Improvement of health-related quality of life in depression after transcranial magnetic stimulation in a naturalistic trial is associated with decreased perfusion in precuneus

Major depressive disorder (MDD) [1] remains one of the leading causes of disability in developed countries despite pharmacological and psychological treatments [2]. A new alternative for depressed individuals is repetitive transcranial magnetic stimulation (rTMS), a non-invasive well-tolerated technique [3‐5]. rTMS protocols have been developed using high-frequency stimulation (> 5 Hz) of the left dorsolateral prefrontal cortex (DLPFC) or low-frequency (< 1 Hz) of the right DLPFC. The choice of distinct frequency comes from electrophysiological data of the motor cortex, showing that high-frequencies may have an excitatory effect while low-frequencies tend to suppress cortical excitability [6, 7]. Effectiveness of rTMS has been investigated in most studies using clinical outcomes, such as change in depressive symptomatology [8, 9]. Thereby, meta-analyses have highlighted a threshold of 50% decrease in symptom severity, in up to 76% of patients [10‐12]. Interestingly, the efficiency of low-frequency rTMS stimulation of the right DLPFC and of high-frequency rTMS stimulation of the left DLPFC seems to be similar in depressed patients [11, 13, 14].

On the other hand, Health-related Quality of life (HRQoL) questionnaires are considered valuable and necessary tools to evaluate care and treatments provided to patients with MDD, in addition to the traditional assessment of clinical outcomes [15‐17]. HRQoL may add interesting information that is oriented toward a more global service to individuals including the subjective experience of their illness, with regard to their symptoms but also their functioning embedded in social and environmental context [15]. However, HRQoL remains under-utilized to assess the effectiveness of rTMS in research or in a routine clinical setting [8], and more globally in psychiatric clinical practice [18, 19]. In congruence with prior investigations on HRQoL in MDD following antidepressant pharmacotherapy [20, 21], only two recent studies, using the World Health Organization's Quality of Life Measure , brief version (WHOQOL BREF) [22] and the Medical Outcome Study 36-item Short Form (SF-36) [23, 24] questionnaires, have shown improvement in HRQoL domains following high-frequency rTMS [8, 25]. These important findings should be confirmed using low-frequency rTMS which is better tolerated than high-frequency rTMS in terms of seizure risk [26].

The primary objective of this exploratory study was to investigate the impact of low-frequency rTMS on HRQoL using the SF-36 questionnaire, in patients with MDD. In addition, a better understanding of the mechanism underlying HRQoL changes is of particular interest in depression, as already proposed in schizophrenia [27, 28]. A secondary objective was thus to study the functional neural substrate underlying HRQoL changes using neuroimaging with 99 m Tc-ethyl cysteinate dimer single-photon emission computed tomography (99mTc-ECD-SPECT), a valuable tool to investigate the regional cerebral blood flow (rCBF), in a range of psychiatric disorders such as depression [29‐31].

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.

This study suggests low-frequency rTMS can improve HRQoL, through its role-physical problems dimension, in patients with MDD. This improvement is associated with a decreased perfusion of the precuneus, a brain area involved in self-focus and self-processing, arguing for a neural substrate to the impact of rTMS on HRQoL.