dDual-target rTMS treatment for adolescent depression with headache: a case report

Abstract

Background

Adolescent patients with major depressive disorders (MDD) frequently co-occur with headache, contributing to substantial disease burden and social functional impairment. Repetitive transcranial magnetic stimulation (rTMS) has been supported for MDD and pain conditions, but clinical evidence for a combined affect and pain network targeting strategy in comorbid phenotypes remains limited.

Case presentation

A 16-year-old male student presented with a 2-year history of depression accompanied by paroxysmal headache. We administered a dual-target rTMS protocol targeting the dorsolateral prefrontal cortex and primary motor cortex. After 2 weeks of treatment (40 sessions), the patient’s depressive and headache symptoms improved significantly.

Conclusions

This case suggests that an intensified dual-target rTMS approach engaging both affect regulation and pain modulation targets may be feasible for adolescents with comorbid depression and headache. Prospective studies are needed to determine optimal parameters, durability, and safety.

Clinical trial number

Not applicable.

Introduction

Major depressive disorders (MDD) and headache disorders are widely regarded as neuropsychiatric conditions that impose a substantial global burden of disability. According to the latest updates from the Global Burden of Disease, Injuries, and Risk Factors Study 2021 (GBD 2021), an estimated 2.0 billion people worldwide were affected by tension-type headache and approximately 1.2 billion by migraine in 2021, underscoring headache disorders as a major global health burden [1, 2]. In addition, emotional comorbidity has been frequently observed among individuals with headache disorders [3]. Recent evidence indicates that the comorbidity rate of headache and MDD was approximately 43% [4], and this comorbidity appears to be even more pronounced in adolescents [5].

Repetitive transcranial magnetic stimulation (rTMS) is one of the neuromodulation techniques with the strongest evidence base for the treatment of psychiatric disorders, and it was approved by the U.S. Food and Drug Administration (FDA) in 2008 for treatment-resistant depression [6]. In clinical practice and research, the left dorsolateral prefrontal cortex (DLPFC) has been most commonly selected as a stimulation target for MDD [7]. In recent years, more precise stimulation strategies centered on the DLPFC have been developed. For example, the Stanford Neuromodulation Therapy proposed by Cole and colleagues was designed to stimulate an individualized site in the left DLPFC with the most negative functional connectivity to the subgenual anterior cingulate cortex for stimulation under functional magnetic resonance imaging guidance. In an open-label study of treatment-resistant depression, a remission rate of up to 90% was reported after a 5-day accelerated course [8]. In addition to the left DLPFC, stimulation of the right DLPFC has also been shown to improve depressive symptoms [9]. A recent study reported that accelerated intermittent theta burst stimulation over the left DLPFC and accelerated continuous theta burst stimulation over the right DLPFC produced comparable improvements in depressive symptoms [10]. Notably, compared with high-frequency stimulation of the left DLPFC, low-frequency stimulation of the right DLPFC has been associated with a lower incidence of adverse events such as seizure induction and pain, and better tolerability has been reported [11], which may be particularly relevant for adolescents. Consistently, a recent study also found that low-frequency stimulation of the right DLPFC could improve depressive symptoms in adolescents with treatment-resistant depression [12]. In the present case, low-frequency stimulation of the right DLPFC was selected.

Neuromodulation techniques have also been widely applied in the treatment of pain-related disorders. In recent years, increasing attention has been paid to the use of noninvasive rTMS for pain, with the the primary motor cortex (M1) commonly selected as a principal target. A randomized controlled trial in patients with headache showed that rTMS targeting M1 significantly reduced the mean Visual Analog Scale (VAS) score, headache attack frequency, and Migraine Disability Assessment score, and these improvements were maintained at the 1-month follow-up [13]. Beyond headache phenotypes, available evidence has also suggested that M1-rTMS can be effective for both central and peripheral neuropathic pain [14]. With respect to the choice of stimulation laterality, it is generally recommended that for unilateral pain, the M1 contralateral to the painful side should be stimulated, whereas for bilateral pain, the left M1 is preferred [7]. Notably, several expert consensuses and clinical guidelines have included M1-rTMS among recommended indications for pain-related conditions, covering neuropathic pain, post-traumatic headache, migraine prevention, and postoperative pain [15]. In the 2020 revised rTMS clinical practice guidelines, high-frequency rTMS applied to M1 contralateral to pain was assigned level A evidence for the treatment of neuropathic pain [7].

MDD and pain are highly comorbid in clinical settings, and these conditions co-occur so frequently that terms such as “depression–pain syndrome” and “depression–pain dyad” have been introduced [16]. In a global large-sample meta-analysis, it was estimated that approximately 40% of patients with pain also experienced depressive symptoms [17]. This comorbidity has also been observed in children and adolescents. In a meta-analysis including 51 studies, a significant association was reported between headache and depressive symptoms in adolescents, and higher rates of depression were observed in those with headache compared with those without headache [5]. Importantly, a bidirectional relationship between headache and depression was also proposed. Sleep reduction and avoidance behaviors driven by headache may increase the risk of MDD, while high-risk factors for MDD, such as childhood trauma, may further increase the risk of developing headache [5]. Consistently, the study by Jafari and colleagues indicated that MDD are common among adolescents with migraine and may be associated with more severe attacks [18]. From a mechanistic perspective, several bio-psycho-social pathways have been proposed to be shared between headache and depression, including partially overlapping genetic vulnerability, dysregulation of neurotransmitter systems, and potential structural and functional brain changes [19–22]. In a structural magnetic resonance imaging meta-analysis, common cortical deficits were identified across chronic pain, major depressive disorder, and anxiety disorders in regions involving the anterior cingulate cortex related circuits with the insula and or inferior frontal gyrus, as well as the left middle temporal gyrus [23]. These findings suggest that shared neural correlates of cognitive and affective processing may be present across these highly comorbid conditions.

Taken together, rTMS is considered to have important potential clinical value in patients with comorbid MDD and headache in adolescents, and targeting the DLPFC and M1 may offer dual benefits for affective and pain symptoms. Based on this rationale, the present case involved an adolescent patient with MDD comorbid with headache who was treated using a dual-target rTMS approach involving the DLPFC and M1.

Case presentation

The patient was a 16-year-old male student who presented with a 2-year history of low mood and anhedonia accompanied by headache. Approximately 2 years earlier, low mood developed without an apparent precipitating factor. Persistent sadness was present, with markedly reduced pleasure throughout the day. Interest in daily activities was diminished, and communication with others decreased. Social activities were avoided. Headache was also reported. The pain was paroxysmal, with variable duration and no fixed location. Sleep quality declined. Difficulty initiating sleep occurred, often due to headache, and early morning awakening was noted, followed by difficulty returning to sleep. Appetite decreased and weight loss occurred. Study performance and daily functioning were impaired. At times, life was felt to be meaningless, with suicidal ideation. Hopelessness about the future was described, along with the belief that the headache would not improve. The patient was evaluated at Zhongda Hospital, Southeast University, where brain magnetic resonance imaging and electroencephalography were performed and no obvious abnormalities were identified, the 24-item Hamilton Depression Rating Scale (HAMD-24) score was 57 and the pain intensity VAS score was 80 mm [24, 25]. The HAMD-24 is one of the most widely used clinician-administered depression severity measures in clinical trials. Standard severity cutoffs were applied: 0 ~ 10 (normal/remission), 11 ~ 17 (mild depression), 18 ~ 24 (moderate depression), and ≥ 25 (severe depression) [26]. The VAS used in this study was a 100 mm horizontal line anchored at the left end (0 mm) with “no pain” and at the right end (100 mm) with “worst pain imaginable” for pain assessments, and “no symptom” to “worst symptom imaginable” for other symptom ratings. Higher scores indicate greater severity [27]. For clinical interpretation, scores were categorized as follows: 0 ~ 4 mm (no pain/symptom), 5 ~ 44 mm (mild), 45 ~ 74 mm (moderate), and 75 ~ 100 mm (severe) [28]. The patient was diagnosed as MDD with Mini International Neuropsychiatric Interview for Children and Adolescents. Pharmacotherapy was initiated with sertraline (50 ~ 100 mg/day). After 2 months, no marked improvement was observed. Sertraline was then gradually replaced with duloxetine (40 ~ 120 mg/day) for 1 month. Depressive symptoms partially improved, whereas headache showed no obvious relief. The re-evaluation score for the HAMD-24 was 35, and the VAS was 70 mm. Therefore, we further administered rTMS treatment to the patient, with the pre-treatment HAMD-24 and VAS scores remaining at 35 and 70 mm, respectively.

After written informed consent was obtained, rTMS was administered using a YRD CCY-1 transcranial magnetic stimulator (Yiruide Medical Equipment New Technology Co., Ltd.). The resting motor threshold (RMT) was first determined, and stimulation intensity was adjusted according to the RMT. The RMT was determined using standard electromyography (EMG) procedures. The participant was seated comfortably in a reclining chair with both forearms resting on padded supports. Surface EMG electrodes were placed over the abductor pollicis brevis (APB) muscle of the contralateral hand, with the active electrode positioned over the muscle belly, the reference electrode over the tendon, and the ground electrode on the dorsum of the hand. Single-pulse TMS was delivered using a YRD CCY-1 transcranial magnetic stimulator with a figure-of-eight coil positioned over the hand area of the left primary motor cortex. The coil was initially placed 5 cm lateral and 2 cm anterior to the vertex, with the handle pointing posteriorly and laterally at a 45° angle to the sagittal plane. The optimal scalp position for eliciting maximal motor evoked potentials (MEPs) in the APB muscle was identified through a systematic search procedure, with the coil moved in 1 cm increments until the site with the largest and most consistent MEP amplitude was located. At this optimal site, the RMT was defined as the minimum stimulator intensity required to elicit MEPs with peak-to-peak amplitude ≥ 50 µV in at least 5 out of 10 consecutive trials. The intensity was initially set at 50% of maximum stimulator output and adjusted in 5% decrements until no MEPs ≥ 50 µV were observed, then increased in 1% increments to determine the precise threshold. This procedure was repeated twice, and the mean of the two measurements was calculated as the final RMT. Low-frequency stimulation was first delivered to the right DLPFC (1 Hz, 90% RMT, 20 pulses per train, 1 s inter-train interval, 900 total pulses, total stimulation time 15 min and 45 s), followed by high-frequency stimulation of the left M1 (10 Hz, 80% RMT, 20 pulses per train, 8 s inter-train interval, 600 total pulses, total stimulation time 7 min and 30 s). The second site (left M1) was stimulated immediately following completion of the first site (right DLPFC), with a brief coil repositioning period of approximately 2ཞ3 minutes. No extended break was provided between sites to maintain the accelerated treatment schedule and minimize total clinic time. Treatment was administered four times daily with a 2 h interval between sessions for 10 working days, for a total of 40 sessions. The selection of this intensified protocol was based on emerging evidence supporting accelerated rTMS paradigms in treatment-resistant depression. Accelerated rTMS protocols, involving multiple sessions per day, have demonstrated comparable efficacy to standard protocols with potentially faster onset of therapeutic effects [29, 30]. Similar accelerated approaches have been successfully applied in adolescent populations with acceptable safety profiles [31]. The rationale for implementing this schedule in the present case was to achieve rapid symptomatic improvement given the severity of treatment-resistant symptoms and the urgent clinical need. Comprehensive safety monitoring was implemented throughout the treatment course, including daily assessment of adverse effects, headache exacerbation, mood instability, and seizure risk. Immediate availability of medical personnel during and after each session to manage any acute adverse events. No serious adverse events were observed, and the patient tolerated the accelerated protocol well.

After treatment, the assessment was conducted on a separate day, 24 h after the final rTMS session. This 24-hour interval was selected to allow for acute neurophysiological effects of rTMS to subside, thereby capturing more stable treatment-related changes rather than transient post-stimulation effects; and minimize potential confounding from immediate post-session fatigue or headache that could influence subjective symptom ratings. Marked improvements were observed in depressive symptoms and pain severity. On reassessment, the HAMD-24 score was 3, and the VAS score was 1 mm. The reduction in HAMD-24 score from 35 at baseline to 3 at reassessment represents a 91.4% reduction, which far exceeds established criteria for clinically meaningful response. Standard conventions define treatment response as ≥ 50% reduction in symptom severity, and remission as scores ≤ 7 [32]. Our patient demonstrated both robust response and complete remission. This magnitude of improvement is particularly notable given the patient’s ultraresistant depression status, having failed multiple prior antidepressant trials and electroconvulsive therapy. Similarly, the reduction in pain intensity VAS from 70 mm at baseline to 1 mm at reassessment represents an 98.6% reduction. According to IMMPACT recommendations, a ≥ 50% reduction in pain intensity corresponds to “substantial improvement“ [33]. Our patient’s improvement approaches the “complete relief” category. In addition to the significant decrease in scale scores, the patient’s clinical symptoms and social functioning also improved markedly, transitioning from being unable to study or perform daily activities normally to returning to school with improved academic performance and reestablishing social relationships. This convergence of symptomatic and functional recovery supports the clinical relevance of the observed changes beyond mere statistical significance.

In addition, a noninvasive neuroimaging tool, functional near-infrared spectroscopy (fNIRS), was used to measure changes in oxygenated hemoglobin during a verbal fluency task before and 24 h after the final rTMS treatment. An improvement in prefrontal function was observed after treatment compared with baseline (Fig. 1). The integral score, representing the total hemodynamic response (area under the curve), showed a marked increase from pre-treatment to post-treatment assessments. This indicates enhanced overall prefrontal activation during cognitive engagement, reflecting improved neurovascular coupling and greater recruitment of prefrontal cortical resources. The centroid value, corresponding to the time point of peak hemodynamic response, shifted toward earlier latencies post-treatment. This temporal advancement suggests more efficient neural processing and faster hemodynamic response dynamics, indicative of optimized prefrontal cortex function and improved cognitive processing speed. The slope of the hemodynamic response curve, representing the rate of oxyhemoglobin increase, became steeper following treatment. This accelerated rise reflects more rapid and robust prefrontal activation upon task initiation, demonstrating enhanced neural efficiency and improved vascular responsiveness in the prefrontal cortex. The mean oxyhemoglobin concentration during the VFT increased substantially after treatment. This elevated baseline activation level indicates sustained and stronger prefrontal engagement throughout the cognitive task, consistent with improved executive function and working memory capacity. Collectively, these parameter changes, including increased integral score, earlier centroid, steeper slope, and higher mean value, suggest enhanced prefrontal functional integrity following the accelerated rTMS protocol.

Fig. 1.

The changes of near-infrared spectra as well as characteristic values of the prefrontal lobe before and after treatment. Abbreviations: HbO, oxyhemoglobin; HbR, reduced hemoglobin; HbT, Total Hemoglobin

During the course of treatment, no obvious adverse reactions were observed. Historical and current information from this episode of care is summarized in Table 1.

Table 1.

Key clinical milestones

Time	Events
~ 2 years before presentation	Onset of low mood and anhedonia with paroxysmal headache; sleep and appetite decline; functional impairment.
Initial evaluation	MRI and EEG: no obvious abnormalities. HAMD-24 57; VAS 8. Diagnosis: MDD. Sertraline initiated (50–100 mg/day).
After 2 months	No marked improvement with sertraline; switched to duloxetine (40–120 mg/day).
After 1 month	Partial improvement in depressive symptoms; headache showed no obvious relief. HAMD-24 35; VAS 7.
Dual-target rTMS (40 sessions)	Right DLPFC: 1 Hz, 90% RMT, 900 pulses; Left M1: 10 Hz, 80% RMT, 600 pulses. Four sessions/day with 2-hour intervals; total 40 sessions.
End of treatment	HAMD-24 3; VAS 1. fNIRS during verbal fluency task suggested improved prefrontal function (Fig. 1).

Discussion

To our knowledge, there are very few reports describing a dual-target rTMS strategy simultaneously addressing affective and pain symptoms in adolescents. Our findings suggest that, when adolescent depression is comorbid with headache, a combined targeting strategy that engages both affect regulation and pain modulation networks may have substantial clinical value. This case also provides reference evidence to support future validation of the efficacy and feasibility of such an intensified protocol in larger samples.

In the present case, a dual-target intervention was applied by stimulating the right DLPFC and the left M1. After only 10 days of treatment, clinical remission was achieved for depressive symptoms and pain. In prior studies, whether rTMS was delivered to the DLPFC for depression or to M1 for pain, the reported remission rates have generally been much lower than those observed in this case. On this basis, it may be inferred that dual-target stimulation could have produced a synergistic effect and contributed to the rapid onset of benefit. Stimulation of the right DLPFC may not only improve depressive symptoms but may also modulate pain, which could help explain a plausible basis for synergy in the dual-target approach. For example, Tanwar and colleagues applied low-frequency rTMS to the right DLPFC in patients with fibromyalgia. Compared with the control group, significantly lower pain ratings were observed in the treatment group, and this reduction was maintained over a 6-month follow-up period [34]. Similar findings were also reported by the same group when an identical stimulation protocol was used in patients with tension-type headache [35]. In another study, rTMS targeting M1 was compared with rTMS targeting the left DLPFC in patients with neuropathic pain. Marked pain improvement was observed in the M1 group, whereas no clear clinical benefit was obtained in the left DLPFC group [36]. Notably, the benefits of M1 stimulation may not be restricted to the pain domain. In some studies, M1-rTMS was found to improve comorbid depressive and anxiety symptoms to a certain extent [37]. Such effects on mood may be partly mediated by improvements in accompanying symptoms, which may in turn facilitate better overall behavior and functioning. In addition, changes in serum kynurenine levels have been reported after M1-rTMS [38], and kynurenine has been implicated as a pathogenic factor in the pathophysiology of depression [39]. Taken together, the right DLPFC and the left M1 can be viewed as targets that engage affect regulation and pain modulation networks, respectively. Combined dual-target stimulation may therefore yield faster and more comprehensive clinical benefits in an affective disorder and pain comorbidity phenotype through the additive and mutually reinforcing effects of multiple pathways.

The reduction in HAMD-24 score from 35 (severe depression) to 3 (remission range) represents an 91.4% improvement-far exceeding conventional benchmarks for treatment response. This magnitude of change is particularly remarkable given the patient’s treatment-resistant status, with documented failure of multiple antidepressant trials, augmentation strategies, and electroconvulsive therapy. The achievement of remission, defined as HAMD-24 ≤ 10 (or more stringently ≤ 7), is the optimal therapeutic outcome in depression treatment and is often elusive even in responsive patients [32, 40]. Response rates in standard rTMS protocols for treatment-resistant depression typically range from 30 ~ 50%, with remission rates of 20 ~ 30% [41, 42]. Accelerated protocols have shown somewhat higher response rates in preliminary studies, but remission remains uncommon in severely resistant populations. The complete remission observed here-particularly the rapid onset within 10 days-exceeds outcomes reported in most randomized controlled trials and suggests that the combination of accelerated delivery, bilateral sequential targeting, and multimodal symptom approach may offer synergistic benefits. Several factors may have contributed to this remarkable outcome. Firstly, the compressed treatment schedule may have prevented the inter-session decay of synaptic plasticity that occurs with standard weekly protocols, producing more robust and sustained circuit reorganization [43]. Secondly, simultaneous engagement of mood-regulating and pain-modulating-circuits may have addressed interconnected neural substrates of depression and chronic pain, producing synergistic clinical effects [16]. What’s more, the patient’s age may have conferred heightened neuroplasticity, facilitating more rapid and extensive cortical reorganization in response to neuromodulation [44].

Additionally, the significant efficacy observed in this patient may also be attributed to the treatment parameters we selected. The 1 Hz rTMS protocol applied to the right DLPFC was selected based on its established efficacy in reducing cortical excitability and producing localized functional inhibition [45]. This approach is grounded in the interhemispheric competition model of MDD, which posits that depression is associated with relative hypoactivity of the left DLPFC and hyperactivity of the right DLPFC [46]. Low-frequency stimulation of the right DLPFC aims to correct this imbalance by reducing excessive right-sided prefrontal activity. The 1 Hz frequency is below the threshold for inducing long-term potentiation and reliably produces long-term depression (LTD)-like effects, with demonstrated antidepressant efficacy in multiple randomized controlled trials [47]. Slightly subthreshold intensity (90% RMT) was selected to ensure robust cortical engagement while maintaining safety margins below seizure-inducing thresholds [48]. The pulse count (900) aligns with standard inhibitory protocols showing clinical efficacy, typically ranging from 600 to 1600 pulses per session [49]. The extended duration (15 min 45 s) reflects the inherently slower nature of low-frequency stimulation, with inter-train intervals allowing adequate recovery to prevent cumulative neurophysiological fatigue. The 10 Hz protocol applied to the left M1 was selected based on its established efficacy in motor cortex stimulation for neuropathic pain and its modulatory effects on descending pain inhibitory pathways [50]. This frequency falls within the range most effective for inducing long-term potentiation (LTP)-like effects and has demonstrated optimal efficacy in pain modulation studies [51]. Frequencies of 5–20 Hz have shown comparable efficacy, with 10 Hz being the most extensively validated [52]. Submotor threshold intensity (80% RMT) was selected to preferentially activate corticospinal and cortico-subcortical pathways involved in pain modulation without inducing unnecessary motor contractions [7]. The conservative pulse count (600) reflects the lower threshold for motor cortex excitability changes and aligns with established analgesic protocols [53]. The shorter duration (7 min 30 s) compared to DLPFC stimulation reflects the higher frequency and more efficient temporal summation at 10 Hz, with longer inter-train intervals (8 s versus 1 s) allowing adequate recovery between trains to prevent seizure risk while maintaining therapeutic efficacy. In a word, the sequential application of right DLPFC 1 Hz followed by left M1 10 Hz was designed to address both affective and sensory components of the patient’s presentation. The extended DLPFC session duration prioritizes mood regulation, while the shorter, more intense M1 session targets pain pathways efficiently. This combination approach is supported by evidence that multimodal rTMS targeting distinct neural circuits may produce synergistic effects in patients with comorbid depression and chronic pain [16]. This specific combination of parameters is not standard and represents a personalized protocol, that need for systematic validation in larger samples.

The accelerated protocol employed in this case represents a substantial intensification compared to standard rTMS regimens (typically 20–30 sessions over 4–6 weeks). The patient demonstrated excellent tolerability throughout treatment, with no serious adverse events, no session interruptions. This favorable profile aligns with emerging evidence that accelerated rTMS protocols are generally well-tolerated when appropriate safety monitoring is implemented. Tolerability data in adolescent populations receiving accelerated or intensified rTMS remain limited but encouraging. Croarkin et al. [31]reported that adolescent patients with depression tolerated twice-daily sessions of bilateral rTMS without significant adverse effects, with headache and scalp discomfort being the most common complaints. Wall et al. [54] similarly observed acceptable tolerability in adolescents receiving adjunctive rTMS, with no seizures or manic switches despite treatment-resistant presentations. More recently, open-label studies of accelerated theta-burst stimulation in youth have demonstrated rapid symptom reduction with side effect profiles comparable to adult populations [55]. Our findings extend this literature by demonstrating that even more intensified protocols (four sessions daily) can be safely administered in adolescents when comprehensive monitoring is employed. The absence of seizure activity, mood switching, or cognitive deterioration in our patient suggests that accelerated approaches may be viable in complex adolescent presentations when vigilance for neuropsychiatric adverse effects is maintained. The favorable outcome in this case likely reflects our systematic safety protocol, including: (1) pre-treatment screening for seizure risk factors; (2) daily clinical assessments for mood, cognitive, and somatic symptoms; (3) conservative parameter selection (submotor threshold for M1, extended inter-train intervals); and (4) immediate medical availability during all sessions. These safeguards are particularly critical in adolescents, who may exhibit heightened neuroplasticity and variable pharmacokinetic interactions. We emphasize that this single-case observation cannot establish the general safety of ultra-accelerated protocols in adolescents. The absence of adverse effects in one patient does not preclude risks in others, particularly those with comorbid neurological conditions, substance use, or unstable medical status. Systematic studies with larger samples and active safety monitoring are essential to define the risk-benefit profile of intensified rTMS in this vulnerable population.

The fNIRS data demonstrated marked improvement in prefrontal hemodynamic response during the verbal fluency task following accelerated rTMS treatment. Specifically, increases in integral score, mean oxygenated hemoglobin concentration, and slope of the hemodynamic response curve, alongside earlier centroid values, collectively indicate enhanced prefrontal cortical activation and improved neurovascular coupling. These changes are consistent with normalization of the prefrontal hypoactivation typically observed in major depression [56]. The rapid emergence of prefrontal functional improvement within 24 h of completing treatment is notable. Standard rTMS protocols typically require several weeks to produce detectable neuroimaging changes [57]. The accelerated schedule employed here may have induced more robust or rapidly consolidating synaptic plasticity, potentially through cumulative effects on neurotrophic signaling and glutamatergic neurotransmission [58]. This temporal profile supports the hypothesis that intensified stimulation paradigms can expedite neural circuit reorganization. The correlation between prefrontal functional improvement and clinical symptom reduction (depression and pain) suggests that fNIRS may serve as a sensitive biomarker of treatment response. The verbal fluency task engages dorsolateral prefrontal regions implicated in both cognitive control and pain modulation, making it particularly relevant to this patient’s comorbid presentation [59]. These preliminary findings support the potential utility of fNIRS as a noninvasive, low-cost tool for monitoring rTMS treatment response.

Several limitations should be acknowledged. First, this is a single-case observation without a control condition, and the effects of spontaneous symptom fluctuation, placebo responses, or other nonspecific factors cannot be excluded; therefore, causal inference and generalizability are limited. Second, the headache phenotype was heterogeneous, with variable location and marked fluctuations with emotional state, making it difficult to classify the presentation into a specific headache subtype or diagnostic category; this limits the precision of interpretation and extrapolation across the headache spectrum. Third, follow-up was limited, and the durability of response, relapse risk, and the need for maintenance or consolidation strategies remain uncertain; long-term safety also warrants further evaluation. Prospective controlled studies in larger samples are needed to confirm efficacy, safety, and reproducibility, and to further define the applicable clinical phenotype and long-term management strategies.

Conclusion

In a comorbidity phenotype in which MDD is tightly intertwined with headache, rTMS treatment strategies may be shifted from a single affective target to a network-based approach that gives equal emphasis to affect regulation and pain modulation. In this case, a dual-target, short-course intensified protocol consisting of low-frequency stimulation of the right DLPFC combined with high-frequency stimulation of the left M1, was associated with concurrent and marked improvements in depression and pain. These findings suggest that this approach may be feasible in clinical practice and may provide added benefit for patients with complex symptom profiles, such as comorbid depression with pain, who require rapid symptom relief. Given the inherent limitations of single-case evidence and potential confounding factors, prospective studies are still needed to further define the optimal parameter combinations, treatment duration, and maintenance strategies. Efficacy durability and safety should also be confirmed using controlled designs, in order to advance individualized neuromodulation pathways for populations with affective and pain comorbidity.

Abbreviations

DLPFC

Dorsolateral prefrontal cortex

EEG

Electroencephalography

FDA

U.S. Food and Drug Administration

HAMD-24

24-item Hamilton Depression Rating Scale

M1

Primary motor cortex

MDD

Major depressive disorder

MRI

Magnetic resonance imaging

fNIRS

Functional near-infrared spectroscopy

RMT

Resting motor threshold

VAS

Visual Analog Scale

rTMS

Repetitive transcranial magnetic stimulation

Author contributions

Guangwei Sun wrote the main manuscript text. Yingying Yin was involved in assessment and treatment of the patient. All authors additionally reviewed and revised the manuscript.

Funding

This study was funded by National Natural Science Foundation of China (81801349, Y. Yin). Jiangsu Province Frontier Technology Research and Development Program (Health Sector) (BF2025611).

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This case report was fully approved by the Ethics Committee of Zhongda Hospital, Southeast University. Ethical approval number: 2024ZDKYSB070. The methods were performed in accordance with the guidelines of the Declaration of Helsinki.

Consent for publication

Written informed consent for publication was obtained from the patient and the patient’s parent(s).

Competing interests

The authors declare no competing interests.