High-definition tDCS regulate the prefrontal-limbic-striatal connectivity and reduce depression in youth with first-episode depression

Abstract

Background:

Transcranial direct current stimulation (tDCS) has emerged as a promising approach to alleviate depressive symptoms in depression. However, the underlying therapeutic mechanisms remain largely unexplored. This study aims to investigate the improvement in symptoms and changes in resting-state brain activities in youth with first-episode depression (FED) before and after a two-week high-definition tDCS (HD-tDCS) intervention.

Method

This study included 18 young adults with FED and 14 healthy controls. Participants received ten sessions of HD-tDCS (2 mA, 20 min, stimulation target: left dorsolateral prefrontal) administered once a day over a two-week period. Clinical assessment and resting-state magnetic resonance imaging were conducted on all participants at baseline and post-treatment. We used voxel-wise functional connectivity (FC) analysis to explore changes in FC within emotion-related regions in the FED group following HD-tDCS and explored potential correlations between these FC alterations and improvements in depressive symptoms.

Results

The FED group exhibited significant improvement in depression and anxiety scores after treatment. The FC in the prefrontal-limbic-striatal system was decreased between AMYG, HIP, NAcc as well as FG and the prefrontal cortex. The reduction in depression severity was significantly positively correlated with decreased FC values between right FG and right middle frontal gyrus.

Conclusion

This study suggests that tDCS may be an effective intervention for young adults with FED. The improvement in depressive symptoms induced by tDCS was associated with modulation of brain connectivity in cortical and subcortical regions within the prefrontal-limbic-striatal system. Our study provides novel neurobiological evidence for the treatment of depression with tDCS.

Introduction

Major depressive disorder (MDD) is a leading cause of disability worldwide, with a dramatic increase in prevalence during adolescence and a peak incidence in early adulthood [1–5]. Adolescents with depressive disorders often exhibit a mixture of emotional instability and impaired psychosocial functioning, leading to various behavioral problems such as self-injury, suicidality, or substance abuse, which significantly interfere with their academic and personal development [6, 7]. Currently, there are several clinical treatment modalities available including medical therapy, psychotherapy, and neuromodulation therapy. While these treatments offer some benefits, they also have limitations, such as incomplete symptom relief and potential drug side effects [8]. The high morbidity and mortality rates, poor adherence, and ineffective pharmacologic and psychotherapeutic treatments for adolescent depression place a heavy burden on individuals, families, and society.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that involves placing positive and negative electrodes on the scalp. By applying a weak electric current to a specific area of the cerebral cortex, it induces changes in neuronal membranes, modulates cortical plasticity, and induces functional changes, thereby enhancing cognitive function [9–11]. In addition to its effects on neuroplasticity, tDCS has been shown to significantly influence the brain functional connectivities [12]. The technique was first used and studied in animals and humans in the 1960s and 1970s, demonstrating its effectiveness in reducing depressive symptoms [13]. In recent years, tDCS has emerged as a novel approach for treating depression, improving patients’ mental health and alleviating depressive symptoms [9, 13, 14]. Based on imaging evidence in depression, the left dorsolateral prefrontal cortex (DLPFC) is often used as tDCS target to exert an antidepressant effect by regulating cortical excitability, metabolic activity, and synaptic plasticity of the DLPFC and other functional nodes of the depression network [15]. However, traditional tDCS has limitations, such as poor targeting and mostly inability to exclude interference from medication factors. High-definition transcranial direct current stimulation (HD-tDCS) is more advanced neuromodulation technique that using a ring electrode array to concentrate current directly to the target brain area, which, compared to traditional tDCS, maintains a high current density in the target area while minimizing stimulation of non-targeted regions, offering more precise targeting and greater potential in the study of neuropsychiatric disorders [16].

Previous studies have indicated that the prefrontal cortex (PFC), limbic system, and striatal structures play a crucial role in emotionality and emotional processing [17, 18]. Accumulated evidence suggests that depression is a system-level disorder, with abnormalities potentially residing within the prefrontal-limbic-striatal system. This system encompasses the emotion regulation network, which includes the PFC, anterior cingulate cortex (ACC), amygdala (AMYG), hippocampus (HIP), and ventral striatum, such as the nucleus accumbens (NAcc) [19, 20]. The PFC is closely associated with emotional processing, and its functions are involved in the interplay between emotion and cognition. It has been hypothesized that changes in the frontal lobes may contribute to imbalances in emotional processing observed in individuals with depression [21]. In addition to the frontal lobe, other brain regions also exhibit abnormalities in depressed adolescents. For instance, hyperactivation of the AMYG and its increased functional connectivity with other regions can heighten responses to emotional and social stimuli in these individuals [22]. Abnormal activation levels have been observed in several brain regions during emotional processing and executive function tasks, including the subgenual ACC, parahippocampal gyrus, dorsal anterior insula, and nucleus accumbens [23–25]. Neuroimaging studies have shown that tDCS can alter functional activation and connectivity in brain regions, including those distant from the stimulating electrodes [26, 27]. Therefore, the mechanism by which tDCS alleviates depression can be explored through combined neurostimulation and neuroimaging research. By altering the electrical state of cortical tissue, it becomes possible to gain deeper insights into the functional role of specific brain areas and their connections within brain networks [28]. However, the changes in prefrontal-limbic-striatal connectivity induced by HD-tDCS in patients with depression remain largely unclear.

To this end, the present study aims to conduct a two-week intervention using HD-tDCS in young adult patients with a first depressive episode. The primary goal is to evaluate the clinical efficacy of a tDCS protocol targeting the left dorsolateral prefrontal cortex (DLPFC). Subsequently, we will explore the underlying neural mechanisms by analyzing functional connectivity using resting-state functional magnetic resonance imaging (fMRI) data. We hypothesize that HD-tDCS, as a novel therapeutic approach, can alleviate depressive symptoms and modulate connectivity within the prefrontal-limbic-striatal network. This research seeks to provide a theoretical foundation for further discussions on the pathogenesis and treatment of depression.

Materials and methods

Participants

This study is part of the China Depression Cohort Study conducted at the Second Xiangya Hospital of Central South University. A total of 18 youth patients with first-episode depression (FED) who met the enrollment criteria were recruited from the psychiatric outpatient clinic between November 2020 and August 2022 to undergo a two-week treatment of HD-tDCS. Additionally, 15 healthy volunteers (HVs), matched for age, sex, and years of education, were recruited from the community. The inclusion criteria were as follows: 1) visiting a psychiatric outpatient clinic for a first depressive episode, meeting the diagnostic criteria for depressive episodes in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) [29]; 2) aged between 18 and 26 years; 3) no history of psychiatric medication prior to the visit; 4) a score of ≥ 8 on the Beck Depression Inventory (BDI-13); 5) ability to listen, read, and write to complete the study; 6) right-handed; 7) understanding of the nature of the study, willingness to participate, and signing of a written informed consent form. The exclusion criteria were as follows: 1) presence of neurological or serious somatic diseases; 2) history of substance abuse or psychoactive substance use; 3) serious suicidal tendencies; 4) excessive head movement during MRI scan; 5) discomfort with the HD-tDCS pretest, etc. One HV was excluded due to excessive head movement during the MRI scan, leaving 18 patients in the HD-tDCS group and 14 HVs who completed the clinical scale assessment and MRI scan in this study. Informed consent was obtained from all participants before the study commenced. Ethical approval for this study was obtained from the Ethics Committee of the Second Xiangya Hospital of the Central South University (Fig. 1).

Fig. 1.

The flowchart of subject registration in this study

HD-tDCS intervention protocol

In this study, all youth patients with FED underwent a two-week intervention using the same model of HD-tDCS (Soterix: 4 × 1 NJ Vogel), with sessions held once daily from Monday to Friday, for a total of 10 sessions. The experiment was conducted by two professionally trained psychiatrists in an environment with controlled temperature and lighting to ensure the subjects remained relaxed. Prior to the treatment, the operator explained the general procedure and any potential sensations that might occur. Subjects were informed that they could stop the treatment at any time if they experienced discomfort, ensuring their safety throughout the process. The electrodes were positioned using the International 10-20 system, with the central electrode placed in the left dorsolateral prefrontal area (F3) and the four return electrodes placed at a distance of approximately 3.5 cm away from the diameter of F3, corresponding to FC1, AF3, F7, and FC5. We used conductive electrode gel in this study to reduce the contact impedance between the scalp and the electrodes. Electrode impedance values were checked before each session. The electrode impedance is kept below 30 kΩ. Before the first treatment, subjects underwent a pre-stimulation mode where the current was gradually increased from 0.5 mA to 2 mA, and the treatment current intensity was at 2 mA for 20 min. During the HD-tDCS treatment, the patients did not use any medications.Clinical trial registration number: ChiCTR2200059016.

Sociodemographic and clinical measurement

A self-administered questionnaire was utilized to gather sociodemographic and clinical information from youth patients with FED including their gender, age, and educational level [30]. The Beck Depression Inventory-13 (BDI-13) [31] was applied to assess depressive symptoms and severity over the past two weeks. The BDI-13 used in this study is a self-report depressive symptom scale and consists of 13 items, each on a four-point scale from 0 to 3, with higher scores associated with greater severity of depressive symptoms. The reduction rate was calculated as (BDI-13 score_{pre-treatment} - BDI-13 score_{post-treatment})/BDI-13 score_{pre-treatment} × 100%, with a reduction of more than 50% considered significant [32]. The response rate was determined as (number of significant/total) × 100%, and remission was defined as a total BDI score of less than 8 points [33]. The Beck Anxiety Inventory (BAI) [34] is a self-rating scale that measures the severity of anxiety symptoms containing 21 items, each rated on a scale of 0–3, with higher total scores indicating more severe anxiety symptoms. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [35] evaluates the cognitive functioning and consists of twelve subtests to assess cognitive functioning in five cognitive domains: immediate memory, visuospatial/structural, verbal, attention, and delayed memory. Raw scores are converted to scale scores, and the total score provides an overall assessment of cognitive functioning, with higher scores reflecting better cognitive performance.

Outcome measures

The BDI-13, BAI, and RBANS were assessed on youth patients with FED before the first HD-tDCS treatment and within 24 hours after the end of the last HD-tDCS treatment. The reduction rate in depression scale scores before and after treatment, as well as the remission rate, were used as indicators of the antidepressant efficacy. Additionally, changes in total cognitive scale scores from pre- to post-treatment were utilized to assess the level of cognitive function.

MRI data acquisition

All youth patients with FED underwent two resting-state magnetic resonance imaging (fMRI) scans: one before the first HD-tDCS treatment and another within 24 hours after last session. Data were acquired using the Skyra, SIMENS 3.0 Tesla MRI scanner at the Second Xiangya Hospital of Central South University. Structural images were acquired using a 3D magnetization-prepared rapid gradient echo (MPRAGE) sequence with the following parameters: repetition time (TR) = 2000 ms, echo time (TE) = 2.01 ms, field of view (FOV) = 256 × 256 mm², voxel size = 1 × 1 × 1 mm³, flip angle (FA) = 12°, 1 mm slice thickness with no gap, 192 slices. Resting-state fMRI data were acquired using an echo-planar imaging sequence with the following parameters: 200 volumes, TR = 2,000 ms, TE = 30 ms, FOV = 220 × 220 mm², voxel size = 3.44 × 3.44 × 4 mm³, FA = 80°, 4 mm slice thickness with gap of 4 mm, and 36 slices.

Data preprocessing

The following pre-processing steps were preformed using the Data Processing Assistant for Resting-State fMRI (DPARSF V7.0, http://rfmri.org/DPARSF) [36]: 1) The first 10 original volumes were removed; 2) Slice timing correction was applied; 3) Head realignment was conducted; 4) Images were reoriented; 5) Normalization to the MNI space was performed using the DARTEL algorithm; 6) Smoothing was applied with a full-width at half maximum of 6 mm; 7) Linear detrending was conducted; 8) Friston-24 head motion parameters, white matter, and cerebrospinal fluid were regressed out; 9) Band-pass filtering was applied with a range of 0.01–0.1 Hz; 10) Scrubbing was performed using cubic spline interpolation. We also computed the mean frame-wise displacement (FD) for each group [2, 17, 37]. One HV was excluded due to head motion exceeding 2 mm or 2 degrees in any direction.

Functional connectivity analysis

Based on previous studies, we selected six emotion-related regions of interest (ROI) in the study: the ACC, AMYG, HIP, NAcc, insula (INS) and fusiform gyrus (FG) in this study. The ACC masks were parcellated using AAL atlas [38], while other masks were generated using Human Brainnetome Atlas [37, 39]. Then, all generated masks were resampled to size of 3 × 3 × 3 mm³. The FC maps for final statistical analysis were produced by calculating the Pearson correlation coefficient between the time courses of ROIs and other regions using a voxel-wise method, followed by a Fisher-z transformation.

Statistical analyses

For demographic data, after data collection and cleaning, statistical analysis was conducted using SPSS 26.0. Gender, age, and education level were described using mean ± standard deviation (Mean ± SD). Chi-square test was employed to compare gender groups. Levine’s variance alignment test was used to determine whether the data met the assumption of equal variances. two-sample t-tests was applied between groups that conformed to a normal distribution, while Mann-Whitney U-test was used between groups not conforming to a normal distribution. Gender, age, and education were also included as covariates in partial correlation analyses involving brain regions of interest.

Next, the effect of HD-tDCS intervention was evaluated by conducting the paired t-test on the functional connectivity (FC) maps, and the functional differences between the pre-tDCS and the post-tDCS groups were analyzed. Two sample t-tests were performed to investigate the functional differences between the pre-tDCS group or post-tDCS and HV group, with gender, age, years of education and mean FD regressed out in the statistical analysis (Gaussian random field (GRF) corrected, voxel p < 0.05, cluster p < 0.05). Spearman correlation analysis was adapted to explore the relationships between FC changes in emotion-related regions (AMYG, HIP, NAcc, and INS as ROIs) following HD-tDCS with improvement of depression.

Results

Demographic information at baseline

Table 1 presents the demographic characteristics of the study participants. From November 2020 and August 2022, a total of 18 young patients with FED completed the 2-week HD-tDCS intervention, including 3 (16.7%) males and 15 (83.3%) females. The mean age was 22.3 years (±2.9) and the average education level was 15.6 (±2.6) years. Additionally, 14 HV were recruited from the community, consisting of 4 (28.6%) males and 10 (71.4%) females. Their mean age was 22.6 years (±2.0), and the mean education level was 16.6 years (±1.5). Statistical analysis revealed no significant differences between the FED and HV groups in terms of gender, age and years of education (p > 0.05) (Table 1).

Table 1.

Demographic and clinical characteristics of all the participants in this study

Demographics	FEDs (N = 18)	HVs (N = 14)		χ2/t	P
Gender (M/F)	3/15	4/10		0.653	0.419
Age (yrs)	22.3 ± 2.9	22.6 ± 2.0		−0.364	0.716
Education (yrs)	15.6 ± 2.6	16.6 ± 1.5		−1.293	0.206
Clinical scale	Pre-treatment (N = 18)	Post-treatment (N = 18)	HVs (N = 14)	t/Z	P
BDI-13	18.9 ± 5.9	9.3 ± 5.5	1.1 ± 1.7	−4.821 −4.201 6.475	＜0.001a ＜0.001b ＜0.001c
BAI	25.2 ± 11.9	10.9 ± 8.6	2.6 ± 2.8	−4.647 −3.097 5.558	＜0.001a 0.002b ＜0.001c
RBANS
Total	94.2 ± 10.1	106.5 ± 10.8	99.6 ± 14.9	−1.228 1.510 −7.145	0.229a 0.141b ＜0.001c
Instant memory	85.6 ± 11.7	102.6 ± 13.3	88.4 ± 15.5	−0.571 2.788 −6.620	0.572a 0.009b ＜0.001c
Visual amplitude	101.9 ± 10.2	103.1 ± 8.0	100.7 ± 15.2	0.274 0.524 −0.474	0.786a 0.607b 0.642c
Verbal function	95.2 ± 16.0	97.1 ± 17.5	95.1 ± 19.7	0.013 0.298 −0.590	0.990a 0.768b 0.563c
Attention	109.6 ± 11.2	118.3 ± 8.4	116.4 ± 12.8	−1.422 −0.804 −3.301	0.155a 0.421b 0.001c
Delayed memory	93.3 ± 11.9	103.9 ± 9.5	98.2 ± 12.0	−1.244 1.493 −3.726	0.214a 0.146b ＜0.001c
Mean FD	0.09 ± 0.05	0.11 ± 0.06	0.09 ± 0.04	0.164	0.125a 0.989b 0.423c
				0.014
				0.813

Values are presented as mean ± SD. The χ² values for gender distribution was computed by chi-square test. The p values were obtained using two-sample t-tests or Mann-Whitney U-test; ^a, Comparison between healthy and pre-treatment case groups; ^b, Comparison between healthy and post-treatment case groups; ^c, Comparison between pre-treatment and post-treatment case groups. SD, standard deviation; FED: first-episode depression; HVs: healthy volunteers; M: male; F: female; yrs: years. BDI-13: the Beck Depression Inventory-13; BAI: the Beck Anxiety Inventory; RBANS: the Repeatable Battery for the Assessment of Neuropsychological Status.

Clinical feature

Prior to treatment, the patient group exhibited higher depression and anxiety scores, as well as lower total cognitive scores compared to HVs. Following the intervention, there was significant reductions in both depression and anxiety levels, as evidenced by decreased scores compared to pre-treatment levels (p＜0.05). However, these scores remained higher than those observed in HVs (p＜0.05). In addition, we found an interesting phenomenon that the total cognitive scores of the subjects after HD-tDCS treatment were higher than those of the HV group (106.5 ± 10.8 v.s 99.6 ± 14.9) (Table 1).

Effect of HD-tDCS treatment on depression

The efficacy of the treatment was evaluated by measuring the changes in BDI-13 scores before and after the tDCS intervention in youth patients with FED (Fig. 2A). The treatment was deemed significantly efficacious ( > 50% score reduction) in 10 individuals, with a response rate (percentage of individuals who were significantly efficacious) of 55.56%. The remission rate (percentage of participants with a post-treatment BDI score below 8) was 38.89%. Regarding adverse reactions, two subjects reported experiencing tingling sensations on their skin during the treatment, leading to an adverse event incidence rate of 11.1% (2 out of 18).

Fig. 2.

A) changes in BDI-13 score in MDD patients before HD-tDCS and after HD-tDCS; B) correlation between the changed FC between right FG and MFG and improvement of depression

Longitudinal FC alterations between pre-tDCS and post-tDCS

After 10 days of HD-tDCS, differences in FC in prefrontal-limbic-striatal system were observed between the pre-tDCS and post-tDCS groups (Table 2 , Fig. 3; gender, age, years of education and mean FD regressed out). Specifically, in contrast to the pre-tDCS group, the post-tDCS group displayed significantly lower FC values between left AMYG and right medial superior frontal gyrus (med SFG), between right AMYG and right superior frontal gyrus (SFG), between left HIP and left medial orbital frontal cortex (med OFC), between right HIP and right med SFG, between right NAcc and left orbital part of inferior frontal gyrus (inf ORB) and left med SFG, between left FG and right med OFC and right med SFG, and between right FG and right orbital part of superior frontal gyrus (sup ORB) and right middle frontal gyrus (MFG).

Table 2.

Differences in FC in patients before tDCS and after treatment

Seed regions	Post-tDCS v.s Pre-tDCS
	Brain regions	MNI coordinate (x, y, z)	Voxel	T-value
L. AMYG	R. med SFG	3, 57, 3	184	−3.85
R. AMYG	R. SFG	15, 45, 45	347	−3.72
L. HIP	L. med OFC	−9, 42, −24	30	−3.89
R.HIP	R. med SFG	6, 57, 3	234	−4.74
R. NAcc	L. inf ORB	−39, 30, −3	109	−4.93
	L. med SFG	−9, 51, 12	173	−4.07
L. FG	R. med OFC	18, 18, −21	86	−2.80
	R. med SFG	12, 57, 0	102	−3.65
R. FG	R. sup ORB	24, 33, −18	96	−2.52
	R. MFG	39, 36, 15	287	−4.26

MNI: Montreal Neurological Institute; AMYG, amygdala; HIP, hippocampus; NAcc, nucleus accumbens; FG, fusiform gyrus; SFG, superior frontal gyrus; MFG, middle frontal gyrus; med SFG, medial superior frontal gyrus; med OFC, medial orbital frontal cortex; inf ORB, orbital part of inferior frontal gyrus; sup ORB, orbital part of superior frontal gyrus; L, left hemisphere; R, right hemisphere; pre-tDCS, before the tDCS intervention; post-tDCS, after the tDCS intervention

Fig. 3.

FC differences between the post-tDCS and the pre-tDCS group. A: left AMYG as seed region; B: right AMYG as the seed region; C: right NAcc as seed region; D: left HIP as seed region; E: right HIP as seed region; F: left FG as seed region; G: right FG as seed region. AMYG, amygdala; HIP, hippocampus; NAcc, nucleus accumbens; FG, fusiform gyrus; SFG, superior frontal gyrus; MFG, middle frontal gyrus; med SFG, medial superior frontal gyrus; med OFC, medial orbital frontal cortex; inf ORB, orbital part of inferior frontal gyrus; sup ORB, orbital part of superior frontal gyrus; L, left; R, right; pre-tDCS, before the tDCS intervention; post-tDCS, after the tDCS intervention; *, p < 0.05; ** p < 0.01

Correlations between the changes of FC value and improvement of depression

The FC values between the right FG and the right MFG demonstrated significant positive association with the reduction in depression scores (r = 0.612, p = 0.007, uncorrected, Fig. 2B). No significant association was observed between the improvement of clinical symptoms and the altered FC values of the remaining regions in this study.

Adverse effects

During the experiment, at the end of each intervention, we will inquire about and record adverse reactions experienced by the subjects. These reactions may include symptoms such as dizziness, headache, and fatigue, as well as sensations like tingling, itching, and numbness in the stimulated area. Two subjects reported experiencing mild skin tingling as an adverse reaction. However, the discomfort was alleviated once the treatment was paused. To further address their discomfort, we attempted to optimize the treatment by gradually increasing the current from a low starting level.

Discussion

The current study sought to investigate the FC alterations in emotion-related regions among young adults with FED after HD-tDCS intervention by using resting-state fMRI technique. We observed a significant reduction in depression and anxiety scale scores, along with improvements in cognitive abilities following the intervention. Besides, the FC within the prefrontal-limbic-striatal system was increased in pre-tDCS while decreased after HD-tDCS intervention in youth patients with FED, suggesting that HD-tDCS had modulated the emotion-related network in this study. Furthermore, the FC values between the right FG and the right MFG revealed a significant positive correlation with the improvement of depression. These findings indicated that the effects of HD-tDCS are not limited to local brain areas near the electrode sites but also involve subcortical regions.

Specifically, the post-tDCS group showed significant reduction in FC values between bilateral AMYG and right SFG, between left HIP and left OFC, between right HIP and right SFG, between right NAcc and right inf ORB and left med SFG, between left FG and right med OFC and SFG, and between right FG and right sup ORB and MFG, compared to the pre-tDCS group. Additionally, changed FC values between the right FG and the right MFG were positively correlated with the reduction in depression scores. Previous research has indicated that HD-tDCS could promote the changes of neural plasticity and alter the functional connectivity between cortical and subcortical regions by regulating neurotransmitter [21, 40]. Furthermore, prior studies have illustrated that tDCS could enhance various cognitive functions, including attention, working memory, executive function and social cognition [41, 42]. These findings provided further validation for our hypothesis, demonstrating that FC alterations in emotion-related regions within the prefrontal-limbic-striatal system could be a potential mechanism by which HD-tDCS improves depressive symptoms and cognitive function.

The AMYG is a key region of the limbic system, exhibiting extensive interconnections with numerous brain areas and playing a vital role in emotional processing and stress response, both positive and negative emotions are associated with its activity [43]. A meta-analysis encompassing 12 studies on drug-naïve patients with depressive disorder revealed significantly robust hyperactivity in AMYG during resting-state as compared to healthy subjects [44]. This hyperactivation is believed to amplify emotional responses in people with depression [22]. The neurobiological limbic-cortical model has proposed that depressive disorders stem from increased activity in AMYG and HIP, along with insufficient inhibition by prefrontal cortex (PFC) [45]. The PFC is instrumental in various critical functions, including not only the processing and regulation of emotions and rewards but also cognitive processes such as attention, memory, decision-making, and execution [5, 17, 46, 47]. It typically co-activates co-activate with AMYG to co-regulate the expression of negative emotions and exerts top-down inhibitory control over the activation of AMYG to suppress negative emotions [48]. Although findings have been inconsistent, alterations in FC between the AMYG and PFC have been associated with antidepressant treatment [49–51]. Zhang et al. demonstrated a reduction in resting-state FC between AMYG and PFC among drug-naive patients with depressive disorder following fluoxetine treatment, supporting our findings [51]. Furthermore, evidence indicates that depressive patients treated with antidepressant drugs or cognitive behavioral therapy exhibit decreased AMYG activity [52, 53], which may be related to the antidepressant effect observed with HD-tDCS in this study.

The HIP is also a component of the limbic system and is considered as a crucial region in the formation of memory as well as emotion processing. Deficiencies in its function and structure could contribute to explaining the pathogenesis of depression according to the limbic-cortical model [54, 55]. When recalling unpleasant experiences, people commonly attempt to alleviate their distress by stopping the retrieval of memories, a process that involves a powerfully inhibitory interaction between the PFC and HIP [56]. Some studies have shown enhanced FC between the HIP and PFC in individuals with depression while at resting-state, indicating that an impaired HIP-PFC circuit might be responsible for lower levels of motivation, loss of memory, and production of negative emotion in patients [57]. A study employing repetitive transcranial magnetic stimulation (rTMS) has suggested that PFC-orbitofrontal cortex (OFC)-HIP circuit serve as a critical mechanism for the remission of depressive symptoms [58]. Therefore, we speculated that the reduced HIP-PFC connectivity following HD-tDCS may be related to the cessation of unpleasant memory retrieval, emotion regulation, and cognitive improvement, and may offer a possible explanation for alleviating depression.

Anhedonia is a core symptom of depression, and there is an evident connection between anhedonia and abnormalities in both the structure and function of reward circuits, with the most significant being the ventral tegmental area (VTA)-NAcc circuit. The key reward-related regions, including the VTA, NAcc, OFC, and PFC, are linked together by medial forebrain bundle [59]. The NAcc, a vital nucleus of the basal ganglia, is highly correlated with the subjective perception of pleasurable rewards, while the PFC is capable of estimating the potency of rewards and regulating behavioral reactions through its evaluations. Some researchers have proposed that increased mPFC excitability exerts top-down inhibitory control over the interactions between midbrain and the NAcc, thereby regulating emotions and reward-related behavior [60–62]. Task-state fMRI results have demonstrated that abnormal connectivity between NAcc and PFC during task is the neural basis of anhedonia in people with depressive disorder [63]. Furthermore, during resting state there was a positively correlation between elevated connectivity in NAcc and PFC and anhedonia symptoms as well as depression scores, suggesting that the enhanced FC at rest might be a compensatory response to dysfunction in the reward circuit [64, 65]. A study involving animals similarly supported the potential contribution of reward circuits to the antidepressant benefits of tDCS [66]. Therefore, we presume that HD-tDCS may ameliorate depression by modulating the NAcc-PFC and NAcc-OFC connectivity, thereby reducing anhedonia.

Despite the FG playing a crucial role in the identification, perception, and processing of face stimuli, it also has a distinct impact on emotions [67]. Previous studies have extensively reported abnormalities in the structure of the FG among people with depressive disorder, including decreased gray matter volume, surface area and cortical folding [68]. According to prior reports, in comparison to HVs, individuals diagnosed with depressive disorder exhibited heightened activation in FG when exposed to both negative and positive facial expressions. Furthermore, a negative correlation has been observed between the level of depression and the activation in the FG specifically during positive facial expressions [69, 70]. Likewise, alterations in resting-state activity in the FG have been detected to be related to depression, such as a raise in fractional amplitude of low-frequency fluctuations (fALFF) value, and a significant reduction in fALFF values in the FG were observed after eight electroconvulsive therapies [71]. Similarly, in our study, we noticed that alterations in FC values between the right FG and the right MFG was positively correlated with the reduction in depression scores in patients. Both down-top emotion processing (e.g., hyperactivation of AMYG, HIP, and FG, etc.) and top-down cognitive control (e.g., reduced activation of PFC) are involved in production of negative emotion [45, 72, 73]. Our findings indicated that tDCS has successfully modulated neural activity of cortical structures with the emotion-regulation system in individuals with depression.

This study represents an important initial step toward understanding the neural mechanisms of tDCS as a neuromodulation treatment for depression. We employed a newer and more complete HD-tDCS intervention method compared to traditional studies, utilizing a ring-focused 4 × 1 circuit to improve the focus of the stimulation target, without the need to consider the return electrode, and is easy to use. In addition, the case group was selected from patients who experiencing their first depressive episode and were not taking medication for their first depressive episode, thus avoiding the influence of medication on efficacy as much as possible. On the other hand, due to its pilot nature, this study is limited by the small sample size. Moreover, this study lacks a sham stimulation group, so the placebo effect cannot be excluded. Second, the data for this study were mainly collected by self-report, which may be subject to recall bias. Further validation through large-scale cohort and double-blind, sham-controlled and randomized clinical trial studies is needed.

Conclusions

The findings of the current study provide a neurological mechanism for the antidepressant effects of prefrontal HD-tDCS in youth patients with FED. We showed that the reduction of depression was related with the modulation of FC within the prefrontal-limbic-striatal system, as accompanied by improvements in anxiety symptoms and cognitive function. Further studies should be conducted to confirm our results and explore the long-term effects of HD-tDCS with a larger sample size. Overall, our results offer a partial theoretical basis for the notion that HD-tDCS not only modulates local regions near the electrode sites but also affects the distributed emotion-regulation network.

Abbreviations

tDCS

Transcranial direct current stimulation

FED

First-episode depression

HD-tDCS

High-definition tDCS

FC

Functional connectivity

MDD

Major depressive disorder

DLPFC

Dorsolateral prefrontal cortex

PFC

Prefrontal cortex

NAcc

Nucleus accumbens

ACC

Anterior cingulate cortex

AMYG

Amygdala

HIP

Hippocampus

INS

Insula

FG

Fusiform gyrus

fMRI

Functional magnetic resonance imaging

Author contributions

Xianliang Chen, Jiali Liu, and Peiqu Liu conceived and designed the study. Huajia Tang, Hui Chen, Jiali Liu and Xianliang Chen participated in the acquisition of data. Xianliang Chen and Huajia Tang analyzed the data. Xianliang Chen and Huajia Tang drafted the manuscript, Fengmei Lu and Jiansong Zhou revised the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the STI2030-Major Projects (2021ZD0200700), the National Natural Science Foundation of China (82071543, 82471568), and the Key Research and Development Program of Hunan Province (2023SK2028), the General Program of Natural Science Foundation of Sichuan Province (2026NSFSC0468), the Science and Technology Bureau of Chengdu Program (2024-YF05-00873-SN), and the Medical Research Project of Chengdu (2024150).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was performed in accordance with the Declaration of Helsinki and was approved by the ethics review board of the Second Xiangya Hospital, Central South University. Written informed consent was obtained from all participants prior to participation.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.