Background and rationale
Major depressive disorder (MDD) is a common mental disorder among adolescents worldwide [
1], By the end of puberty, up to 20% of adolescents may have experienced it [
2], leading to a significant burden in both low-income and high-income countries [
3,
4]. The COVID-19 pandemic has further increased the prevalence of anxiety and depression, with youth being one of the most affected groups [
5]. Depression in adolescents is closely associated with suicide and other adverse outcomes, such as recurrent MDD in adulthood, impaired social function, and physical illness [
4,
6,
7].
Anhedonia, the inability to experience pleasure, is a key marker of depression vulnerability [
8] and significantly contributes to the severity of depression. It predicts reduced treatment efficacy and an elevated risk of relapse and suicidality [
9‐
11]. Despite access to empirically supported treatments like cognitive-behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), or their combination, many adolescents with depression exhibit treatment resistance [
12]. Anhedonia, therefore, plays a detrimental role in the onset, management, and prognosis of MDD in adolescents. Yet, the therapeutic outcomes for addressing anhedonia remain far from optimal.
Previous researches have underscored a connection between anhedonia and irregularities within the reward circuitry. Individuals with MDD [
13,
14], who frequently experience anhedonia [
15] show weaker neurobiological responses to anticipating rewards when compared to healthy controls. This is most pronounced in the nucleus accumbens (NAc), which plays a crucial role in reward processing [
16]. A comprehensive longitudinal study involving adolescents has found that a diminished response in the ventral striatum during reward anticipation can presage the onset of anhedonia two years later in adolescents who were initially healthy. This predictive relationship is distinct from the one involving low mood without anhedonia [
17,
18]. This indicates that the ventral striatum, particularly the NAc, could be a biomarker and potential target for anhedonia. However, conventional noninvasive techniques for treating the NAc can be difficult due to its deep-seated position in the brain. Repetitive transcranial magnetic stimulation (rTMS) may offer a solution by indirectly influencing the NAc through functional connectivity (FC) with the brain’s superficial cortex [
19]. Studies employing rTMS to target the most positively correlated FC between the dorsolateral prefrontal cortex (DLPFC) and the NAc have shown significant amelioration in anhedonia in adults subjects [
20]. However, effective intervention targets for anhedonia in adolescent patients, a crucial period for managing MDD, remain elusive. Therefore, testing this hypothesis specifically within this demographic is paramount and forms the basis of our study.
RTMS is a safe and noninvasive neuromodulation technology that has received FDA approval [
21]. By intensifying synaptic connections and modifying FC and activity patterns in distant regions of the same brain region, high-frequency rTMS has demonstrated the potential to treat mental disorders, particularly MDD [
22,
23], through a novel approach called individual target-transcranial magnetic stimulation (IT-TMS) [
24‐
26]. It is believed to be the mechanism by which rTMS addresses anhedonia, a hallmark symptom of MDD, involves enhancing the FC between the left DLPFC and the NAc using IT-TMS [
19].
We are planning to conduct a randomized controlled trial (RCT) to evaluate the efficacy of rTMS in managing anhedonia, which is a core symptom of MDD, in adolescents. The specific target areas for this study will be the DLPFC-NAc. We will use an intelligent neural navigation system to generate personalized targets based on resting-state fcMRI analysis, which will involve identifying the left DLPFC region that has the highest functional connectivity with the NAc in each participant. Our research aims to determine the preliminary efficacy, safety, and tolerability of the rTMS protocol using fcMRI-guided targeting. We hypothesized that adolescents who suffer from MDD and anhedonia will have altered neural functional patterns. We anticipate that these patterns will normalize after exposure to stimuli. Additionally, we aimed to explore changes in FC and neuropsychological functioning that are associated with anhedonia and MDD. By conducting this study, we hope to demonstrate that our hypothesis has the potential to improve the treatment of anhedonia.