Our study provides important information on the impact of rTMS on HRQoL in patients with MDD. Firstly, using a low-frequency rTMS administered on the right DLPFC, our findings tend to confirm the preliminary results of Berlim et al.[
8], and Hadley et al.[
25] using a high-frequency rTMS on the left DLPFC. Role-Physical Problems dimension improved significantly from baseline and showed moderate effect size. Five SF-36 dimension scores and the two composite scores showed effect sizes higher than 0.28, suggesting a small to moderate “clinically” meaningful improvement of HRQoL. Although the HRQoL increase in our study showed less magnitude on physical, psychological and overall domains (respective Cohen’s d, 0.44, 0.44, 0.57) than those found in Berlim’s study [
8] and on physical functioning, vitality, social functioning and mental health dimensions than in Hadley’s study [
25], precaution should be taken in this comparison. This difference may be explained by a higher effect of high-frequency rTMS on HRQoL than low-frequency rTMS. However, the study of Berlim et al. did not use the same questionnaire, and the SF-36 and WHOQOL-BREF appear to measure distinct concepts related to HRQoL [
37]. Concerning the study of Hadley et al., the baseline HRQoL levels were significantly higher than in our sample, and differential change in means from baseline may simply be due to skewness interacting with baseline differences [
38]. Future studies should thus compare the impact of high and low-frequency rTMS on HRQoL using both questionnaires.
Moreover, this whole-brain voxel-based study is the first to investigate the neural substrate underlying HRQoL changes in patients with MDD treated by rTMS. We show that improvement of HRQoL for social and mental health dimensions SF-36-scores after rTMS is associated with a decreased perfusion of the precuneus. The precuneus has reciprocal connections with the DLPFC [
39]. So, the decreased activity of the precuneus can result from the inhibitory effects of low-frequency rTMS over the right DLPFC, which can induce activity changes in distant brain regions via the neural pathways [
40].
This report strengthens the scientific conceptual basis of HRQoL. The psychosocial construct of HRQoL, which required accurate self-assessment by individuals of their own inner feelings and state of well-being, appears consistent with precuneus involvement [
31]. Indeed, precuneus has been mainly implicated in subjective experience and conscious self-representation [
31,
41]. In healthy subjects, precuneus is activated in self-related mental representations: at rest, through the default mode network [
39], and during tasks about reflection on one’s own personality traits and physical appearance [
42]. Precuneus has been also involved in the subjective well-being and distress of patients with post-traumatic stress disorder [
43].
Our findings attempt to provide some clues for a better understanding of the mechanism underlying the relationship between depression and HRQoL found in previous studies [
15,
44,
45]. Indeed, patients with depression suffer from an increased self-focus (i.e. link negative affect and episodic memory deficit with an increased attention to the self) [
46], and exaggerated self-processing (i.e. the appraisal of stimuli as strongly related to one’s own person) [
47]. Exaggerated self-referential processing (SRP) especially distorts interpretations of social cues and maintains social fears because of maladaptive cognitions regarding self (i.e. as socially incompetent) and others (i.e. as critical judges) [
48]. Decreased activation in the precuneus could thus reflect a restored deactivation of the default mode network [
49]. We hypothesize that decreased rCBF of the precuneus may be associated to a reduction of SRP allowing patients to focus their own attention on their environment, relatives and friends and then explaining an improvement of HRQoL. On the other hand, precuneus has been also involved in the theory of mind (ToM) [
50,
51] which is conceived as a set of abilities that enable humans to understand other peoples' mental states and intentions. In particular, ToM is interrelated with self-focus attention and self-emotional awareness [
51]. Moreover, previous studies have reported that ToM performance was associated with an increased perfusion of the precuneus [
28,
31]. Interestingly, Wolkenstein et al. [
52] found that depressed patients were more accurate in decoding negative than neutral and positive mental states. The precuneus hypoperfusion found in our study may reflect a better attention for positive episodes and a decreased emotional response to negative thoughts [
43] and thus be associated with improved mental health HRQoL concerning feelings of nervousness, peacefulness, and happiness [
28,
31].
Our findings should be considered in treatment of patients with MDD, supporting the use of therapeutic interventions targeting self-focus and SRP, such as mindfulness-based cognitive therapy [
53] or cognitive base-therapy, to improve HRQoL. On the other hand, the impact of rTMS applied specifically to precuneus in patients with MDD on HRQoL should be investigated in future studies.
Lastly, the links between precuneus perfusion and HRQoL on the one hand, and those between HRQoL and depression on the other hand, help to better understand the mechanism of action of rTMS. The impact of rTMS may not only relieve the symptoms of MDD, but also affects other relevant psychosocial domains measured by HRQoL, which may in turn influence mood improvement. In accordance with this hypothesis, recent studies have shown HRQoL to be a prognostic factor associated with clinical outcome in various chronic diseases [
54,
55]. These findings may provide a support to integrate HRQoL in clinical practice, as complementary information to that traditionally collected in psychiatry.
Limitations
Several limitations have to be considered in this exploratory study. The first limitation is the small sample size (n
=
15); the lack of power may explain the contrast between the non-significant statistical results and the small to moderate level of effect sizes. Second, the absence of control group limits our ability to attribute the HRQoL changes exclusively to rTMS. However, although controlled trials are appropriate for establishing potentially causal associations, more naturalistic studies have the advantage of assessing “real life” situations of patients under treatment. These distinct limitations, also present in the previous reports [
8,
25], should be considered in future studies. Third, we used the standard 5-cm localization procedure for applying rTMS over the right DLPFC, instead of using a neuronavigational method, which seems to enhance response to rTMS [
56]. Fourth, the unbalanced sample regarding gender might have bias our findings. However, the influence of gender on HRQoL is still unclear [
57-
59], and gender is not associated with difference in rTMS outcomes [
60]. Sixth, some patients were receiving medical treatment during the study, including benzodiazepins that modify cortical excitability. Therefore, the effects of these medications on HRQoL and rCBF cannot be excluded. Finally, the use a self-rating subjective scale (BDI-II) to assess the severity of depression could be criticized. However, studies support a satisfactory convergent validity between BDI-II and Hamilton Depression Rating Scale or Clinical Global Impression [
61,
62].
1,2 Raphaëlle Richieri,1,2,5 Eric Guedj,3,4,5 Pascal Auquier,2,6 Christophe Lancon,1,2 and Laurent Boyer2,6
