECN as well (Nawijn et al., 2022; Pannekoek et
al., 2015). Here, however, other functions of the DMN and ECN are
considered central to the symptomology, namely their role in the
regulation of emotion and fear response (Sylvester et al., 2012). The
DMN has been shown to be linked to emotion regulation (Macêdo et al.,
2022), with a focus on emotion perception (Kim & Yoon, 2018),
reinforcement expectancy (Blair, 2007) and fear extinction (Sylvester et
al., 2012). The ECN on the other hand has been associated with more
conscious and control oriented emotional regulation strategies, such as
redirection of attention towards non-emotional stimuli and suppression
of amygdala responses when attention is engaged with a non-emotional
stimulus (Bishop et al., 2004; Sylvester et al., 2012). Impaired
switching between the DMN and the ECN by the VAN is thought to be
associated with less adequate control over fear responses and emotional
regulation (Sylvester et al., 2012).
In summary, alterations within the triple network in the context of MDD
are interpreted in terms of an inadequate switch between internally
(DMN) and externally (ECN) oriented attention and stimulus processing.
In contrast, in the context of AD, alterations in the triple network are
interpreted as an imbalance between a more automated and unconscious
processing of emotions (DMN) and conscious, cognitively controlled
emotion regulation (ECN).
In this context, studying patients with comorbid MDD and AD serves to
identify those neurological alterations within the triple network, that
distinguish this important group of patients from those with MDD alone.
We found reduced connectivity between the DMN and the VAN with clusters
in the right middle and anterior cingulate and paracingulate cortex and
the left cingulate cortex, between the ECN and the VAN, with clusters in
the left and right middle cingulate and paracingulate gyrus and the
right superior frontal gyrus, and within the ECN with a cluster in the
left middle frontal gyrus. In the context of the interpretation of
alterations discussed above, the alterations we found could lead to
additional difficulties switching between the DMN and the ECN and in
turn contribute to the specific symptomology of ADs by impairing the
switch from unconscious, automated modes of emotional regulation to more
conscious, cognitively controlled strategies (Fan et al., 2017). This
could manifest in the high degree of internally oriented attention
characteristic for AD (Fan et al., 2017). Additionally, the
hypoconnectivity found within the ECN may be associated with a higher
difficulty in using and applying these strategies effectively (Sylvester
et al., 2012).
Furthermore, while anxiety symptoms accompanying depression are often
associated with higher depression severity (Gaspersz et al., 2017), this
was not the case in the current study as both groups showed similar
severity of depression symptoms. Additionally, the severity of anxiety
symptoms measured with the BAI was also not significantly different
between groups. For this reason, our results may provide important
indications of specific network signatures of comorbid MDD and anxiety
disorders as opposed to greater overall symptom severity in the patient
groups. Another result supporting this notion was our finding that the
strength of the RSFC was not associated with symptom severity within the
patient groups. This is consistent with previous findings (Pannekoek et
al., 2015). Pannekoek et al. (2015) suggested that this may be due to
the changes in RSFC being a result of trait rather than state
characteristics or alternatively, the relatively mild overall symptom
severity of their patient groups. However, as our patients were
recruited from an inpatient setting, typically shortly after admission,
our findings may further reinforce the qualitative nature of these
alterations.