Rationale
Major Depressive Disorder (MDD) is the most prevalent psychiatric disorder, with a lifetime prevalence of 19% [
1] and a highly recurrent nature [
2,
3]. History of recurrence is an important predictor of relapse [
4,
5], making prevention of relapse early in the course of the disease an important clinical goal. Understanding the mechanisms facilitating relapse can give insight into the core processes essential for relapse prevention, and may provide markers to guide clinicians in selecting preventive strategies [
6].
One way of gaining a better understanding of relapse vulnerability is investigating the neurocognitive mechanisms of existing therapeutic interventions that proved effective in preventing relapse [
7,
8]. Clinically, cognitive therapy during the depressive episode has been shown to have an enduring preventive effect [
9‐
11]. Applying preventive cognitive therapy (PCT; a cognitive-therapy based psychological intervention) in the remitted state has shown effectivity in lowering relapse-risk up to 10 years, compared to both no therapeutic interventions and to (tapering) maintenance antidepressant use [
12‐
17]. Studying the working mechanisms of PCT can provide insight into which cognitive and affective processes put an individual at risk for relapse, and which changes therein mediate a lowered vulnerability risk following treatment.
Studies in the acute phase of MDD have shown that cognitive therapy affects neurocognitive functioning, including lowering cognitive biases [
18,
19] and increasing prefrontal cortical control over limbic structures during emotional processing [
20‐
22]. These processes are thought to lay at the core of the pathophysiology of MDD [
23‐
29], and might add to the development and perpetuation of depression through overrepresentation and overinterpretation of negative information and negative affect [
23,
30‐
33]. Several studies have shown that abnormalities in the prefrontal cortex persist in the remitted phase of MDD [
34‐
37] and may predict disease course [
38‐
43]. Furthermore, abnormal prefrontal regulation has been related to specific MDD typical cognitive processes [
23,
44‐
49] that may persist after remission and have been linked to recurrence, such as cognitive biases towards negative information [
49‐
51], heightened cognitive reactivity to stressful situations [
52‐
54], negative rumination [
55‐
58], affective reactivity [
59], and inadequate emotion regulation (reflected in an increased tendency to engage in, and difficulty to disengage from, negative mood states) [
32,
60,
61]. Whether the protective effect of PCT is obtained via alternations in these neurocognitive processes and how individual differences therein hamper such effect is yet unknown.
Though often neglected, difficulties in processing reward and maintaining positive emotions may similarly contribute to relapse vulnerability in MDD. Abnormalities in processing positive emotions have been consistently associated with MDD, also in the remitted phase [
37,
62‐
68]. Moreover, neural responsivity in regions important for reward processing has been related to a history of depressive episodes [
69] and both psychological and pharmacological treatment response [
70]. In acute MDD, difficulties sustaining positive emotions have been suggested to reflect reduced fronto-striatal capacity [
71,
72]. In remitted MDD, Matsubara and colleagues [
73] found abnormal fronto-limbic activity during effortful regulation of positive emotions, while others did not [
61,
74]. Whether PCT obtains part of its preventive effects by impacting neurocognitive processing of positive emotional material, is not yet known.
Aims
In the Neurocognitive Working Mechanisms of the Prevention of Relapse In Depression (NEWPRIDE) study, the neurocognitive mechanisms of preventive therapy will be investigated using a within-subject longitudinal comparison of cognitive biases and fMRI characteristics related to positive and negative emotion processing before and after PCT, as compared to a waiting list control group. At baseline, a healthy control (HC) group will be included for cross-sectional comparison of residual abnormalities.
The present study has four main aims. Firstly, we aim to cross-sectionally examine whether cognitive biases and functional magnetic resonance imaging (fMRI) responses during the regulation of positive and negative emotions in medication-free, highly recurrent, remitted MDD (rrMDD) patients differ from controls. We hypothesize residual abnormalities in rrMDD patients compared to HC in (i) an amygdala-insular-subgenual anterior cingulate cortex (ACC)-ventrolateral prefrontal cortex (PFC) circuitry associated with biased processing of negative emotional information, (ii) a striatal-medial PFC circuitry associated with biased processing of positive emotional information, and (iii) the lateral-and medial PFC circuitry associated with cognitive control [
75].
Secondly, this randomized controlled fMRI-study is the first to investigate the neurocognitive working mechanisms of PCT (compared to a waiting list condition) in rrMDD patients. We hypothesize that PCT will result in increased lateral and medial prefrontal activation, dampened activation of limbic regions, and improved connectivity between these regions during emotion regulation, which will coincide with normalised processing and regulation of negative information and a lowered likelihood of a prevailing negative mood. Furthermore, we hypothesize that increased PFC activation following PCT relates to increased preferential processing of positive information [
70,
76].
Thirdly, we aim to identify pre-treatment neurocognitive markers predictive of long-term PCT success measured at 18-month follow-up. It is expected that low pre-treatment insular and PFC activation [
39,
77] and low PFC connectivity with emotion processing areas during emotion processing predicts favourable treatment response [
78]. Also, we hypothesize that participants with larger pre-post differences on neurocognitive measures, will show lowest relapse up until18-month follow-up.
Finally, we aim to investigate the value of the pupil dilation response (PDR) as a new predictor of frontal regulatory efforts during emotion regulation and PCT effects as a means of providing cheaper, non-imaging, yet imaging-informed, neurocognitive markers of treatment-success in rrMDD [
79‐
81]. We hypothesize that increased PFC activation following PCT will be reflected in an increased PDR during emotion regulation, and that low pre-treatment PDR-response during emotional regulation will be predictive of PCT effects.