Acupuncture for Psychomotor Retardation in Patients with Moderate Major Depressive Disorder: Protocol for a Randomized Controlled Trial

Acupuncture for Psychomotor Retardation in Patients with Moderate Major Depressive Disorder: Protocol for a Randomized Controlled Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Method Article Acupuncture for Psychomotor Retardation in Patients with Moderate Major Depressive Disorder: Protocol for a Randomized Controlled Trial Mo Huiting, Li sheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9686192/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Psychomotor retardation (PMR) is a core yet consistently under-targeted symptom domain of major depressive disorder (MDD). Despite its association with functional impairment and poor treatment response, PMR-specific endpoints and multi-dimensional objective measurement remain rare in clinical trials. This protocol describes a randomized controlled trial evaluating whether acupuncture, acupuncture as an adjunctive pharmacological co-treatment to sertraline, improves PMR in patients with moderate MDD. Methods and Analysis: Thisparallel-group, randomized, single-blind, sham-controlled trial will enroll 60 participants allocated 1:1 to acupuncture plus sertraline (n = 30) or sham acupuncture plus sertraline (n = 30). The acupuncture prescription comprises Baihui (GV20), Yintang (EX-HN3), bilateral Hegu (LI4), bilateral Taichong (LR3), bilateral Touwei (ST8), bilateral Shenmen (HT7), Zhongwan (CV12), Xiawan (CV10), Qihai (CV6), and Guanyuan (CV4), administered three times weekly for eight weeks (24 sessions), followed by a four-week follow-up. Assessments are conducted at baseline (T0), week 4 (T1), week 8 (T2), and week 12 (T3). The primary outcome is the SRRS reduction rate at T2. Secondary outcomes include the CORE Retardation Subscale, HAMD-17, Speech Pause Test (speech rate, phonation time, total pause duration, silence quotient), TMT-A completion time, and FTT tapping frequency. Safety is monitored throughout. Ethics and Dissemination: Ethical approval will be obtained from the Medical Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine. The trial will be prospectively registered on a recognized clinical trials registry. Written informed consent will be obtained from all participants. Results will be published in peer-reviewed journals regardless of outcome. Psychiatry psychomotor retardation major depressive disorder acupuncture randomized controlled trial Figures Figure 1 Introduction Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric condition characterized by persistent low mood, cognitive impairment, and functional decline. Among its core symptom clusters, psychomotor retardation (PMR) — characterised by observable slowing of movement, speech, and ideation — affects approximately one-third to nearly two-thirds of patients depending on clinical subtype [ 1 ] . PMR is not merely an epiphenomenon: it is strongly associated with greater illness severity, longer episode duration, higher rates of recurrent suicidal behaviour, and, critically, poorer antidepressant response [ 4 ] . This treatment-resistance gap may be partly explained at the neurobiological level: selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological standard, operate primarily on monoaminergic serotonin pathways yet exert minimal direct modulation of the dopaminergic motor circuitry whose dysfunction is increasingly recognised as a pathophysiological substrate of PMR. From a neuroimaging perspective, this represents a clear mechanistic mismatch. The neurobiological architecture of PMR has become considerably clearer in recent years. Convergent evidence implicates dysfunction within the subcortical–cortical motor circuit, anchored by dopaminergic projections from the substantia nigra through the striatum to the motor cortex [ 8 ] . Neuroimaging studies have consistently identified reduced dopamine synthesis capacity and elevated D2-receptor binding potential in the striatum of patients with PMR, reflecting hypodopaminergic states that translate into attenuated motor initiation and execution [ 7 ] . Together, PMR is characterised as a disorder of hypoperfused, hypoconnected motor cortical circuitry driven by dopaminergic insufficiency. Accumulating evidence suggests that acupuncture may exert therapeutic effects in depression through multimodal mechanisms, including neurotransmitter regulation, restoration of neuroendocrine balance, enhancement of neuroplasticity, and anti-inflammatory effects [ 8 ] .Reviews document that acupuncture modulates the SMN — specifically engaging the precentral and postcentral gyri, putamen, and caudate — alongside limbic-prefrontal nodes including the anterior cingulate cortex, amygdala, and dorsolateral prefrontal cortex [ 15 ] . A meta-analysis of LR3-targeted fMRI studies further confirmed activation patterns spanning basal ganglia, sensorimotor, and salience networks[24].Despite advances in mechanistic understanding, the objective assessment of PMR in existing acupuncture trials for MDD remains essentially absent,no published RCT has designated PMR as a primary outcome and the findings are largely derived from small-scale or uncontrolled studies,high-quality randomized controlled trials specifically targeting PMR are still lacking. To address these gaps, the present study focuses specifically on patients with clinically significant PMR and adopts a symptom-domain-oriented design. Sertraline is used as the background pharmacological treatment, while acupuncture is introduced as an adjunctive intervention to explore potential additive effects. The selection of outcome measures reflects an effort to capture both subjective and objective aspects of PMR. Methods and Design Setting and Design This parallel-group, randomized, single-blind (participant-blind), sham-controlled trial will be conducted at the Acupuncture and Moxibustion Department of Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, from 2026-06-01 to 2027-06-01. The protocol adheres to the SPIRIT 2013 guidelines [ 2 ] , STRICTA 2010 (MacPherson et al., 2010), and will be reported per the CONSORT 2010 statement[4]. Sixty eligible participants will be randomized 1:1 to either the acupuncture group or the sham acupuncture control group; both groups receive concurrent sertraline throughout. The treatment phase is eight weeks (three sessions per week, 24 sessions total) followed by a four-week follow-up. Table 1 presents the study timeline and assessment schedule, and Fig. 1 shows the CONSORT flow diagram. Table 1 Study timeline and assessment schedule. Assessment / Procedure T0 Baseline (Wk 0) T1 Mid-treatment (Wk 4) T2 End of treatment (Wk 8) T3 Follow-up (Wk 12) Eligibility screening & consent ✓ Randomization ✓ Active acupuncture (3×/week) Wks 1–8 → → Sham acupuncture (3×/week) Wks 1–8 → → Sertraline (both groups) Continuous → → → SRRS (Primary) ✓ ✓ ✓ ★ ✓ CORE Retardation Subscale ✓ ✓ ✓ ✓ HAMD-17 ✓ ✓ ✓ ✓ Speech Pause Test ✓ ✓ ✓ ✓ TMT-A ✓ ✓ ✓ ✓ FTT ✓ ✓ ✓ ✓ Adverse events / TESS Continuous → → → Blinding assessment ✓ Abbreviations: SRRS, Saldia Retardation Rating Scale; HAMD-17, Hamilton Depression Rating Scale-17; CORE, CORE Retardation Subscale; TMT-A, Trail Making Test Part A; FTT, Finger Tapping Test; TESS, Treatment Emergent Symptom Scale. ★ Primary outcome assessment time point. Notes: Baseline assessments (T0) are completed prior to the first acupuncture or sham acupuncture session, immediately following randomization. T1 assessments (week 4) are conducted midway through the treatment phase to capture early-phase response trajectories. T2 assessments (week 8) constitute the primary endpoint evaluation and are performed within two working days of the final treatment session. T3 assessments (week 12) are conducted four weeks after treatment completion to evaluate durability of effects; no acupuncture or sham acupuncture is administered during the follow-up period, though sertraline continues as clinically indicated. SRRS and all objective performance measures (Speech Pause Test, TMT-A, FTT) are administered by blinded assessors in a dedicated assessment room physically separated from the treatment area. Speech Pause Test recordings are made using a standardized device at a fixed distance of 30 cm; only one recording is obtained per time point due to the potential for learning effects. TMT-A is administered using parallel versions or alternative stimulus orderings at T1–T3 where available to minimize practice-related performance gains. FTT is administered using three trials with 30–60 s rest intervals; the median tapping count is used for analysis. TESS is administered at all assessment time points for participants receiving sertraline. Adverse events are monitored from the first intervention session through the T3 follow-up visit. Participants Participants will be recruited from the outpatient clinic and inpatient ward of Guangdong Provincial Hospital of Chinese Medicine through clinical referrals, in-hospital advertisements, and social media. Diagnosis of MDD is established per DSM-5 criteria, confirmed by qualified psychiatrists. Inclusion criteria Age 18–50 years. DSM-5 diagnosis of major depressive disorder. Moderate severity: HAMD-17 score > 27 and ≤ 35. Clinically identifiable PMR: SRRS ≥ 20. No antidepressant treatment in the past three weeks, or currently on a stable regimen unchanged for ≥ three weeks. Written informed consent. Exclusion criteria Neurodegenerative or movement disorders (Parkinson’s disease, Lewy body dementia, Huntington’s disease, or other extrapyramidal syndromes). Active suicidal intent, suicidal behavior, or psychotic symptoms. Lifetime diagnosis of schizophrenia, bipolar disorder, or schizoaffective disorder. Personality disorder significantly affecting adherence. Alcohol or substance use disorder. Significant organic brain disease (severe traumatic brain injury, epilepsy, brain tumor, cerebrovascular sequelae). Severe medical comorbidity or contraindications to acupuncture (metallic implants, coagulation disorders). Fear of acupuncture or anticipated poor compliance. Pregnancy or breastfeeding. Screening proceeds in two steps: HAMD-17 to confirm moderate severity, followed by SRRS to confirm PMR. Candidates passing both proceed to full eligibility review, informed consent, and baseline assessment. Participants are withdrawn if they complete fewer than 20 of 24 sessions, withdraw voluntarily, or deteriorate clinically. Participants are eliminated post-randomization for retrospective eligibility failure, unauthorized concomitant antidepressant treatment, or protocol deviations that substantially confound assessment. For participants withdrawing after at least one post-baseline assessment, data are retained and missing values are imputed by the Last Observation Carried Forward (LOCF) method for the intention-to-treat (ITT) analysis. Randomization and Blinding A simple randomization sequence is generated by SPSS software (two-group, N = 60). An independent staff member prepares sequentially numbered, opaque, sealed envelopes; each eligible participant opens the next available envelope after baseline assessment. Acupuncturists cannot be blinded. Participant blinding is achieved with non-penetrating sham needles (flat-tipped, collapsible-handle design) visually identical to genuine needles. Outcome assessors and data analysts remain blinded throughout; physical separation of treatment and assessment areas is maintained. Blinding integrity is formally assessed at T2 by asking participants which treatment they believe they received, and sensitivity analyses stratified by blinding success are pre-specified. Interventions Concomitant pharmacotherapy (both groups) All participants receive sertraline hydrochloride (50 mg starting dose; adjusted to 75–200 mg/day after one week based on clinical response). Participants already on a stable regimen for ≥ three weeks continue unchanged. If no improvement is observed after three weeks, the supervising psychiatrist determines whether the participant should withdraw. Antidepressant dose at each assessment time point is recorded and treated as a covariate in statistical analyses. Acupuncture group Acupoint locations follow WHO standard specifications. The prescription comprises Baihui (GV20), Yintang (EX-HN3), bilateral Hegu (LI4) and Taichong (LR3) (the Four Gates), bilateral Touwei (ST8), bilateral Shenmen (HT7), Zhongwan (CV12), Xiawan (CV10), Qihai (CV6), and Guanyuan (CV4) (Table 2 ). Sterile 0.25 × 25 mm needles are used throughout; Baihui and Yintang are inserted obliquely (30°, 4–5 mm) with uniform rotation to de qi; Hegu and Taichong are needled perpendicularly (10–12 mm) with even lifting-thrusting and rotation to de qi; remaining points are needled perpendicularly to de qi. Needles are retained for 30 minutes. Sessions are delivered three times per week with a minimum inter-session interval of 24 hours. A standardized operating procedure (SOP) is developed prior to trial initiation; all acupuncturists complete SOP-based training and a practical competency assessment, with treatment fidelity monitored by periodic random review of video-recorded sessions. Table 2 Acupoint prescription and needling specifications. Acupoint Anatomical Location (WHO Standard) Gauge Depth & Technique Baihui (GV20) Head, 5 cun superior to anterior hairline midpoint 0.35×25 mm Oblique 30°, 4–5 mm; uniform rotation to de qi Yintang (EX-HN3) Midpoint between medial ends of the two eyebrows 0.35×25 mm Oblique/flat insertion; uniform rotation to de qi Hegu (LI4) bilateral Dorsum of hand, midpoint of 2nd metacarpal on radial side 0.35×25 mm Perpendicular, 10–12 mm; lifting-thrusting and rotation to de qi Taichong (LR3) bilateral Dorsum of foot, depression distal to 1st–2nd metatarsal junction 0.35×25 mm Perpendicular, 10–12 mm; lifting-thrusting and rotation to de qi Touwei (ST8) bilateral Head, 0.5 cun within anterior hairline, 4.5 cun lateral to GV24 0.35×25 mm Oblique/flat insertion to de qi Shenmen (HT7) bilateral Wrist, ulnar end of transverse crease, radial to flexor carpi ulnaris 0.35×25 mm Perpendicular to de qi Zhongwan (CV12) Upper abdomen, 4 cun superior to umbilicus, midline 0.35×25 mm Perpendicular to de qi Xiawan (CV10) Upper abdomen, 2 cun superior to umbilicus, midline 0.35×25 mm Perpendicular to de qi Qihai (CV6) Lower abdomen, 1.5 cun inferior to umbilicus, midline 0.35×25 mm Perpendicular to de qi Guanyuan (CV4) Lower abdomen, 3 cun inferior to umbilicus, midline 0.35×25 mm Perpendicular to de qi Sham acupuncture control group Participants receive non-penetrating sham needles (flat-tipped, collapsible-handle device) at the same acupoints as the active group. The device applies blunted-tip pressure against the skin surface without penetration, secured by an adhesive foam pad [ 20 ] ; no needle manipulation, de qi, or subcutaneous retention occurs. Treatment frequency, session duration, and total sessions are identical to the active group. Treatment duration and follow-up The treatment period is eight weeks (three sessions per week; protocol completers require ≥ 20 sessions). A four-week post-treatment follow-up follows, during which no acupuncture or sham acupuncture is administered; sertraline continues as clinically indicated. Outcome assessment at follow-up is conducted at week 12 (T3). Outcomes and Assessments Primary outcome The primary outcome is the SRRS reduction rate at T2 (end of treatment, week 8), calculated as: (baseline score − T2 score) / baseline score × 100%. The SRRS (Saldia Retardation Rating Scale) is regarded as the gold standard instrument for quantifying PMR, encompassing three objective domains — motor function (gait, limb/trunk movement), speech (verbal flow, tone, response latency), and observable cognitive performance — alongside five subjective dimensions covering fatigue, interest, time perception, memory, and concentration [ 21 ] . Secondary outcomes All secondary outcomes will be assessed at T0, T1, T2, and T3 by blinded outcome assessors. CORE Retardation Subscale: A clinician-rated observational scale that does not rely on language-based responses, making it particularly suitable for identifying PMR in melancholic depression subtypes independently of verbal ability. It will serve as a complementary PMR measure to the SRRS. HAMD-17: The Hamilton Depression Rating Scale-17 will provide an overall index of depression severity as well as a specific retardation factor score. Total score change from baseline will be reported at each assessment time point. Speech Pause Test: The Speech Pause Test provides an objective, ecologically valid index of verbal PMR. Following standardized instructions and establishment of rapport, participants will be asked: “Please count from 1 to 20 at your normal speaking pace.” The instruction will be delivered once without further prompting. Audio will be recorded using a standardized recording device at a fixed distance of 30 cm. The recording segment of 20–30 seconds will be selected for analysis, excluding the interviewer’s voice and any pre-onset silent pause preceding the participant’s first utterance. Audio will be analyzed offline using Praat software (version 6.x). A standardized analysis protocol will define the minimum pause threshold at 0.15 seconds. The following indices will be extracted: (1) speech rate (syllables per second), (2) phonation time (total voiced duration in seconds), (3) total pause duration (sum of all pauses ≥ 0.15 seconds), and (4) silence quotient (total pause duration divided by total recording duration, expressed as a proportion). Due to the potential for learning effects, only one recording will be made per assessment time point. All analysis will be performed by a single trained analyst blinded to group allocation, using a pre-defined analysis script to minimize inter-rater variability. Trail Making Test Part A (TMT-A): TMT-A will assess psychomotor processing speed. The participant is required to connect numbered circles (1 to 25) in ascending order as rapidly as possible on a standard test sheet. Prior to the formal test, a brief practice trial will be administered to ensure task comprehension. Completion time in seconds will be recorded from initiation to the final connection. If a connection error occurs, the assessor will immediately indicate the error and instruct the participant to correct it without pausing the timer. Due to significant learning effects associated with repeated administration of the same test form, parallel versions or alternative stimulus orderings will be used at T1, T2, and T3 where available, and all versions used will be documented. Finger Tapping Test (FTT): FTT will assess pure motor speed. Using the dominant hand with the wrist stabilized on a flat surface, the participant will tap a mechanical counter as rapidly as possible for 30 seconds. Three consecutive trials will be conducted, with 30–60 seconds of rest between each trial. The median tapping count across the three trials will be used as the outcome variable for statistical analysis, as median values are more robust to isolated performance outliers than mean values. Safety Assessment: All adverse events (AEs) occurring during the treatment period and follow-up will be recorded on the Case Report Form. For participants receiving sertraline, the Treatment Emergent Symptom Scale (TESS) will be administered at each assessment time point to systematically document medication-related side effects. AEs will be classified by type, severity, onset, duration, and presumed relationship to the study intervention. Serious adverse events (SAEs) will be reported to the institutional ethics committee within 24 hours of the investigator’s awareness. Any participant developing active suicidal ideation, manic symptoms, or psychotic features during the trial will be immediately referred to the supervising psychiatrist for specialist evaluation and managed independently of the trial protocol. Monitoring and Quality Control All outcome assessors complete a standardized training program for SRRS, CORE, and HAMD-17 administration, with inter-rater reliability confirmed by an intraclass correlation coefficient (ICC) of ≥ 0.80. Speech Pause Test analysts complete a unified Praat training program. All acupuncturists complete SOP-based training and practical certification; treatment fidelity is monitored by periodic video audit. Outcome data are recorded on paper CRFs and concurrently entered into a password-protected electronic database with double entry and automated discrepancy checking. Assessors are physically separated from treatment personnel. A dual-track safety monitoring system operates throughout: structured session-level assessment for acupuncture-specific AEs (hematoma, dizziness, needle pain, local infection), and systematic daily documentation of all AEs. An independent safety monitor reviews all SAEs and may recommend trial suspension if pre-specified safety thresholds are exceeded; a 24-hour psychiatry liaison is available for participants exhibiting clinical deterioration. Sample Size This is an exploratory trial. In the absence of published PMR-specific effect size data for acupuncture, a formal power calculation cannot be reliably derived. A total sample of 60 participants (30 per group) is proposed based on feasibility considerations and the scope of prior exploratory acupuncture trials in MDD. This sample size is sufficient to estimate between-group effect sizes and variance parameters to power a subsequent confirmatory trial. Anticipating approximately 20% withdrawal, all enrolled participants completing at least one post-baseline assessment will be included in the ITT analysis, with LOCF applied to missing data. Statistical Analysis The ITT population comprises all randomized participants receiving at least one session and completing at least one post-baseline assessment; missing data are handled by LOCF. A per-protocol (PP) sensitivity analysis includes only participants completing ≥ 20 of 24 sessions and attending all four assessments. All tests are two-tailed (α = 0.05). Analyses are performed using SPSS version 20.0 (IBM Corporation, USA). The primary outcome (SRRS reduction rate at T2) is compared between groups by independent samples t-test or Mann-Whitney U test, according to normality (Shapiro-Wilk test and Q-Q plots). Between-group mean difference and 95% confidence interval are reported; effect size is expressed as Cohen’s d. Secondary outcomes over the four time points (T0–T3) are analyzed by repeated-measures ANOVA with Bonferroni correction for pairwise comparisons; Greenhouse-Geisser correction is applied when sphericity is violated (Mauchly’s test p < 0.05). Generalized linear mixed models are applied to non-normally distributed secondary outcomes. Antidepressant dose is included as a covariate in a pre-specified sensitivity analysis. An exploratory Pearson correlation analysis (Spearman if normality is not met) will examine the association between change in Speech Pause Test total pause duration from T0 to T2 and SRRS reduction rate at T2, to provide initial validity evidence for the Speech Pause Test as an objective PMR treatment-response index. Ethics and Confidentiality The protocol will be submitted to the Medical Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine for review and approval prior to recruitment. The trial will be conducted in accordance with the Declaration of Helsinki (2013 revision) and applicable Good Clinical Practice guidelines, and prospectively registered on the Chinese Clinical Trial Registry (ChiCTR) or ClinicalTrials.gov prior to enrolment. Written informed consent will be obtained from all participants. Participant data will be coded with unique study identification numbers; personally identifiable information will be stored separately in a password-protected file accessible only to the principal investigator. Study documents will be retained for a minimum of five years. Protocol amendments will be submitted to the ethics committee and updated in the trial registry before implementation. Patient and Public Involvement No patient or public involvement occurred in the design or planning of this study. Findings will be disseminated to participants who request results following publication. Protocol Amendments Any modifications affecting trial conduct, participant safety, or data integrity will be documented, submitted for ethics committee approval, and updated in the trial registry. The principal investigator retains final authority for all amendments. Dissemination Plan Results will be published in peer-reviewed journals regardless of findings and reported per CONSORT 2010 and STRICTA 2010. The trial protocol will be published or registered prior to data collection completion. Findings will be presented at national and international scientific conferences. De-identified summary data will be available upon reasonable request to the corresponding author after publication. Discussion Psychomotor retardation, which involves motor and cognitive slowing, is a core feature of depression. It has been associated with greater depression severity, a delayed response to antidepressants, and persistent functional impairment after mood symptoms improve. PMR may become more pronounced with recurrent depressive episodes, underscoring the need for early intervention[22]. However, most antidepressant trials rely on global depression scales that do not adequately assess PMR as a separate domain. Depression rating scales typically include only one item for psychomotor disturbance. By restricting eligibility to patients with confirmed PMR and adopting a symptom-domain-specific primary endpoint, this design is expected to improve the interpretability of treatment effects at the symptom level by reducing heterogeneity introduced by participants without clinically meaningful psychomotor impairment and enhancing signal detection. Because the symptoms of PMR are complex and multifaceted, we have specifically adopted a multidimensional assessment strategy to address these characteristics.The SRRS is employed as the primary endpoint due to its capacity to integrate observable motor slowing with subjective cognitive retardation within a single validated framework, providing broader construct coverage than single-domain instruments. To complement this, a set of objective performance-based measures is incorporated to mitigate the influence of expectation effects and evaluator bias inherent in rating scales. These measures are functionally non-redundant, capturing distinct subdimensions of PMR, including motor execution speed, cognitive-motor integration, and verbal output dynamics.Additionally, the pre-specified correlation analysis between changes in speech pause duration and SRRS reduction examines whether objectively quantifiable verbal slowing correlates with overall PMR improvement. This multidimensional assessment strategy detects overall treatment effects and characterizes domain-specific responsiveness. Within this framework, the inclusion of the Speech Pause Test serves a dual role as both an outcome measure and an exploratory methodological probe. Speech production can be conceptualized as a higher-order psychomotor process requiring the integration of cognitive planning and motor execution, and increased pause duration may reflect delayed initiation and reduced efficiency of cognitive–motor coordination, which are core features of PMR [ 23 ] . Regardless of the direction of the findings, this analysis will contribute meaningful evidence regarding the criterion validity of speech-based metrics as treatment-sensitive markers of PMR. The trial design further reflects consideration of mechanistic complementarity in its combination of acupuncture with sertraline. While Sertraline exerts its primary antidepressant effects through normalization of serotonin-regulated circuits, with fMRI evidence demonstrating improvements in amygdala-prefrontal functional connectivity and partial normalization of default mode network (DMN) hyperactivation following SSRI treatment [ 16 ] . Notably, acupuncture's neuroimaging profile complements this pattern: a multicenter RCT showed that active acupuncture enhances functional connectivity between the striatum and the frontal inferior triangular region and between the striatum and the cerebellum. These are precisely the circuits that are abnormally elevated in MDD patients relative to healthy controls [ 18 ] . Resting-state fMRI studies demonstrate that acupuncture engages the sensorimotor network in a sustained fashion that persists well beyond the period of active needling. This property is especially relevant for conditions characterized by chronic SMN hypoactivation, such as PMR.Taken together, these neuroimaging observations suggest a pattern of complementary rather than redundant neural targeting: sertraline acts preferentially on the serotonin-regulated DMN and limbic-prefrontal circuits, while acupuncture acts preferentially on dopaminergic striato-cortical and sensorimotor circuits. In the context of the dual-network model of PMR — wherein DMN overactivation and SMN hypoactivation represent two inter-related but mechanistically separable dimensions of psychomotor dysfunction [ 8 ][ 10 ] — the combination of sertraline and acupuncture may provide more complete network-level correction than either treatment alone. If the behavioural data demonstrate incremental PMR benefit from active acupuncture over sham, this would provide the empirical motivation for a future fMRI substudies. Several limitations should be acknowledged. The single-center design may limit generalizability across different clinical settings and patient populations. The modest sample size, while appropriate for an exploratory trial, reduces statistical power and increases the risk of type II error, particularly for secondary outcomes. Repeated administration of performance-based tests may introduce learning effects that attenuate between-group differences, and the relatively short follow-up period restricts assessment of the durability of treatment effects. In addition, the absence of neurobiological or imaging markers precludes direct examination of the mechanisms underlying any observed clinical changes. If the findings demonstrate that acupuncture confers additional benefit for PMR beyond standard pharmacotherapy, this would support its role as a non-pharmacological adjunct for patients with residual psychomotor symptoms. More broadly, the study provides a methodological framework for future PMR-targeted trials by integrating symptom-specific endpoints with multidimensional assessment strategies and exploratory validation of objective markers. These results will inform the design of subsequent confirmatory studies with larger samples, extended follow-up, and incorporation of neuroimaging and biomarker-based endpoints to further elucidate underlying mechanisms. References Walther S, Hügli S, Höfle O et al (2012) Frontal white matter integrity is related to psychomotor retardation in major depression. Neurobiol Dis 47(1):13–19 Chan AW, Tetzlaff JM, Altman DG et al (2013) SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 158(3):200–207 MacPherson H, Altman DG, Hammerschlag R et al (2010) Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. PLoS Med 7:e1000261 Schrijvers D, Hulstijn W, Sabbe BG (2008) Psychomotor symptoms in depression: a diagnostic, pathophysiological and therapeutic tool. 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Psychiatr Clin North Am 6(1):27–40 Goldsmith DR, Haroon E, Woolwine BJ et al (2016) Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder. Brain Behav Immun 56:281–288 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9686192","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Method Article","associatedPublications":[],"authors":[{"id":638676309,"identity":"a43066bf-91e6-412b-b063-d4d0d2222951","order_by":0,"name":"Mo Huiting","email":"","orcid":"","institution":"广东省中医院","correspondingAuthor":false,"prefix":"","firstName":"Mo","middleName":"","lastName":"Huiting","suffix":""},{"id":638676310,"identity":"25a07b0c-e97e-4875-96f0-cd6e82c649ad","order_by":1,"name":"Li sheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBACfvn33398/POPh5+9gUgtkg0JBpIzGw7ISPYcIFKLwYEEA2nOhgM2BjMSiHXZgQMJxow77vAYSD7eeIOhxiaaoA7GxoYDyYVnnvGYS6cVWzAcS8ttIKSFmZmx4fAMNmYey9k5ZhJANmEtbGzMjM08QC0GN88QqYUHqJyZt+0wj8ENHiK1SEjwsDHOOJPGI9kD9EsCMX6xv8HDxvChwsaen/3wxhsfamwIa0EGBhIJpCiHaCFVxygYBaNgFIwMAAD0Qz3cRhbErQAAAABJRU5ErkJggg==","orcid":"","institution":"广东省中医院","correspondingAuthor":true,"prefix":"","firstName":"Li","middleName":"","lastName":"sheng","suffix":""}],"badges":[],"createdAt":"2026-05-12 04:08:59","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9686192/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9686192/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109276765,"identity":"39b9aa90-434f-4242-9caa-fe2349a56218","added_by":"auto","created_at":"2026-05-14 15:20:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102882,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT flow diagram.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9686192/v1/52a8ef3efb8f577f129a5ab3.jpg"},{"id":109296370,"identity":"9dfb302e-70bf-4df1-b9c8-f3efdab44a36","added_by":"auto","created_at":"2026-05-15 08:46:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":317308,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9686192/v1/261f2c24-5a61-4869-90c1-8f6da8e4353a.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAcupuncture for Psychomotor Retardation in Patients with Moderate Major Depressive Disorder: Protocol for a Randomized Controlled Trial\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMajor depressive disorder (MDD) is a highly prevalent and disabling psychiatric condition characterized by persistent low mood, cognitive impairment, and functional decline. Among its core symptom clusters, psychomotor retardation (PMR) \u0026mdash; characterised by observable slowing of movement, speech, and ideation \u0026mdash; affects approximately one-third to nearly two-thirds of patients depending on clinical subtype\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. PMR is not merely an epiphenomenon: it is strongly associated with greater illness severity, longer episode duration, higher rates of recurrent suicidal behaviour, and, critically, poorer antidepressant response\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. This treatment-resistance gap may be partly explained at the neurobiological level: selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological standard, operate primarily on monoaminergic serotonin pathways yet exert minimal direct modulation of the dopaminergic motor circuitry whose dysfunction is increasingly recognised as a pathophysiological substrate of PMR. From a neuroimaging perspective, this represents a clear mechanistic mismatch.\u003c/p\u003e \u003cp\u003eThe neurobiological architecture of PMR has become considerably clearer in recent years. Convergent evidence implicates dysfunction within the subcortical\u0026ndash;cortical motor circuit, anchored by dopaminergic projections from the substantia nigra through the striatum to the motor cortex\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Neuroimaging studies have consistently identified reduced dopamine synthesis capacity and elevated D2-receptor binding potential in the striatum of patients with PMR, reflecting hypodopaminergic states that translate into attenuated motor initiation and execution\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Together, PMR is characterised as a disorder of hypoperfused, hypoconnected motor cortical circuitry driven by dopaminergic insufficiency.\u003c/p\u003e \u003cp\u003eAccumulating evidence suggests that acupuncture may exert therapeutic effects in depression through multimodal mechanisms, including neurotransmitter regulation, restoration of neuroendocrine balance, enhancement of neuroplasticity, and anti-inflammatory effects\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.Reviews document that acupuncture modulates the SMN \u0026mdash; specifically engaging the precentral and postcentral gyri, putamen, and caudate \u0026mdash; alongside limbic-prefrontal nodes including the anterior cingulate cortex, amygdala, and dorsolateral prefrontal cortex\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. A meta-analysis of LR3-targeted fMRI studies further confirmed activation patterns spanning basal ganglia, sensorimotor, and salience networks[24].Despite advances in mechanistic understanding, the objective assessment of PMR in existing acupuncture trials for MDD remains essentially absent,no published RCT has designated PMR as a primary outcome and the findings are largely derived from small-scale or uncontrolled studies,high-quality randomized controlled trials specifically targeting PMR are still lacking.\u003c/p\u003e \u003cp\u003eTo address these gaps, the present study focuses specifically on patients with clinically significant PMR and adopts a symptom-domain-oriented design. Sertraline is used as the background pharmacological treatment, while acupuncture is introduced as an adjunctive intervention to explore potential additive effects. The selection of outcome measures reflects an effort to capture both subjective and objective aspects of PMR.\u003c/p\u003e"},{"header":"Methods and Design","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSetting and Design\u003c/h2\u003e \u003cp\u003e This parallel-group, randomized, single-blind (participant-blind), sham-controlled trial will be conducted at the Acupuncture and Moxibustion Department of Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, from 2026-06-01 to 2027-06-01. The protocol adheres to the SPIRIT 2013 guidelines\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, STRICTA 2010 (MacPherson et al., 2010), and will be reported per the CONSORT 2010 statement[4]. Sixty eligible participants will be randomized 1:1 to either the acupuncture group or the sham acupuncture control group; both groups receive concurrent sertraline throughout. The treatment phase is eight weeks (three sessions per week, 24 sessions total) followed by a four-week follow-up. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the study timeline and assessment schedule, and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the CONSORT flow diagram.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy timeline and assessment schedule.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAssessment / Procedure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT0 Baseline (Wk 0)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT1 Mid-treatment (Wk 4)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT2 End of treatment (Wk 8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT3 Follow-up (Wk 12)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEligibility screening \u0026amp; consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRandomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActive acupuncture (3\u0026times;/week)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWks 1\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSham acupuncture (3\u0026times;/week)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWks 1\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSertraline (both groups)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSRRS (Primary)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓ ★\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCORE Retardation Subscale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHAMD-17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpeech Pause Test\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTMT-A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events / TESS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026rarr;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlinding assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e✓\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: SRRS, Saldia Retardation Rating Scale; HAMD-17, Hamilton Depression Rating Scale-17; CORE, CORE Retardation Subscale; TMT-A, Trail Making Test Part A; FTT, Finger Tapping Test; TESS, Treatment Emergent Symptom Scale.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e★ Primary outcome assessment time point.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNotes: Baseline assessments (T0) are completed prior to the first acupuncture or sham acupuncture session, immediately following randomization. T1 assessments (week 4) are conducted midway through the treatment phase to capture early-phase response trajectories. T2 assessments (week 8) constitute the primary endpoint evaluation and are performed within two working days of the final treatment session. T3 assessments (week 12) are conducted four weeks after treatment completion to evaluate durability of effects; no acupuncture or sham acupuncture is administered during the follow-up period, though sertraline continues as clinically indicated. SRRS and all objective performance measures (Speech Pause Test, TMT-A, FTT) are administered by blinded assessors in a dedicated assessment room physically separated from the treatment area. Speech Pause Test recordings are made using a standardized device at a fixed distance of 30 cm; only one recording is obtained per time point due to the potential for learning effects. TMT-A is administered using parallel versions or alternative stimulus orderings at T1\u0026ndash;T3 where available to minimize practice-related performance gains. FTT is administered using three trials with 30\u0026ndash;60 s rest intervals; the median tapping count is used for analysis. TESS is administered at all assessment time points for participants receiving sertraline. Adverse events are monitored from the first intervention session through the T3 follow-up visit.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003e Participants will be recruited from the outpatient clinic and inpatient ward of Guangdong Provincial Hospital of Chinese Medicine through clinical referrals, in-hospital advertisements, and social media. Diagnosis of MDD is established per DSM-5 criteria, confirmed by qualified psychiatrists.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAge 18\u0026ndash;50 years.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDSM-5 diagnosis of major depressive disorder.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eModerate severity: HAMD-17 score\u0026thinsp;\u0026gt;\u0026thinsp;27 and \u0026le;\u0026thinsp;35.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eClinically identifiable PMR: SRRS\u0026thinsp;\u0026ge;\u0026thinsp;20.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eNo antidepressant treatment in the past three weeks, or currently on a stable regimen unchanged for \u0026ge;\u0026thinsp;three weeks.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eWritten informed consent.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eExclusion criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eNeurodegenerative or movement disorders (Parkinson\u0026rsquo;s disease, Lewy body dementia, Huntington\u0026rsquo;s disease, or other extrapyramidal syndromes).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eActive suicidal intent, suicidal behavior, or psychotic symptoms.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLifetime diagnosis of schizophrenia, bipolar disorder, or schizoaffective disorder.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePersonality disorder significantly affecting adherence.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAlcohol or substance use disorder.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSignificant organic brain disease (severe traumatic brain injury, epilepsy, brain tumor, cerebrovascular sequelae).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSevere medical comorbidity or contraindications to acupuncture (metallic implants, coagulation disorders).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFear of acupuncture or anticipated poor compliance.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePregnancy or breastfeeding.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eScreening proceeds in two steps: HAMD-17 to confirm moderate severity, followed by SRRS to confirm PMR. Candidates passing both proceed to full eligibility review, informed consent, and baseline assessment. Participants are withdrawn if they complete fewer than 20 of 24 sessions, withdraw voluntarily, or deteriorate clinically. Participants are eliminated post-randomization for retrospective eligibility failure, unauthorized concomitant antidepressant treatment, or protocol deviations that substantially confound assessment. For participants withdrawing after at least one post-baseline assessment, data are retained and missing values are imputed by the Last Observation Carried Forward (LOCF) method for the intention-to-treat (ITT) analysis.\u003c/p\u003e\n\u003ch3\u003eRandomization and Blinding\u003c/h3\u003e\n\u003cp\u003eA simple randomization sequence is generated by SPSS software (two-group, N\u0026thinsp;=\u0026thinsp;60). An independent staff member prepares sequentially numbered, opaque, sealed envelopes; each eligible participant opens the next available envelope after baseline assessment. Acupuncturists cannot be blinded. Participant blinding is achieved with non-penetrating sham needles (flat-tipped, collapsible-handle design) visually identical to genuine needles. Outcome assessors and data analysts remain blinded throughout; physical separation of treatment and assessment areas is maintained. Blinding integrity is formally assessed at T2 by asking participants which treatment they believe they received, and sensitivity analyses stratified by blinding success are pre-specified.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eConcomitant pharmacotherapy (both groups)\u003c/h2\u003e \u003cp\u003eAll participants receive sertraline hydrochloride (50 mg starting dose; adjusted to 75\u0026ndash;200 mg/day after one week based on clinical response). Participants already on a stable regimen for \u0026ge;\u0026thinsp;three weeks continue unchanged. If no improvement is observed after three weeks, the supervising psychiatrist determines whether the participant should withdraw. Antidepressant dose at each assessment time point is recorded and treated as a covariate in statistical analyses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAcupuncture group\u003c/h2\u003e \u003cp\u003eAcupoint locations follow WHO standard specifications. The prescription comprises Baihui (GV20), Yintang (EX-HN3), bilateral Hegu (LI4) and Taichong (LR3) (the Four Gates), bilateral Touwei (ST8), bilateral Shenmen (HT7), Zhongwan (CV12), Xiawan (CV10), Qihai (CV6), and Guanyuan (CV4) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Sterile 0.25 \u0026times; 25 mm needles are used throughout; Baihui and Yintang are inserted obliquely (30\u0026deg;, 4\u0026ndash;5 mm) with uniform rotation to de qi; Hegu and Taichong are needled perpendicularly (10\u0026ndash;12 mm) with even lifting-thrusting and rotation to de qi; remaining points are needled perpendicularly to de qi. Needles are retained for 30 minutes. Sessions are delivered three times per week with a minimum inter-session interval of 24 hours. A standardized operating procedure (SOP) is developed prior to trial initiation; all acupuncturists complete SOP-based training and a practical competency assessment, with treatment fidelity monitored by periodic random review of video-recorded sessions.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAcupoint prescription and needling specifications.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcupoint\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnatomical Location (WHO Standard)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGauge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDepth \u0026amp; Technique\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaihui (GV20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHead, 5 cun superior to anterior hairline midpoint\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOblique 30\u0026deg;, 4\u0026ndash;5 mm; uniform rotation to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYintang (EX-HN3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMidpoint between medial ends of the two eyebrows\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOblique/flat insertion; uniform rotation to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHegu (LI4) bilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDorsum of hand, midpoint of 2nd metacarpal on radial side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePerpendicular, 10\u0026ndash;12 mm; lifting-thrusting and rotation to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTaichong (LR3) bilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDorsum of foot, depression distal to 1st\u0026ndash;2nd metatarsal junction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePerpendicular, 10\u0026ndash;12 mm; lifting-thrusting and rotation to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTouwei (ST8) bilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHead, 0.5 cun within anterior hairline, 4.5 cun lateral to GV24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOblique/flat insertion to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShenmen (HT7) bilateral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWrist, ulnar end of transverse crease, radial to flexor carpi ulnaris\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePerpendicular to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhongwan (CV12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpper abdomen, 4 cun superior to umbilicus, midline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePerpendicular to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eXiawan (CV10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpper abdomen, 2 cun superior to umbilicus, midline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePerpendicular to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQihai (CV6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLower abdomen, 1.5 cun inferior to umbilicus, midline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePerpendicular to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuanyuan (CV4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLower abdomen, 3 cun inferior to umbilicus, midline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35\u0026times;25 mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePerpendicular to de qi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSham acupuncture control group\u003c/h3\u003e\n\u003cp\u003eParticipants receive non-penetrating sham needles (flat-tipped, collapsible-handle device) at the same acupoints as the active group. The device applies blunted-tip pressure against the skin surface without penetration, secured by an adhesive foam pad\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e; no needle manipulation, de qi, or subcutaneous retention occurs. Treatment frequency, session duration, and total sessions are identical to the active group.\u003c/p\u003e\n\u003ch3\u003eTreatment duration and follow-up\u003c/h3\u003e\n\u003cp\u003eThe treatment period is eight weeks (three sessions per week; protocol completers require\u0026thinsp;\u0026ge;\u0026thinsp;20 sessions). A four-week post-treatment follow-up follows, during which no acupuncture or sham acupuncture is administered; sertraline continues as clinically indicated. Outcome assessment at follow-up is conducted at week 12 (T3).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and Assessments\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cp\u003eThe primary outcome is the SRRS reduction rate at T2 (end of treatment, week 8), calculated as: (baseline score\u0026thinsp;\u0026minus;\u0026thinsp;T2 score) / baseline score \u0026times; 100%. The SRRS (Saldia Retardation Rating Scale) is regarded as the gold standard instrument for quantifying PMR, encompassing three objective domains \u0026mdash; motor function (gait, limb/trunk movement), speech (verbal flow, tone, response latency), and observable cognitive performance \u0026mdash; alongside five subjective dimensions covering fatigue, interest, time perception, memory, and concentration\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eAll secondary outcomes will be assessed at T0, T1, T2, and T3 by blinded outcome assessors.\u003c/p\u003e \u003cp\u003eCORE Retardation Subscale: A clinician-rated observational scale that does not rely on language-based responses, making it particularly suitable for identifying PMR in melancholic depression subtypes independently of verbal ability. It will serve as a complementary PMR measure to the SRRS.\u003c/p\u003e \u003cp\u003eHAMD-17: The Hamilton Depression Rating Scale-17 will provide an overall index of depression severity as well as a specific retardation factor score. Total score change from baseline will be reported at each assessment time point.\u003c/p\u003e \u003cp\u003e Speech Pause Test: The Speech Pause Test provides an objective, ecologically valid index of verbal PMR. Following standardized instructions and establishment of rapport, participants will be asked: \u0026ldquo;Please count from 1 to 20 at your normal speaking pace.\u0026rdquo; The instruction will be delivered once without further prompting. Audio will be recorded using a standardized recording device at a fixed distance of 30 cm. The recording segment of 20\u0026ndash;30 seconds will be selected for analysis, excluding the interviewer\u0026rsquo;s voice and any pre-onset silent pause preceding the participant\u0026rsquo;s first utterance. Audio will be analyzed offline using Praat software (version 6.x). A standardized analysis protocol will define the minimum pause threshold at 0.15 seconds. The following indices will be extracted: (1) speech rate (syllables per second), (2) phonation time (total voiced duration in seconds), (3) total pause duration (sum of all pauses\u0026thinsp;\u0026ge;\u0026thinsp;0.15 seconds), and (4) silence quotient (total pause duration divided by total recording duration, expressed as a proportion). Due to the potential for learning effects, only one recording will be made per assessment time point. All analysis will be performed by a single trained analyst blinded to group allocation, using a pre-defined analysis script to minimize inter-rater variability.\u003c/p\u003e \u003cp\u003eTrail Making Test Part A (TMT-A): TMT-A will assess psychomotor processing speed. The participant is required to connect numbered circles (1 to 25) in ascending order as rapidly as possible on a standard test sheet. Prior to the formal test, a brief practice trial will be administered to ensure task comprehension. Completion time in seconds will be recorded from initiation to the final connection. If a connection error occurs, the assessor will immediately indicate the error and instruct the participant to correct it without pausing the timer. Due to significant learning effects associated with repeated administration of the same test form, parallel versions or alternative stimulus orderings will be used at T1, T2, and T3 where available, and all versions used will be documented.\u003c/p\u003e \u003cp\u003eFinger Tapping Test (FTT): FTT will assess pure motor speed. Using the dominant hand with the wrist stabilized on a flat surface, the participant will tap a mechanical counter as rapidly as possible for 30 seconds. Three consecutive trials will be conducted, with 30\u0026ndash;60 seconds of rest between each trial. The median tapping count across the three trials will be used as the outcome variable for statistical analysis, as median values are more robust to isolated performance outliers than mean values.\u003c/p\u003e \u003cp\u003eSafety Assessment: All adverse events (AEs) occurring during the treatment period and follow-up will be recorded on the Case Report Form. For participants receiving sertraline, the Treatment Emergent Symptom Scale (TESS) will be administered at each assessment time point to systematically document medication-related side effects. AEs will be classified by type, severity, onset, duration, and presumed relationship to the study intervention. Serious adverse events (SAEs) will be reported to the institutional ethics committee within 24 hours of the investigator\u0026rsquo;s awareness. Any participant developing active suicidal ideation, manic symptoms, or psychotic features during the trial will be immediately referred to the supervising psychiatrist for specialist evaluation and managed independently of the trial protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eMonitoring and Quality Control\u003c/h2\u003e \u003cp\u003eAll outcome assessors complete a standardized training program for SRRS, CORE, and HAMD-17 administration, with inter-rater reliability confirmed by an intraclass correlation coefficient (ICC) of \u0026ge;\u0026thinsp;0.80. Speech Pause Test analysts complete a unified Praat training program. All acupuncturists complete SOP-based training and practical certification; treatment fidelity is monitored by periodic video audit. Outcome data are recorded on paper CRFs and concurrently entered into a password-protected electronic database with double entry and automated discrepancy checking. Assessors are physically separated from treatment personnel. A dual-track safety monitoring system operates throughout: structured session-level assessment for acupuncture-specific AEs (hematoma, dizziness, needle pain, local infection), and systematic daily documentation of all AEs. An independent safety monitor reviews all SAEs and may recommend trial suspension if pre-specified safety thresholds are exceeded; a 24-hour psychiatry liaison is available for participants exhibiting clinical deterioration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSample Size\u003c/h2\u003e \u003cp\u003eThis is an exploratory trial. In the absence of published PMR-specific effect size data for acupuncture, a formal power calculation cannot be reliably derived. A total sample of 60 participants (30 per group) is proposed based on feasibility considerations and the scope of prior exploratory acupuncture trials in MDD. This sample size is sufficient to estimate between-group effect sizes and variance parameters to power a subsequent confirmatory trial. Anticipating approximately 20% withdrawal, all enrolled participants completing at least one post-baseline assessment will be included in the ITT analysis, with LOCF applied to missing data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe ITT population comprises all randomized participants receiving at least one session and completing at least one post-baseline assessment; missing data are handled by LOCF. A per-protocol (PP) sensitivity analysis includes only participants completing\u0026thinsp;\u0026ge;\u0026thinsp;20 of 24 sessions and attending all four assessments. All tests are two-tailed (α\u0026thinsp;=\u0026thinsp;0.05). Analyses are performed using SPSS version 20.0 (IBM Corporation, USA).\u003c/p\u003e \u003cp\u003eThe primary outcome (SRRS reduction rate at T2) is compared between groups by independent samples t-test or Mann-Whitney U test, according to normality (Shapiro-Wilk test and Q-Q plots). Between-group mean difference and 95% confidence interval are reported; effect size is expressed as Cohen\u0026rsquo;s d. Secondary outcomes over the four time points (T0\u0026ndash;T3) are analyzed by repeated-measures ANOVA with Bonferroni correction for pairwise comparisons; Greenhouse-Geisser correction is applied when sphericity is violated (Mauchly\u0026rsquo;s test p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Generalized linear mixed models are applied to non-normally distributed secondary outcomes. Antidepressant dose is included as a covariate in a pre-specified sensitivity analysis. An exploratory Pearson correlation analysis (Spearman if normality is not met) will examine the association between change in Speech Pause Test total pause duration from T0 to T2 and SRRS reduction rate at T2, to provide initial validity evidence for the Speech Pause Test as an objective PMR treatment-response index.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eEthics and Confidentiality\u003c/h2\u003e \u003cp\u003e The protocol will be submitted to the Medical Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine for review and approval prior to recruitment. The trial will be conducted in accordance with the Declaration of Helsinki (2013 revision) and applicable Good Clinical Practice guidelines, and prospectively registered on the Chinese Clinical Trial Registry (ChiCTR) or ClinicalTrials.gov prior to enrolment. Written informed consent will be obtained from all participants. Participant data will be coded with unique study identification numbers; personally identifiable information will be stored separately in a password-protected file accessible only to the principal investigator. Study documents will be retained for a minimum of five years. Protocol amendments will be submitted to the ethics committee and updated in the trial registry before implementation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003ePatient and Public Involvement\u003c/h2\u003e \u003cp\u003eNo patient or public involvement occurred in the design or planning of this study. Findings will be disseminated to participants who request results following publication.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eProtocol Amendments\u003c/h2\u003e \u003cp\u003eAny modifications affecting trial conduct, participant safety, or data integrity will be documented, submitted for ethics committee approval, and updated in the trial registry. The principal investigator retains final authority for all amendments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eDissemination Plan\u003c/h2\u003e \u003cp\u003eResults will be published in peer-reviewed journals regardless of findings and reported per CONSORT 2010 and STRICTA 2010. The trial protocol will be published or registered prior to data collection completion. Findings will be presented at national and international scientific conferences. De-identified summary data will be available upon reasonable request to the corresponding author after publication.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePsychomotor retardation, which involves motor and cognitive slowing, is a core feature of depression. It has been associated with greater depression severity, a delayed response to antidepressants, and persistent functional impairment after mood symptoms improve. PMR may become more pronounced with recurrent depressive episodes, underscoring the need for early intervention[22]. However, most antidepressant trials rely on global depression scales that do not adequately assess PMR as a separate domain. Depression rating scales typically include only one item for psychomotor disturbance. By restricting eligibility to patients with confirmed PMR and adopting a symptom-domain-specific primary endpoint, this design is expected to improve the interpretability of treatment effects at the symptom level by reducing heterogeneity introduced by participants without clinically meaningful psychomotor impairment and enhancing signal detection.\u003c/p\u003e \u003cp\u003eBecause the symptoms of PMR are complex and multifaceted, we have specifically adopted a multidimensional assessment strategy to address these characteristics.The SRRS is employed as the primary endpoint due to its capacity to integrate observable motor slowing with subjective cognitive retardation within a single validated framework, providing broader construct coverage than single-domain instruments. To complement this, a set of objective performance-based measures is incorporated to mitigate the influence of expectation effects and evaluator bias inherent in rating scales. These measures are functionally non-redundant, capturing distinct subdimensions of PMR, including motor execution speed, cognitive-motor integration, and verbal output dynamics.Additionally, the pre-specified correlation analysis between changes in speech pause duration and SRRS reduction examines whether objectively quantifiable verbal slowing correlates with overall PMR improvement. This multidimensional assessment strategy detects overall treatment effects and characterizes domain-specific responsiveness.\u003c/p\u003e \u003cp\u003eWithin this framework, the inclusion of the Speech Pause Test serves a dual role as both an outcome measure and an exploratory methodological probe. Speech production can be conceptualized as a higher-order psychomotor process requiring the integration of cognitive planning and motor execution, and increased pause duration may reflect delayed initiation and reduced efficiency of cognitive\u0026ndash;motor coordination, which are core features of PMR\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Regardless of the direction of the findings, this analysis will contribute meaningful evidence regarding the criterion validity of speech-based metrics as treatment-sensitive markers of PMR.\u003c/p\u003e \u003cp\u003eThe trial design further reflects consideration of mechanistic complementarity in its combination of acupuncture with sertraline. While Sertraline exerts its primary antidepressant effects through normalization of serotonin-regulated circuits, with fMRI evidence demonstrating improvements in amygdala-prefrontal functional connectivity and partial normalization of default mode network (DMN) hyperactivation following SSRI treatment\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Notably, acupuncture's neuroimaging profile complements this pattern: a multicenter RCT showed that active acupuncture enhances functional connectivity between the striatum and the frontal inferior triangular region and between the striatum and the cerebellum. These are precisely the circuits that are abnormally elevated in MDD patients relative to healthy controls\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Resting-state fMRI studies demonstrate that acupuncture engages the sensorimotor network in a sustained fashion that persists well beyond the period of active needling. This property is especially relevant for conditions characterized by chronic SMN hypoactivation, such as PMR.Taken together, these neuroimaging observations suggest a pattern of complementary rather than redundant neural targeting: sertraline acts preferentially on the serotonin-regulated DMN and limbic-prefrontal circuits, while acupuncture acts preferentially on dopaminergic striato-cortical and sensorimotor circuits. In the context of the dual-network model of PMR \u0026mdash; wherein DMN overactivation and SMN hypoactivation represent two inter-related but mechanistically separable dimensions of psychomotor dysfunction\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e \u0026mdash; the combination of sertraline and acupuncture may provide more complete network-level correction than either treatment alone. If the behavioural data demonstrate incremental PMR benefit from active acupuncture over sham, this would provide the empirical motivation for a future fMRI substudies.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. The single-center design may limit generalizability across different clinical settings and patient populations. The modest sample size, while appropriate for an exploratory trial, reduces statistical power and increases the risk of type II error, particularly for secondary outcomes. Repeated administration of performance-based tests may introduce learning effects that attenuate between-group differences, and the relatively short follow-up period restricts assessment of the durability of treatment effects. In addition, the absence of neurobiological or imaging markers precludes direct examination of the mechanisms underlying any observed clinical changes.\u003c/p\u003e \u003cp\u003eIf the findings demonstrate that acupuncture confers additional benefit for PMR beyond standard pharmacotherapy, this would support its role as a non-pharmacological adjunct for patients with residual psychomotor symptoms. More broadly, the study provides a methodological framework for future PMR-targeted trials by integrating symptom-specific endpoints with multidimensional assessment strategies and exploratory validation of objective markers. These results will inform the design of subsequent confirmatory studies with larger samples, extended follow-up, and incorporation of neuroimaging and biomarker-based endpoints to further elucidate underlying mechanisms.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWalther S, H\u0026uuml;gli S, H\u0026ouml;fle O et al (2012) Frontal white matter integrity is related to psychomotor retardation in major depression. Neurobiol Dis 47(1):13\u0026ndash;19\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan AW, Tetzlaff JM, Altman DG et al (2013) SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 158(3):200\u0026ndash;207\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMacPherson H, Altman DG, Hammerschlag R et al (2010) Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. PLoS Med 7:e1000261\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrijvers D, Hulstijn W, Sabbe BG (2008) Psychomotor symptoms in depression: a diagnostic, pathophysiological and therapeutic tool. J Affect Disord 109(1\u0026ndash;2):1\u0026ndash;20\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuyukdura JS, McClintock SM, Croarkin PE (2011) Psychomotor retardation in depression: biological underpinnings, measurement, and treatment. Prog Neuropsychopharmacol Biol Psychiatry 35(2):395\u0026ndash;409\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartinot M, Bragulat V, Artiges E et al (2001) Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry 158(2):314\u0026ndash;316\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHickie I, Ward P, Scott E et al (1999) Neo-striatal rCBF correlates of psychomotor slowing in patients with major depression. Psychiatry Res Neuroimaging 92(2\u0026ndash;3):75\u0026ndash;81\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNorthoff G, Hirjak D, Wolf RC, Magioncalda P, Martino M (2021) All roads lead to the motor cortex: psychomotor mechanisms and their biochemical modulation in psychiatric disorders. Mol Psychiatry 26(1):92\u0026ndash;102\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin Y, Wang M, Wang Z et al (2018) Decreased cerebral blood flow in the primary motor cortex in major depressive disorder with psychomotor retardation. Prog Neuropsychopharmacol Biol Psychiatry 81:438\u0026ndash;444\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConio B, Martino M, Magioncalda P et al (2020) Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders. Mol Psychiatry 25(1):82\u0026ndash;93\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePier MPBI, Hulstijn W, Sabbe BGC (2004) Differential patterns of psychomotor functioning in unmedicated melancholic and nonmelancholic depressed patients. J Psychiatr Res 38(4):425\u0026ndash;435\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGorwood P, Richard-Devantoy S, Bayle F, Cl\u0026eacute;ry-Melin ML (2014) Psychomotor retardation is a scar of past depressive episodes, revealed by simple cognitive tests. Eur Neuropsychopharmacol 24(10):1630\u0026ndash;1640\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmour M, Smith CA, Wang LQ et al (2019) Acupuncture for depression: a systematic review and meta-analysis. J Clin Med 8(8):1140\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang NN, Lin LL, Li YJ et al (2022) Potential mechanisms and clinical effectiveness of acupuncture in depression. Curr Neuropharmacol 20:738\u0026ndash;750\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao B, Li Z, Wang Y et al (2019) Can acupuncture combined with SSRIs improve clinical symptoms and quality of life in patients with depression? Complement Ther Med 45:295\u0026ndash;302\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Wang Z, Liu J, Chen J, Liu X, Nie G et al (2016) Repeated acupuncture treatments modulate amygdala resting state functional connectivity of depressive patients. Neuroimage Clin 12:746\u0026ndash;752\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Wang X, Liu J, Chen J, Liu X, Nie G et al (2017) Acupuncture treatment modulates the corticostriatal reward circuitry in major depressive disorder. J Psychiatr Res 84:18\u0026ndash;26\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu XT, Tu MQ, Yu ZL et al (2025) The efficacy and cerebral mechanism of intradermal acupuncture for major depressive disorder: a multicenter randomized controlled trial. Neuropsychopharmacology 50:1075\u0026ndash;1083\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulz KF, Altman DG, Moher D, CONSORT Group (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 340:c332\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e陆丽明 陈晨,陈一鸣,等.针灸对美沙酮减量的疗效: 一项随机临床试验[C]//世界针灸学会联合会,中国中医科学院.世界针灸学会联合会2024国际针灸学术研讨会论文集.广州中医药大学,针灸康复临床医学院,华南针灸研究中心,临床研究与大数据实验室;广东省中医院珠海医院,审计科;中山市中医院;广州中医药大学,针灸康复临床医学院,华南针灸研究中心;广州医科大学附属脑科医院(广州惠爱医院);肇庆市第三人民医院;中山市第二人民医院;佛山市第三人民医院;佛山顺德伍仲珮医院;广州市白云区妇幼保健院;麦克马斯特大学,健康研究方法、证据和影响系;中国中医科学院,广安门医院,中西医结合循证医学中心-团结协作组;广东省第二人民医院,临床流行病学与方法学中心;中山市第三人民医院,精神科;中山市第三人民医院,研究实验室;广州中医药大学第一附属医院,针灸科;,2024:28\u0026ndash;31\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDantchev N, Widl\u0026ouml;cher DJ (1998) The measurement of retardation in depression. J Clin Psychiatry 59(Suppl 14):19\u0026ndash;25\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBennabi D, Vandel P, Papaxanthis C, Pozzo T, Haffen E (2013) Psychomotor retardation in depression: a systematic review of diagnostic, pathophysiologic, and therapeutic implications. Biomed Res Int 2013:158746\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWidl\u0026ouml;cher DJ (1983) Psychomotor retardation: clinical, theoretical, and psychometric aspects. Psychiatr Clin North Am 6(1):27\u0026ndash;40\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldsmith DR, Haroon E, Woolwine BJ et al (2016) Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder. Brain Behav Immun 56:281\u0026ndash;288\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"psychomotor retardation, major depressive disorder, acupuncture, randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-9686192/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9686192/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003ePsychomotor retardation (PMR) is a core yet consistently under-targeted symptom domain of major depressive disorder (MDD). Despite its association with functional impairment and poor treatment response, PMR-specific endpoints and multi-dimensional objective measurement remain rare in clinical trials. This protocol describes a randomized controlled trial evaluating whether acupuncture, acupuncture as an adjunctive pharmacological co-treatment to sertraline, improves PMR in patients with moderate MDD.\u003c/p\u003e\u003ch2\u003eMethods and Analysis:\u003c/h2\u003e \u003cp\u003eThisparallel-group, randomized, single-blind, sham-controlled trial will enroll 60 participants allocated 1:1 to acupuncture plus sertraline (n\u0026thinsp;=\u0026thinsp;30) or sham acupuncture plus sertraline (n\u0026thinsp;=\u0026thinsp;30). The acupuncture prescription comprises Baihui (GV20), Yintang (EX-HN3), bilateral Hegu (LI4), bilateral Taichong (LR3), bilateral Touwei (ST8), bilateral Shenmen (HT7), Zhongwan (CV12), Xiawan (CV10), Qihai (CV6), and Guanyuan (CV4), administered three times weekly for eight weeks (24 sessions), followed by a four-week follow-up. Assessments are conducted at baseline (T0), week 4 (T1), week 8 (T2), and week 12 (T3). The primary outcome is the SRRS reduction rate at T2. Secondary outcomes include the CORE Retardation Subscale, HAMD-17, Speech Pause Test (speech rate, phonation time, total pause duration, silence quotient), TMT-A completion time, and FTT tapping frequency. Safety is monitored throughout.\u003c/p\u003e\u003ch2\u003eEthics and Dissemination:\u003c/h2\u003e \u003cp\u003e Ethical approval will be obtained from the Medical Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine. The trial will be prospectively registered on a recognized clinical trials registry. Written informed consent will be obtained from all participants. Results will be published in peer-reviewed journals regardless of outcome.\u003c/p\u003e","manuscriptTitle":"Acupuncture for Psychomotor Retardation in Patients with Moderate Major Depressive Disorder: Protocol for a Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-14 15:20:20","doi":"10.21203/rs.3.rs-9686192/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"edcfc5f0-0dde-4ef2-9fb0-3936b4443e48","owner":[],"postedDate":"May 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67974438,"name":"Psychiatry"}],"tags":[],"updatedAt":"2026-05-14T15:20:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-14 15:20:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9686192","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9686192","identity":"rs-9686192","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}