Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial

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Methods This double-blinded randomized controlled trial included 60 participants aged 18-55 with cognitive symptoms related to MDD at Thammasat University Hospital. Participants were divided into two groups: the electroacupuncture group combined with standard antidepressant treatment (EG; n=30) and the control group receiving standard care with placebo acupuncture (CG; n=30). The study assessed 1) executive functions using the Trail making test- B and Stroop Color and Word Test, 2) delayed recall, and 3) subjective cognitive complaint and Quality of life (QoL) using WHODAS 2.0. Depressive symptoms were measured using the Thai version of the Patient Health Questionnaire (PHQ-9). Baseline and post-intervention assessments were conducted over 10 weeks. Mann-Whitney U test analyzed treatment effects by comparing median differences between groups. Results Both groups exhibited similar demographics and cognitive traits. Cognitive improvement was observed in both groups at the endpoint. Intention-to-treat analysis revealed significantly higher median scores for subjective cognitive complaints in the EG compared to the CG (EG: Median = 5.5, CG: Median = 0.0, p=0.049). No serious side effects were identified from either electroacupuncture or placebo acupuncture. Conclusions Electroacupuncture improved subjective complaints in MDD patients with cognitive symptoms, but did not show effects on specific cognitive functions, QoL, or depressive symptoms. This study provides initial evidence supporting the potential of electroacupuncture in MDD patients with cognitive symptoms, suggesting opportunities for further research. Trial registration NCT06239740, February 2, 2024, ClinicalTrials.gov. 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F1000Research 2024, 13 :479 ( https://doi.org/10.12688/f1000research.146897.4 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] Yindee Boontra https://orcid.org/0000-0002-3918-6178 1 , Chommakorn Thanetnit 1 , Muthita Phanasathit https://orcid.org/0000-0002-9196-634X 1,2 Yindee Boontra https://orcid.org/0000-0002-3918-6178 1 , Chommakorn Thanetnit 1 , Muthita Phanasathit https://orcid.org/0000-0002-9196-634X 1,2 PUBLISHED 23 Dec 2024 Author details Author details 1 Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 2 Center of Excellence in Applied Epidemiology, Faculty of Medicine, Thammasat University, Bangkok, Bangkok, 12120, Thailand Yindee Boontra Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation Chommakorn Thanetnit Roles: Supervision, Writing – Review & Editing Muthita Phanasathit Roles: Formal Analysis, Methodology, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Faculty of Medicine – Thammasat University collection. Abstract Objectives To investigate the impact of electroacupuncture on cognitive function, quality of life (QoL), and depression severity in patients with major depressive disorder (MDD). Methods This double-blinded randomized controlled trial included 60 participants aged 18-55 with cognitive symptoms related to MDD at Thammasat University Hospital. Participants were divided into two groups: the electroacupuncture group combined with standard antidepressant treatment (EG; n=30) and the control group receiving standard care with placebo acupuncture (CG; n=30). The study assessed 1) executive functions using the Trail making test- B and Stroop Color and Word Test, 2) delayed recall, and 3) subjective cognitive complaint and Quality of life (QoL) using WHODAS 2.0. Depressive symptoms were measured using the Thai version of the Patient Health Questionnaire (PHQ-9). Baseline and post-intervention assessments were conducted over 10 weeks. Mann-Whitney U test analyzed treatment effects by comparing median differences between groups. Results Both groups exhibited similar demographics and cognitive traits. Cognitive improvement was observed in both groups at the endpoint. Intention-to-treat analysis revealed significantly higher median scores for subjective cognitive complaints in the EG compared to the CG (EG: Median = 5.5, CG: Median = 0.0, p=0.049). No serious side effects were identified from either electroacupuncture or placebo acupuncture. Conclusions Electroacupuncture improved subjective complaints in MDD patients with cognitive symptoms, but did not show effects on specific cognitive functions, QoL, or depressive symptoms. This study provides initial evidence supporting the potential of electroacupuncture in MDD patients with cognitive symptoms, suggesting opportunities for further research. Trial registration NCT06239740, February 2, 2024, ClinicalTrials.gov. READ ALL READ LESS Keywords Electroacupuncture, Depression, Cognition, Humans, Pilot, Randomized Controlled Trial Corresponding Author(s) Muthita Phanasathit ( [email protected] ) Close Corresponding author: Muthita Phanasathit Competing interests: No competing interests were disclosed. Grant information: This study was supported by the Faculty Of Medicine, Thammasat University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Boontra Y et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Boontra Y, Thanetnit C and Phanasathit M. Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.12688/f1000research.146897.4 ) First published: 17 May 2024, 13 :479 ( https://doi.org/10.12688/f1000research.146897.1 ) Latest published: 23 Dec 2024, 13 :479 ( https://doi.org/10.12688/f1000research.146897.4 ) Revised Amendments from Version 3 This version of the article includes several updates and improvements compared to the previously published version. Notably, we have added a new discussion on the mechanisms of cognitive impairment in patients with Major Depressive Disorder (MDD), derived from an extended meta-analysis. The discussion section has been expanded to incorporate recent literature, providing a more comprehensive interpretation of the findings. In response to feedback from readers and reviewers, key methodological details have been clarified to enhance transparency and reproducibility. Additionally, minor typographical errors present in the original version have been corrected. This version of the article includes several updates and improvements compared to the previously published version. Notably, we have added a new discussion on the mechanisms of cognitive impairment in patients with Major Depressive Disorder (MDD), derived from an extended meta-analysis. The discussion section has been expanded to incorporate recent literature, providing a more comprehensive interpretation of the findings. In response to feedback from readers and reviewers, key methodological details have been clarified to enhance transparency and reproducibility. Additionally, minor typographical errors present in the original version have been corrected. See the authors' detailed response to the review by Rosa N Schnyer See the authors' detailed response to the review by Min Cai See the authors' detailed response to the review by Su-Xia Li READ REVIEWER RESPONSES Introduction Depressive disorder is currently considered a significant health issue, with depression affecting up to 264 million people worldwide. Depression has both short-term and long-term consequences, with the most severe impact being suicide. Approximately 800,000 people die by suicide each year, making it the second leading cause of death among individuals aged 15-29 years. According to the World Health Organization (WHO). Approximately 1.5 million people in Thailand suffer from depressive symptoms. 1 Depression leads to cognitive dysfunction, affecting executive function and working memory. 2 , 3 This results in decreased attention and slow thinking, which are key diagnostic criteria for depression according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Even after depressive symptoms have improved, cognitive problems may persist, particularly in terms of work performance. 3 Current research indicates that various treatments may help alleviate cognitive dysfunction in patients with depression. Medications like duloxetine have been shown to improve psychomotor cognitive function, 4 while vortioxetine has demonstrated benefits in executive function, attention, processing speed, and learning and memory. Additionally, treatments such as Electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) have shown potential in improving cognitive function in depressive patients. 5 – 7 Acupuncture, a traditional eastern medicine practice, has been used for over 4,000 years in China. The practice involves inserting tiny needles into specific points on the body to restore balance and harmony. Acupuncture has gained popularity due to its minimal side effects. Some studies have suggested that acupuncture may aid in the treatment of cognitive impairment in patients with schizophrenia, dementia, or mild cognitive impairment. 8 – 10 It has also been found to improve cognitive function and reduce depressive symptoms. 11 Acupuncture may stimulate the release of substances like brain-derived neurotrophic factor (BDNF), 9 which is crucial for neural plasticity, supporting the growth of new neurons in the brain. Electroacupuncture, defined as acupuncture with electrical stimulation, includes inserting needles at acupuncture points and applying a low-level electrical current through them. A small amount of electricity flows through the electrode, resulting in a gentle vibration or soft hum during the treatment, enhancing the effects of acupuncture. This shown to increase the release of vascular endothelial growth factor (VEGF) 12 and enhance cerebral blood flow and volume, ultimately improving motor function in ischemic stroke patients. 13 In animal studies, electroacupuncture has been found to stimulate the release of nitric oxide (NO) and reduce angiotensin II, leading to better blood vessel dilation in the brain. 14 , 15 The authors hypothesized that electroacupuncture has the potential to treat subjective cognitive complaints in depressive patients, which is a relatively new and promising area of research. It is a minimally invasive and well-tolerated treatment option. Methods This trial was registered with the Human Research Ethics Committee of Thammasat University (Medicine), which approved the study (approval code: MTU-EC-PS-1-304/64) for the period from December 24, 2021, to December 23, 2022. The study adhered fully to international ethical guidelines, including the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). The research protocol detailed a double-blinded, randomized controlled trial (RCT) and pilot study conducted at a single center. The study aimed to evaluate the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) and cognitive dysfunction, compared to a control group. Both the experimental and control groups received standard pharmacological treatment for depressive disorders. This study was conducted during the Coronavirus Disease (COVID-19) pandemic, necessitating modifications due to safety concerns and social distancing measures. As a result, the study was adapted to a pilot design with 30 participants in each group. The preliminary findings are intended to guide and inform future large-scale research on the effects of electroacupuncture on cognitive dysfunction in patients with MDD. To enhance research transparency and public accessibility, the authors registered the study with the Thai Clinical Trials Registry ( www.clinicaltrials.in.th ), under the identifier NCT06239740, certified on February 2, 2024. A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-5 16 or DSM-IV-TR criteria, 17 and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptoms were screened using item 7 of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9), 18 which assesses difficulties with concentration or cognitive problems. The question in item 7 reads, “Trouble concentrating on things, such as reading the newspaper or watching television).” The exclusion criteria were: (i) Individuals with severe cognitive deficits from traumatic brain injury, delirium, neurodevelopmental disorders, or intellectual disability; (ii) Individuals with neurological disorders such as stroke, Parkinson’s disease, epilepsy, or other brain lesions; (iii) Individuals with severe medical conditions preventing lying down for 20 minutes; (iv) Individuals with recent electroconvulsive therapy (ECT) within the last 6 months; (v) Individuals with a pacemaker; (vi) Individuals with visual or hearing impairment that could not be corrected with eyeglasses or hearing aids; and (vii) Individuals diagnosed with severe MDD or scoring 20 points or more on the Thai-PHQ-9. Each participant was provided with detailed information regarding the study and informed written consent was obtained for their participation in the research. Subsequently, all participants granted consent for publication. An assistant researcher, who had contact with participants but was not involved in the interventions and outcome assessment, assigned participants to the intervention or control arm using a block of four randomization. The participants were randomly assigned to either the treatment group or the control group in a 1:1 ratio. The treatment group was undergo electroacupuncture (EG), while the control group received sham acupuncture (CG). Both groups received antidepressants with adjunctive medication (i.e., benzodiazepines, tricyclics, or antipsychotics) as the standard treatment. All participants were assessed for executive functions and memory using specific cognitive tests, including the Trail Making Test B (TMT-B), Stroop Color and Word Test (SCWT), category delayed recall in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), 19 , 20 and subjective reports of concern regarding concentration, memory, problem-solving, learning, communication, and quality of life (QoL) concerns using the WHO Disability Assessment Schedule (WHODAS 2.0; sections D1.1-1.6 and H1-3). 21 Additionally, depressive symptoms were assessed using the Thai-PHQ-9. All administrative tasks and data entry were carried out by the research assistant, who was also not involved in the interventions and outcome assessment ( Figure 1A,B ). Figure 1. A) acupoint location at scalp region; B) acupoint location at extremities. This study was double-blinded RCT. All participants and assessors were unaware of group assignments. Before treatment began, participants would not recognize if they were in the real acupuncture or sham group. They were placed in separate, quiet units on different days. The elimination or termination criteria were: (i) participants whose depressive symptoms worsened and required different treatment during the trial, making them unfit to continue. (ii) Participants facing severe adverse events or complications during treatment. (iii) Participants choosing not to continue with the treatment. Interventions This present study utilized applied electroacupuncture from traditional Chinese medicine. In the electroacupuncture group (EG), participants received acupuncture at 10 scalp points. These points included: 1) Baihui [GV20] and Ex-hn 1, with 5 needles inserted to a depth of 0.5 millimeters, 2) the 3 points of intelligence composed of Shenting [GV24] and Benshen [GB13] on both sides, with one needle in each point inserted to a depth of 2 centimeters, and 3) Touwei [ST8] on both sides, with one needle in each point inserted to a depth of 2 centimeters. Additionally, participants in the EG received acupuncture at Tai Chong [LV3], Tai Yuan [LU9], and Tai Xi [KI3] on both sides, totaling 6 needles, inserted to a depth of 2 centimeters, as shown in Figure 1 . All acupuncture was administered without regard to De Qi and retained for 20 minutes. The electroacupuncture in the EG was applied for 20 minutes at Benshen [GB13] and Touwei [ST8] on both sides. The needle stimulation was DC 9 volts with 50 Hertz continuous dense waves (less than 1 milliampere). The electroacupuncture sessions were weekly for 10 weeks. The needles were made from sterilized stainless steel with a size of 0.20×40 millimeters. In the sham acupuncture control group (CG), participants received acupress or a brief needle insertion at He Gu with 2 needles inserted to a depth of 1.3 millimeters on both hands for 20 minutes. The needles were made from sterilized stainless steel with a size of 0.20×1.3 millimeters. The participants in CG received this sham acupuncture only twice, at the first and 10th weeks, marking the endpoint of the study. Both participants in EG and CG received the interventions from the certified acupuncturist (Boontra Y.) from the Department of Thai Traditional and Alternative Medicine, and Hunan University of Chinese Medicine in 2016, with 5 years of experience. Outcome The primary outcome measured specific cognitive functions including the TMT-B, SCWT, ADAS-Cog; category delayed recall; and subjective cognitive, and quality of life complaints from the WHODAS 2.0; sections D1.1-1.6 and H1-3, which is a questionnaire asking about the number of days in the past 30 days when participants experienced difficulties with attention, understanding, and initiating conversation. All of these outcomes were assessed by trained blinded psychologists. The scores from the test at week 10 (T10), which serves as the primary endpoint, were compared to the scores from the test at week 1 (T1) for each participant. Then, the median value of the within-group change scores was calculated. Secondary outcome measured depressive symptoms using the Thai-PHQ-9, which were self-rated by the participants. All treatment outcomes were assessed at baseline (T1) and after the 10-week intervention (T10). Statistic analysis The data was presented as mean ± standard deviation and median, and analyzed using SPSS 22.0 software. 22 A comparison between the electroacupuncture and control groups was conducted using the Mann-Whitney U test, which compared the median differences of the outcomes. Differences between groups were calculated by comparing baseline and endpoint values. A significance level of p < 0.05 was used to determine statistical significance. To compare all outcomes for all participants who were randomized to electroacupuncture and control groups, an intention-to-treat (ITT) analysis was performed with the last observation carried forward technique (LOCF). A per-protocol (PP) analysis was also performed for comparison among participants who completed the treatment. Results Demographic characteristics The study spanned from December 2021 to December 2022. Initially, 60 individuals with MDD were enlisted for the trial. However, 8 participants, including 3 participants from the acupuncture group and 5 participants from the control group, discontinued their involvement during this period due to loss of follow-up. Additionally, 1 participant in the electroacupuncture group withdrew due to a neurosyphilis diagnosis. Consequently, 60 participants were eligible to receive ITT analysis, while 51 patients formed the complete analysis group using PP analysis ( Figure 2 ). Figure 2. The CONSORT flow diagram. In terms of general characteristics (such as gender, age, education, underlying medical conditions, occupation, and severity of illness) of EG and CG were similar, the outcomes were analyzed with unadjusted estimates. Both sample groups are predominantly female, with an average education duration of approximately 15 years. The average age in the experimental group is 28.77 ± 9.16 years, while the average age of the control group is 27.57 ± 8.08 years. Most participants in both the experimental and control groups are employed and do not have pre-existing illnesses. In terms of clinical data, it was found that participants in both the experimental and control groups had similar durations of experiencing depressive symptoms (experimental group 3.3 ± 1.87 years, control group 3.7 ± 2.67 years). The Thai-PHQ-9 scores indicated a similar severity of depressive symptoms in both groups (experimental group 14.53 ± 4.96, control group 15 ± 4.15). Additionally, the average scores of WHODAS 2.0 D1.1-1.6, representing the level of severity in attention and memory-related life impairments, were similar between the two groups ( Table 1 ). Table 1. Demographic data. Variables EG (n = 30) CG (n = 30) Gender Female, n (%) 23 (76.3) 22 (73.3) Male, n (%) 7 (27.6) 8 (26.7) Age (year), mean (SD) 28.77 (9.16) 27.57 (8.08) Age (year), min. - max. 20-49 18-50 Education (year), mean (SD) 15.87 (1.83) 14.50 (2.47) Education (year), min. - max. 9-18 8-16 Underlying , n (%) 20 (66.7) 25 (83.3) - DM 2 (6.7) 0 (0) - HT 2 (6.7) 0 (0) - Dyslipidemia 1 (3.3) 0 (0) - Cardiovascular disease 0 (0) 0 (0) - Other* 8 (26.7) 5 (16.7) Occupation, n (%) - Employed 15 (50.0) 21 (70.0) - Student 11 (36.7) 8 (26.7) - unemployed 4 (13.3) 1 (3.3) Depression (Thai PHQ-9), mean (SD) 14.53 (4.96) 15 (4.15) Depression (Thai PHQ-9), min.-max. 3-19 4-19 Duration of illness (year), mean (SD) 3.3 (1.87) 3.7 (2.67) Duration of illness (year), min.-max. 0.6-8.2 0.5-14.0 Subjective cognitive complaints, mean (SD) - WHODAS 2.0 (D1.1-1.6) 17.73 (4.66) 16.93 (3.78) min. - max. 8-27 9-24 - WHODAS 2.0 H1 19.47 (8.49) 17.33 (7.91) min. - max. 5-30 3-30 - WHODAS 2.0 H2 7.80 (8.13) 8.20 (8.89) min. - max. 0-30 0-30 - WHODAS 2.0H3 11.27 (10.05) 9.23 (9.04) min. - max. 0-30 0-30 Average number of treatments , mean (SD) 8.53 (2.70) 1.83 (0.379) Average number of treatments , min. - max. 1-10 1-2 Moreover, most participants used medication, primarily SSRIs, and sometimes benzodiazepines in a similar manner (see Table 2 ). Table 2. Pharmacotherapy for major depressive disorder. Medication EG (n=30) n (%) CG (n=30) n (%) Selective Serotonin Reuptake inhibitor (SSRI) 23 (76.7) 27 (90.0) - Sertraline 14 18 - Fluoxetine 8 7 - Escitalopram 1 3 Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) 6 (20.0) 3 (10.0) - Venlafaxine 6 3 Other antidepressants - Trazodone 4 3 - Bupropion 2 0 - Mirtazapine 1 0 - Vortioxetine 1 1 - Agomelatine 0 1 Tricyclic antidepressant (TCA) - Amitriptyline 4 1 - Nortriptyline 6 3 Antipsychotic - Quetiapine 3 2 - Risperidone 3 2 Benzodiazepines 28 (93.33) 24 (80) - Lorazepam 17 14 - Clonazepam 9 7 - Clorazepate 2 3 The assessment of executive function, memory, and subjective cognitive complaints at the baseline (T1) and endpoint (T10) of the study ( Table 3 ), which was conducted at the 10th week for both the electroacupuncture treatment group and the sham acupuncture control group, yielded the following results: Table 3. Scores on assessment of executive function, subjective cognitive and quality of life. Outcomes EG (n=30) CG (n=30) mean (SD) median mean (SD) median Main outcome Executive function: Trail making test B - Trail making test B T1 131.67 (57.79) 112.50 146.60 (59.80) 132.50 - Trail making test B T10 119.87 (92.12) 94 120.20 (58.98) 119.50 Executive function (inhibition capacity): Stroop test - Stroop word test T1 61.40 (9.60) 63.00 63.14 (14.68) 65.50 - Stroop word test T10 68.63 (9.44) 68.50 68.50 (12.73) 64.50 - Stroop color test T1 78.73 (15.52) 80.50 80.13 (16.62) 82.00 - Stroop color test T10 89.43 (10.65) 93.00 87.43 (14.50) 92.00 - Stroop word and color test T1 33.7 (8.64) 34.50 34.90 (9.27) 34.50 - Stroop word and color test T10 39.53 (8.02) 40 36.73 (10.08) 35.5 Memory ADAS-cog delayed recall memory T1 7.43 (1.96) 8.00 7.53 (1.75) 7.50 ADAS-cog delayed recall memory T10 8.80 (1.12) 9.00 8.67 (1.56) 9.00 Subjective cognitive complain WHODAS 2.0 D1.1-1.6 T1 17.73 (4.66) 18.50 16.93 (3.78) 17.00 WHODAS 2.0 D1.1-1.6 T10 13.43 (3.87) 13.00 15.47 (3.37) 15.50 WHODAS 2.0 H1 T1 19.47 (8.49) 20.00 17.33 (7.91) 20.00 WHODAS 2.0 H1 T10 11.97 (10.09) 8.50 13.87 (9.19) 10.00 WHODAS 2.0 H2 7.80 (8.13) 5 8.20 (8.89) 4.50 WHODAS 2.0 H2 T10 4.47 (7.08) 2.00 4.77 (7.29) 2.00 WHODAS 2.0 H3 T1 11.27 (10.05) 8.50 9.23 (9.06) 6.00 WHODAS 2.0 H3 T10 7.97 (9.14) 3.00 8.50 (8.89) 5.00 Secondary outcome depression PHQ-9 T1 14.53 (4.96) 16.50 15.00 (4.15) 16.00 PHQ-9 T10 9.90 (5.81) 9.50 13.10 (5.65) 11.50 In the electroacupuncture treatment group ( Table 4 ), EG, executive function was primarily evaluated using the TMT- B. The average score of the TMT-B at T1 was 131.67 and at T10 was 119.87, indicating a trend of decreasing scores after receiving electroacupuncture. Subcomponents of executive function, such as inhibition capacity, were assessed using neuropsychological battery scores from the Stroop Word Test, Stroop Color Test, Stroop Word-Color Test, and memory scores from the ADAS-Cog Delayed Recall Memory test. The average scores for these subcomponents showed a tendency to improve after receiving electroacupuncture. Additionally, subjective cognitive complaints were evaluated using the Thai version of the WHODAS 2.0: D1.1-1.6. It was observed that there was a reduction in scores, with the average WHODAS 2.0: D1.1-1.6 score at T1 being 17.73 and at T10 being 13.43, suggesting a decrease in cognitive complaints. Furthermore, the secondary outcome, which measured the severity of depressive symptoms using the Thai-PHQ-9, also showed a similar trend of reduction. Table 4. Treatment effects of electroacupuncture (analyses for intention-to-treat using the last observational carried forward method). Outcomes ∆ median Mann-Whitney U test P-value EG (n=30) CG (n=30) Main outcome Executive function: ∆Trail making test B T10-T1 -15.00 -21.50 410.00 0.553 ∆Stroop word test T10-T1 8.00 3.00 366.50 0.216 ∆Stroop color test T10-T1 8.50 0.50 826.50 0.184 ∆Stroop word and color test T10-T1 4.00 1.50 326.00 0.064 Memory ∆ADAS-cog delay recall memory T10-T1 1.50 1.00 403.50 0.476 Subjective cognitive complaint ∆WHODAS 2.0 D1.1-1.6 T10-T1 -5.50 0.00 318.00 0.049 ∆WHODAS 2.0 H1 T10-T1 -5.50 -2 354.50 0.154 ∆WHODAS 2.0 H2 T10-T1 0.00 -2 435.50 0.828 ∆WHODAS 2.0 H3 T10-T1 -1.00 0.00 390.00 0.370 Secondary outcome: depression ∆PHQ-9 T10-T1 -1 -1 331.00 0.077 In the sham acupuncture control group, CG, the assessment of executive function using the TMT-B resulted in an average score of 146.60 at T1 and 120.20 at T10, indicating a trend of decreasing scores after receiving sham acupuncture. Similar to the electroacupuncture group, subcomponent assessments of executive function and memory showed a tendency to increase after receiving sham acupuncture. Subjective cognitive complaints, evaluated using the WHODAS 2.0: D1.1-1.6, also showed a decrease in scores, with the average WHODAS 2.0: D1.1-1.6 score at T1 being 16.93 and at T10 being 15.47, indicating a reduction in cognitive complaints. The secondary outcome, which measured the severity of depressive symptoms using the Thai-PHQ-9, showed a trend of reduction as well. The average Thai-PHQ-9 score at T1 was 15.00, and at T10 it was 13.10. The difference in median scores between week 10 and week 1 in each group, measured using the TMT-B (which assesses flexibility and processing speed in terms of time in seconds), ADAS-cog delayed recall memory (used to evaluate cognitive function in memory), and Stroop Test (which has 3 subparts: Stroop Word Test, Stroop Color Test, and Stroop Word and Color; with Stroop Word and Color representing inhibition capacity), Thai-PHQ-9 (for measure depressive symptom) showed a trend of higher scores in the electroacupuncture group compared to the control group. However, when subjected to the Mann-Whitney U test, no statistically significant difference was found. The analysis revealed that in the electroacupuncture group, the median within-group change score (∆WHODAS 2.0: D1.1-1.6 of T10-T1) was -5.50, indicating a significant improvement in difficulties with attention, understanding, and initiating conversation. On the other hand, in the control group, the median within-group change score (∆WHODAS 2.0: D1.1-1.6 of T10-T1) showed no change at 0 points. The Mann-Whitney U test was performed with a value of 318.00 and a corresponding p-value of 0.049, indicating a statistically significant difference between the experimental and control groups. This suggests that the experimental group experienced a statically significant decrease in difficulties with attention, understanding, and initiating conversation compared to the control group. No severe side effects were observed from the acupuncture treatment, such as nerve injury, internal organ injury, infection, allergies, or adverse reactions. Discussion Findings from the study indicate that electroacupuncture can statically significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group. These complaints encompass difficulties in activities like concentration, thinking, analysis, learning, understanding, and initiating conversations over the past 30 days. Moreover, positive trends were observed in the experimental group, showcasing enhancements in executive function, memory, and a reduction in the frequency and severity of cognitive issues and depressive symptoms. These outcomes might partly arise from the placebo response, where individuals in the control group experience health improvements despite receiving a simulated treatment. This phenomenon is influenced by participants’ perception of the experiment, including their emotions, expectations, and the therapeutic environment. Interestingly, placebo effects can also be seen in the active treatment group. A meta-analysis by Hafliðadóttir, S.H., and colleagues spanning from 1966 to 2008 covering randomized controlled trials, highlighted that contextual effects were notably higher when the outcome assessor was blinded and the allocation was concealed. Such effects were more pronounced in younger patients and with a higher proportion of female participants. 23 In our study, the authors were mindful of the potential for placebo responses and took measures to minimize them, both for participants and assessors. Despite the predominance of female participants in our study, both groups displayed improvements. Notably, the experimental group exhibited significantly greater enhancements in subjective cognitive complaints. This could be attributed to the experimental group receiving more frequent acupuncture interventions, resulting in a more pronounced contextual effect (around 8.53 times) compared to the control group (approximately 1.83 times). However, even though the researcher tried to design sham acupuncture using very small and short needles, believing they might not have any effect at the acupuncture points, the points used were He gu points, which could influence the placebo effect. Therefore, designing sham acupuncture should avoid using actual acupuncture points, as this may better the differences between the two groups. Acupuncture, compared to non-invasive brain stimulation, stands out as a cost-effective, easily accessible treatment with minimal side effects. It brings about an enhanced quality of life for participants, evident from reduced subjective cognitive complaints in both experimental and control groups. This reduction underscores acupuncture’s positive influence. As participants experience relief in subjective cognitive complaints, their apprehensions about resuming daily activities diminish. Worries regarding work capacity decrease, leading to enhanced work efficiency through reduced anxiety and an improved overall quality of life. Positive developments were also noted in other aspects, such as executive function, memory, motor speed, and inhibition. Moreover, acupuncture shows potential to lower the recurrence rate of depressive symptoms. Previous research has shown that acupuncture improves cognitive function. For example, Jinyu Du, et al. studied the clinical effect of scalp acupuncture combined with cognitive training on cognitive impairment after cerebral injury, comparing it to receiving routine treatment and cognitive rehabilitation training for 12 weeks. They found that the scores of cognitive function assessment in both groups were significantly higher than before treatment. Additionally, in the three cognitive sub-domains—orientation, visual motor organization, and thinking operation—the scores of the treatment group were significantly higher than those of the control group. 8 In another study by Zuo-Li Sun, et al., focusing on the efficacy of electroacupuncture (EA) in patients with schizophrenia, it was found that EA significantly improved memory and moderately improved executive functions and problem-solving. However, it did not demonstrate significant improvement in the severity of psychiatric symptoms or BDNF levels between the control and experimental groups. 9 Yujie Jia, et al. conducted a study on the efficacy of acupuncture with manual needle stimulation in patients with mild to moderate Alzheimer’s disease. They found that the group receiving acupuncture with manual needle stimulation showed significant benefits in cognitive functions measured by the ADAS-cog score compared to the group receiving only Donepezil. However, there was no significant difference in activities of daily living between the two patient groups. 24 Notably, successful treatments in those studies involved regular acupuncture on alternate days. Literature review by the researchers spotlighted the dose-dependent effect of acupuncture treatment, categorized as low and high dose. High dose acupuncture exhibits the following attributes: 1) using over 9 needles, 2) administering treatment more than twice weekly, 3) generating a “De qi” sensation with at least 8 needle insertions, and 4) displaying strong positive correlation with treatment outcomes. Prior high dose acupuncture studies involved daily treatment for at least 2 weeks, more than 10 needle insertions, and over 9 needles. In contrast, this study employed once-weekly treatment, over 9 needle insertions (at least 6 lacking the “De qi” sensation at each insertion), not qualifying as high dose acupuncture. Limited participant numbers (n=30) due to time and resource constraints might have contributed to statistically insignificant findings. Cognitive impairment in patients with depressive disorder is linked to inflammation. When inflammation occurs in the central nervous system, known as neuroinflammation, it triggers the production of pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), chemokines, small-molecule messengers such as prostaglandins and nitric oxide (NO), as well as reactive oxygen species from innate immune cells in the CNS. This oxidative stress is associated with damage to DNA, RNA, lipids, and proteins, with pyramidal neurons in the hippocampus being particularly sensitive to energy deficits. This vulnerability contributes to cognitive impairment. Moreover, oxidative stress leads to a decrease in the expression and function of tropomyosin receptor kinase B (Trk B), a receptor that is crucial for brain-derived neurotrophic factor (BDNF), which plays an essential role in promoting brain plasticity. 25 , 26 Due to its ability to stimulate the expression of GSK-3β/PP2A, acupuncture can enhance neurogenesis in the hippocampus. This results in improved cerebral blood flow in the ischemic cortex, hippocampus, and striatum. Additionally, acupuncture increases the levels of neurotrophic factors such as BDNF and VEGF (brain-derived neurotrophic factor and vascular endothelial growth factor). BDNF and VEGF play crucial roles in stimulating neurogenesis, promoting the formation of new neurons, and facilitating neuronal migration in neurogenic areas. Moreover, VEGF itself is a significant contributor to the angiogenic process. 12 During ischemic conditions in the brain, the body naturally responds by promoting the formation of new blood vessels, serving as an essential neuroprotective factor. 27 Electroacupuncture has been shown to stimulate the release of VEGF, which can be detected in peripheral blood, and to increase cerebral blood flow and cerebral blood volume. This also improves motor function in patients with ischemic stroke. 13 Additionally, experiments on rats have demonstrated that acupuncture can stimulate the release of nitric oxide (NO) and reduce the release of angiotensin II, leading to greater dilation of cerebral blood vessels. 14 , 15 When the release of these substances is stimulated, it is found that the half-life of BDNF in the brain is unknown. However, the half-life of nerve growth factor (NGF), a neurotrophin of similar size and charge, is reported to be less than one hour. 28 Since BDNF and NGF both activate the Trk family of receptors, it is likely that the half-life of BDNF is also on the order of hours. Therefore, electroacupuncture should be administered relatively frequently to maintain effective levels of BDNF or VEGF. It is recommended to apply the treatment at a high dose, which means more than twice a week. This may explain why the researcher's study did not yield significant results. Furthermore, no previous research focused on acupuncture for depressive disorder patients with cognitive dysfunction, limiting direct comparison of acupuncture techniques. Depression patients often grapple with cognitive problems, attention, and memory issues. These difficulties often persist even after depressive symptoms alleviate, increasing the risk of mild cognitive impairment (MCI) or Alzheimer’s disease. Acknowledging, diagnosing, and continually monitoring subjective cognitive decline in depressed patients are crucial for proper treatment and follow-up. In this study, interpreting the findings that electroacupuncture potentially reduces subjective cognitive complaints in MDD patients with mild to moderate depressive symptoms and cognitive issues, compared to the control group, should take into account three considerations: firstly, the baseline subjective cognitive assessment in the control group were less severe than those in the experimental group; and secondly, the ceiling effect, as the baseline scores of executive function, subjective cognitive complaints, and quality of life were relatively high in both groups; and thirdly, in the sham group, although the authors believe that the very short length of the needle without De Qi and the small dose of acupuncture may not be effective, future research should use non-acupuncture points to reduce confounding factors. Addressing these concerns, the authors conducted a pilot study suggesting that electroacupuncture may enhance cognitive function more than the control group. These findings pave the way for further research, both clinically and potentially in clinics. Extended studies are proposed, involving non-invasive transcranial stimulation or electroacupuncture with higher doses, frequency, and duration. Additionally, specific acupuncture points correlating with brain function and a larger participant pool could yield clearer effect sizes and concrete evidence, fostering novel knowledge and pioneering treatments for improved mental health services in the future. Limitation This present study was carried out within a specific timeframe, from December 24, 2021, to December 23, 2022, and focused solely on depression patients seeking treatment at Thammasat University Hospital. Consequently, participant numbers were limited, and the study faced constraints due to outpatient treatment frequency. Participants were unable to undergo acupuncture more than once weekly, categorizing the treatment dose as low. As a result, the study’s outcomes might not distinctly exhibit differences. Furthermore, findings from the present study indicate that electroacupuncture might be able to alleviate subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, compared to the control group. However, the clinical significance of the outcomes of electroacupuncture remains unclear. The authors did not include a healthy control group, focusing instead on patients with MDD who had subjective complaints and were receiving standard pharmacological treatment. The present study aimed to see how these patients responded to adjunctive electroacupuncture. Patients with MDD often receive various psychotropic drugs, such as benzodiazepines and antipsychotics, which can affect cognitive function and serve as confounding factors. Previous research suggested that acupuncture can influence cognitive function, so the study focused on its use as an adjunctive treatment in real-world settings. Future studies may include a much larger number of patients with these characteristics to detect conclusive differences between groups, or in a smaller study, limit acupuncture as an augmentation of one specific class of medications. Ethics and consent The Human Research Ethics Committee of Thammasat University (Medicine) has granted approval for this medical research study (MTU-EC-PS-1-304/64) with an approval date from December 24, 2021 to December 23, 2022. It is in full compliance with international guidelines such as the Declaration of Helsinki. Each participant was provided with detailed information regarding the study and informed written consent was obtained for their participation in the research. Subsequently, all participants granted consent for publication. Data availability Underlying data Zenodo: Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial, https://doi.org/10.5281/zenodo.10488186 . 29 Reporting guidelines Zenodo: Checklist for Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial, https://doi.org/10.5281/zenodo.10816401 . 30 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Zenodo: STRICTA 2010 checklist for Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial, https://doi.org/10.5281/zenodo.12515179 . Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). 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PubMed Abstract | Publisher Full Text | Free Full Text 24. Jia Y, et al. : Acupuncture for patients with mild to moderate Alzheimer’s disease: a randomized controlled trial. BMC Complem. Altern. M. 2017; 17 (1): 556. PubMed Abstract | Publisher Full Text | Free Full Text 25. Berk M, Williams LJ, Jacka FN, et al. : So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013; 11 : 200. Publisher Full Text 26. Sies H: Oxidative stress: a concept in redox biology and medicine. Redox Biol. 2015; 4 : 180–183. PubMed Abstract | Publisher Full Text | Free Full Text 27. Vallon M, et al. : Developmental and pathological angiogenesis in the central nervous system. Cell Mol. Life Sci. 2014; 71 (18): 3489–3506. PubMed Abstract | Publisher Full Text | Free Full Text 28. Krewson CE, Saltzman WM: Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res. 1996; 727 (1-2): 169–181. PubMed Abstract | Publisher Full Text 29. Boontra Y, Phanasathit M: Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial. [Data]. Zenodo. 2024. Publisher Full Text 30. Boontra Y, Phanasathit M, Thanetnit C: CONSORT 2010 checklist of the Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial. Zenodo. 2024. Publisher Full Text Comments on this article Comments (0) Version 4 VERSION 4 PUBLISHED 17 May 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 2 Center of Excellence in Applied Epidemiology, Faculty of Medicine, Thammasat University, Bangkok, Bangkok, 12120, Thailand Yindee Boontra Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Visualization, Writing – Original Draft Preparation Chommakorn Thanetnit Roles: Supervision, Writing – Review & Editing Muthita Phanasathit Roles: Formal Analysis, Methodology, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This study was supported by the Faculty Of Medicine, Thammasat University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (4) version 4 Revised Published: 23 Dec 2024, 13:479 https://doi.org/10.12688/f1000research.146897.4 version 3 Revised Published: 15 Aug 2024, 13:479 https://doi.org/10.12688/f1000research.146897.3 version 2 Revised Published: 01 Jul 2024, 13:479 https://doi.org/10.12688/f1000research.146897.2 version 1 Published: 17 May 2024, 13:479 https://doi.org/10.12688/f1000research.146897.1 Copyright © 2024 Boontra Y et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Boontra Y, Thanetnit C and Phanasathit M. Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.12688/f1000research.146897.4 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 3 VERSION 3 PUBLISHED 15 Aug 2024 Revised Views 0 Cite How to cite this report: Cai M. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.170190.r326928 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v3#referee-response-326928 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 28 Nov 2024 Min Cai , The Fourth Military Medical University, Shaanxi, China Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.170190.r326928 In the manuscript titled “Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial”, Yindee Boontra et al. reported a randomized controlled trial to investigate the role of EA on cognitive symptoms and ... Continue reading READ ALL In the manuscript titled “Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial”, Yindee Boontra et al. reported a randomized controlled trial to investigate the role of EA on cognitive symptoms and quality of life in patients suffered from MDD. Some concerns still need to be issued before the conclusion can be got. 1. About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This is totally not be approved in current ethic protocol. 2. About the sample size, how the authors calculated the sample size? In according the previous study, or just set as a pilot study? I think a scientific hypothesis should be added to identify the current sample size is enough to get the conclusion. 3. How to identify the cognitive dysfunction in MDD patients? The criteria should be issued in the revised manuscript. 4. How the double blinded protocol work? I noticed that the real EA treatment protocol and the sham one are totally different, so how the authors blind the operation during the experiment should be calefied 5. About the discussion section, some citations are focused on cerebral ischemia, I think more citations in relevance of cognitive dysfunction should be citated. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Cai M. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.170190.r326928 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v3#referee-response-326928 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 23 Dec 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 23 Dec 2024 Author Response About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This ... Continue reading About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This is totally not be approved in current ethic protocol. Thank you for your valuable feedback regarding the ethics committee approval for our study. We would like to clarify that our research was approved by the Human Research Ethics Committee of Thammasat University (Medicine) on December 24, 2021 (MTU-EC-PS-1-304/64), prior to the data collection phase. This approval adhered to international ethical standards. Regarding the registration of our clinical trial to enhance research transparency and public accessibility, the authors also registered the study in the Thai Clinical Trials Registry (www.clinicaltrials.in.th) with the identifier NCT06239740, which was certified on February 2, 2024. The Manuscript was change from : (First paragraph of Methods) This trial was registered to the ClinicalTrials.gov (NCT06239740), with a registration date of February 2, 2024 and the Human Research Ethics Committee of Thammasat University (Medicine) has granted approval for this medical research study (MTU-EC-PS-1-304/64) with an approval date from December 24, 2021 to December 23, 2022. It is in full compliance with international guidelines such as the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). This study protocol outlined a double-blinded randomized controlled clinical trial (RCT) and pilot study design conducted at a single center, focusing on evaluating the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) who experience cognitive dysfunction when compared to the control group, while both experimental and control groups were under the standard pharmacological treatment for depressive disorder. The present study was conducted during the Coronavirus Disease (COVID-19) pandemic. The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients To this This trial was registered with the Human Research Ethics Committee of Thammasat University (Medicine), which approved the study (approval code: MTU-EC-PS-1-304/64) for the period from December 24, 2021, to December 23, 2022. The study adhered fully to international ethical guidelines, including the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). The research protocol detailed a double-blinded, randomized controlled trial (RCT) and pilot study conducted at a single center. The study aimed to evaluate the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) and cognitive dysfunction, compared to a control group. Both the experimental and control groups received standard pharmacological treatment for depressive disorders. This study was conducted during the Coronavirus Disease (COVID-19) pandemic, necessitating modifications due to safety concerns and social distancing measures. As a result, the study was adapted to a pilot design with 30 participants in each group. The preliminary findings are intended to guide and inform future large-scale research on the effects of electroacupuncture on cognitive dysfunction in patients with MDD. To enhance research transparency and public accessibility, the authors registered the study with the Thai Clinical Trials Registry (www.clinicaltrials.in.th), under the identifier NCT06239740, certified on February 2, 2024. 2. About the sample size, how the authors calculated the sample size? In according the previous study, or just set as a pilot study? I think a scientific hypothesis should be added to identify the current sample size is enough to get the conclusion. Answer: The authors have titled their research "Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial" and have provided details regarding the sample size in the Methods section as follows: "The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients." Initially, the study was designed as a randomized controlled trial (RCT) with a larger sample size, calculated based on statistical power analyses derived from previous studies on similar interventions for cognitive dysfunction in major depressive disorder (MDD). However, due to the unforeseen challenges posed by the COVID-19 pandemic, including safety concerns and the necessity for social distancing, the study was adapted to a pilot study with 30 participants per group. This adjusted sample size is intended to provide preliminary estimates of effect size and variability, which are crucial for designing adequately powered studies in the future. As stated by Totton, N., Lin, J., Julious, S. et al. in their review "A Review of Sample Sizes for UK Pilot and Feasibility Studies on the ISRCTN Registry from 2013 to 2020" (Pilot Feasibility Stud 9, 188, 2023; https://doi.org/10.1186/s40814-023-01416-w), the median sample size per arm in pilot and feasibility studies from 2013 to 2020 was found to be 30 participants. 3. How to identify the cognitive dysfunction in MDD patients? The criteria should be issued in the revised manuscript. Answer: In our study, we used the PHQ-9 to assess subjective cognitive complaints, specifically focusing on item 7, which inquires about difficulties related to concentration and memory. Item 7 asks, "Trouble concentrating on things, such as reading the newspaper or watching television." The authors have revised and added these details in the manuscript. The manuscript was changed from A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-516 or DSM-IV-TR criteria,17 and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptom was screened using the 7th item of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9),18 which assesses experiencing trouble concentrating or cognitive problems (e.g., reading or watching TV). To this : A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-5 16 or DSM-IV-TR criteria 17 , and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptoms were screened using item 7 of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9) 18 , which assesses difficulties with concentration or cognitive problems. The question in item 7 reads, "Trouble concentrating on things, such as reading the newspaper or watching television." 4. How the double blinded protocol work? I noticed that the real EA treatment protocol and the sham one are totally different, so how the authors blind the operation during the experiment should be calefied The details of the double-blinded protocol are provided in the Methods section as follows: "This study was a double-blinded RCT. All participants and assessors were unaware of group assignments. Before treatment began, participants were unable to distinguish whether they were in the real acupuncture or sham group. They were placed in separate, quiet units on different days." In detail, to prevent any interaction between the experimental and control groups, their appointments were scheduled on different days. The control group was only required to attend the initial session and the follow-up at week 10, during which they were kept in a separate room from the experimental group. This scheduling strategy effectively minimized the possibility of participants from both groups meeting. In summary, the researchers intentionally designed the study to ensure that participants, assessors (who are psychologists), and researchers responsible for statistical data analysis were blinded. 5. About the discussion section, some citations are focused on cerebral ischemia, I think more citations in relevance of cognitive dysfunction should be citated. The discussion about cognitive dysfunction was added in the manuscript Cognitive impairment in patients with depressive disorder is linked to inflammation. When inflammation occurs in the central nervous system, known as neuroinflammation, it triggers the production of pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), chemokines, small-molecule messengers such as prostaglandins and nitric oxide (NO), as well as reactive oxygen species from innate immune cells in the CNS. This oxidative stress is associated with damage to DNA, RNA, lipids, and proteins, with pyramidal neurons in the hippocampus being particularly sensitive to energy deficits. This vulnerability contributes to cognitive impairment. Moreover, oxidative stress leads to a decrease in the expression and function of tropomyosin receptor kinase B (Trk B), a receptor that is crucial for brain-derived neurotrophic factor (BDNF), which plays an essential role in promoting brain plasticity. About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This is totally not be approved in current ethic protocol. Thank you for your valuable feedback regarding the ethics committee approval for our study. We would like to clarify that our research was approved by the Human Research Ethics Committee of Thammasat University (Medicine) on December 24, 2021 (MTU-EC-PS-1-304/64), prior to the data collection phase. This approval adhered to international ethical standards. Regarding the registration of our clinical trial to enhance research transparency and public accessibility, the authors also registered the study in the Thai Clinical Trials Registry (www.clinicaltrials.in.th) with the identifier NCT06239740, which was certified on February 2, 2024. The Manuscript was change from : (First paragraph of Methods) This trial was registered to the ClinicalTrials.gov (NCT06239740), with a registration date of February 2, 2024 and the Human Research Ethics Committee of Thammasat University (Medicine) has granted approval for this medical research study (MTU-EC-PS-1-304/64) with an approval date from December 24, 2021 to December 23, 2022. It is in full compliance with international guidelines such as the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). This study protocol outlined a double-blinded randomized controlled clinical trial (RCT) and pilot study design conducted at a single center, focusing on evaluating the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) who experience cognitive dysfunction when compared to the control group, while both experimental and control groups were under the standard pharmacological treatment for depressive disorder. The present study was conducted during the Coronavirus Disease (COVID-19) pandemic. The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients To this This trial was registered with the Human Research Ethics Committee of Thammasat University (Medicine), which approved the study (approval code: MTU-EC-PS-1-304/64) for the period from December 24, 2021, to December 23, 2022. The study adhered fully to international ethical guidelines, including the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). The research protocol detailed a double-blinded, randomized controlled trial (RCT) and pilot study conducted at a single center. The study aimed to evaluate the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) and cognitive dysfunction, compared to a control group. Both the experimental and control groups received standard pharmacological treatment for depressive disorders. This study was conducted during the Coronavirus Disease (COVID-19) pandemic, necessitating modifications due to safety concerns and social distancing measures. As a result, the study was adapted to a pilot design with 30 participants in each group. The preliminary findings are intended to guide and inform future large-scale research on the effects of electroacupuncture on cognitive dysfunction in patients with MDD. To enhance research transparency and public accessibility, the authors registered the study with the Thai Clinical Trials Registry (www.clinicaltrials.in.th), under the identifier NCT06239740, certified on February 2, 2024. 2. About the sample size, how the authors calculated the sample size? In according the previous study, or just set as a pilot study? I think a scientific hypothesis should be added to identify the current sample size is enough to get the conclusion. Answer: The authors have titled their research "Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial" and have provided details regarding the sample size in the Methods section as follows: "The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients." Initially, the study was designed as a randomized controlled trial (RCT) with a larger sample size, calculated based on statistical power analyses derived from previous studies on similar interventions for cognitive dysfunction in major depressive disorder (MDD). However, due to the unforeseen challenges posed by the COVID-19 pandemic, including safety concerns and the necessity for social distancing, the study was adapted to a pilot study with 30 participants per group. This adjusted sample size is intended to provide preliminary estimates of effect size and variability, which are crucial for designing adequately powered studies in the future. As stated by Totton, N., Lin, J., Julious, S. et al. in their review "A Review of Sample Sizes for UK Pilot and Feasibility Studies on the ISRCTN Registry from 2013 to 2020" (Pilot Feasibility Stud 9, 188, 2023; https://doi.org/10.1186/s40814-023-01416-w), the median sample size per arm in pilot and feasibility studies from 2013 to 2020 was found to be 30 participants. 3. How to identify the cognitive dysfunction in MDD patients? The criteria should be issued in the revised manuscript. Answer: In our study, we used the PHQ-9 to assess subjective cognitive complaints, specifically focusing on item 7, which inquires about difficulties related to concentration and memory. Item 7 asks, "Trouble concentrating on things, such as reading the newspaper or watching television." The authors have revised and added these details in the manuscript. The manuscript was changed from A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-516 or DSM-IV-TR criteria,17 and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptom was screened using the 7th item of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9),18 which assesses experiencing trouble concentrating or cognitive problems (e.g., reading or watching TV). To this : A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-5 16 or DSM-IV-TR criteria 17 , and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptoms were screened using item 7 of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9) 18 , which assesses difficulties with concentration or cognitive problems. The question in item 7 reads, "Trouble concentrating on things, such as reading the newspaper or watching television." 4. How the double blinded protocol work? I noticed that the real EA treatment protocol and the sham one are totally different, so how the authors blind the operation during the experiment should be calefied The details of the double-blinded protocol are provided in the Methods section as follows: "This study was a double-blinded RCT. All participants and assessors were unaware of group assignments. Before treatment began, participants were unable to distinguish whether they were in the real acupuncture or sham group. They were placed in separate, quiet units on different days." In detail, to prevent any interaction between the experimental and control groups, their appointments were scheduled on different days. The control group was only required to attend the initial session and the follow-up at week 10, during which they were kept in a separate room from the experimental group. This scheduling strategy effectively minimized the possibility of participants from both groups meeting. In summary, the researchers intentionally designed the study to ensure that participants, assessors (who are psychologists), and researchers responsible for statistical data analysis were blinded. 5. About the discussion section, some citations are focused on cerebral ischemia, I think more citations in relevance of cognitive dysfunction should be citated. The discussion about cognitive dysfunction was added in the manuscript Cognitive impairment in patients with depressive disorder is linked to inflammation. When inflammation occurs in the central nervous system, known as neuroinflammation, it triggers the production of pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), chemokines, small-molecule messengers such as prostaglandins and nitric oxide (NO), as well as reactive oxygen species from innate immune cells in the CNS. This oxidative stress is associated with damage to DNA, RNA, lipids, and proteins, with pyramidal neurons in the hippocampus being particularly sensitive to energy deficits. This vulnerability contributes to cognitive impairment. Moreover, oxidative stress leads to a decrease in the expression and function of tropomyosin receptor kinase B (Trk B), a receptor that is crucial for brain-derived neurotrophic factor (BDNF), which plays an essential role in promoting brain plasticity. Competing Interests: none Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 23 Dec 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 23 Dec 2024 Author Response About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This ... Continue reading About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This is totally not be approved in current ethic protocol. Thank you for your valuable feedback regarding the ethics committee approval for our study. We would like to clarify that our research was approved by the Human Research Ethics Committee of Thammasat University (Medicine) on December 24, 2021 (MTU-EC-PS-1-304/64), prior to the data collection phase. This approval adhered to international ethical standards. Regarding the registration of our clinical trial to enhance research transparency and public accessibility, the authors also registered the study in the Thai Clinical Trials Registry (www.clinicaltrials.in.th) with the identifier NCT06239740, which was certified on February 2, 2024. The Manuscript was change from : (First paragraph of Methods) This trial was registered to the ClinicalTrials.gov (NCT06239740), with a registration date of February 2, 2024 and the Human Research Ethics Committee of Thammasat University (Medicine) has granted approval for this medical research study (MTU-EC-PS-1-304/64) with an approval date from December 24, 2021 to December 23, 2022. It is in full compliance with international guidelines such as the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). This study protocol outlined a double-blinded randomized controlled clinical trial (RCT) and pilot study design conducted at a single center, focusing on evaluating the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) who experience cognitive dysfunction when compared to the control group, while both experimental and control groups were under the standard pharmacological treatment for depressive disorder. The present study was conducted during the Coronavirus Disease (COVID-19) pandemic. The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients To this This trial was registered with the Human Research Ethics Committee of Thammasat University (Medicine), which approved the study (approval code: MTU-EC-PS-1-304/64) for the period from December 24, 2021, to December 23, 2022. The study adhered fully to international ethical guidelines, including the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). The research protocol detailed a double-blinded, randomized controlled trial (RCT) and pilot study conducted at a single center. The study aimed to evaluate the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) and cognitive dysfunction, compared to a control group. Both the experimental and control groups received standard pharmacological treatment for depressive disorders. This study was conducted during the Coronavirus Disease (COVID-19) pandemic, necessitating modifications due to safety concerns and social distancing measures. As a result, the study was adapted to a pilot design with 30 participants in each group. The preliminary findings are intended to guide and inform future large-scale research on the effects of electroacupuncture on cognitive dysfunction in patients with MDD. To enhance research transparency and public accessibility, the authors registered the study with the Thai Clinical Trials Registry (www.clinicaltrials.in.th), under the identifier NCT06239740, certified on February 2, 2024. 2. About the sample size, how the authors calculated the sample size? In according the previous study, or just set as a pilot study? I think a scientific hypothesis should be added to identify the current sample size is enough to get the conclusion. Answer: The authors have titled their research "Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial" and have provided details regarding the sample size in the Methods section as follows: "The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients." Initially, the study was designed as a randomized controlled trial (RCT) with a larger sample size, calculated based on statistical power analyses derived from previous studies on similar interventions for cognitive dysfunction in major depressive disorder (MDD). However, due to the unforeseen challenges posed by the COVID-19 pandemic, including safety concerns and the necessity for social distancing, the study was adapted to a pilot study with 30 participants per group. This adjusted sample size is intended to provide preliminary estimates of effect size and variability, which are crucial for designing adequately powered studies in the future. As stated by Totton, N., Lin, J., Julious, S. et al. in their review "A Review of Sample Sizes for UK Pilot and Feasibility Studies on the ISRCTN Registry from 2013 to 2020" (Pilot Feasibility Stud 9, 188, 2023; https://doi.org/10.1186/s40814-023-01416-w), the median sample size per arm in pilot and feasibility studies from 2013 to 2020 was found to be 30 participants. 3. How to identify the cognitive dysfunction in MDD patients? The criteria should be issued in the revised manuscript. Answer: In our study, we used the PHQ-9 to assess subjective cognitive complaints, specifically focusing on item 7, which inquires about difficulties related to concentration and memory. Item 7 asks, "Trouble concentrating on things, such as reading the newspaper or watching television." The authors have revised and added these details in the manuscript. The manuscript was changed from A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-516 or DSM-IV-TR criteria,17 and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptom was screened using the 7th item of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9),18 which assesses experiencing trouble concentrating or cognitive problems (e.g., reading or watching TV). To this : A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-5 16 or DSM-IV-TR criteria 17 , and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptoms were screened using item 7 of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9) 18 , which assesses difficulties with concentration or cognitive problems. The question in item 7 reads, "Trouble concentrating on things, such as reading the newspaper or watching television." 4. How the double blinded protocol work? I noticed that the real EA treatment protocol and the sham one are totally different, so how the authors blind the operation during the experiment should be calefied The details of the double-blinded protocol are provided in the Methods section as follows: "This study was a double-blinded RCT. All participants and assessors were unaware of group assignments. Before treatment began, participants were unable to distinguish whether they were in the real acupuncture or sham group. They were placed in separate, quiet units on different days." In detail, to prevent any interaction between the experimental and control groups, their appointments were scheduled on different days. The control group was only required to attend the initial session and the follow-up at week 10, during which they were kept in a separate room from the experimental group. This scheduling strategy effectively minimized the possibility of participants from both groups meeting. In summary, the researchers intentionally designed the study to ensure that participants, assessors (who are psychologists), and researchers responsible for statistical data analysis were blinded. 5. About the discussion section, some citations are focused on cerebral ischemia, I think more citations in relevance of cognitive dysfunction should be citated. The discussion about cognitive dysfunction was added in the manuscript Cognitive impairment in patients with depressive disorder is linked to inflammation. When inflammation occurs in the central nervous system, known as neuroinflammation, it triggers the production of pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), chemokines, small-molecule messengers such as prostaglandins and nitric oxide (NO), as well as reactive oxygen species from innate immune cells in the CNS. This oxidative stress is associated with damage to DNA, RNA, lipids, and proteins, with pyramidal neurons in the hippocampus being particularly sensitive to energy deficits. This vulnerability contributes to cognitive impairment. Moreover, oxidative stress leads to a decrease in the expression and function of tropomyosin receptor kinase B (Trk B), a receptor that is crucial for brain-derived neurotrophic factor (BDNF), which plays an essential role in promoting brain plasticity. About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This is totally not be approved in current ethic protocol. Thank you for your valuable feedback regarding the ethics committee approval for our study. We would like to clarify that our research was approved by the Human Research Ethics Committee of Thammasat University (Medicine) on December 24, 2021 (MTU-EC-PS-1-304/64), prior to the data collection phase. This approval adhered to international ethical standards. Regarding the registration of our clinical trial to enhance research transparency and public accessibility, the authors also registered the study in the Thai Clinical Trials Registry (www.clinicaltrials.in.th) with the identifier NCT06239740, which was certified on February 2, 2024. The Manuscript was change from : (First paragraph of Methods) This trial was registered to the ClinicalTrials.gov (NCT06239740), with a registration date of February 2, 2024 and the Human Research Ethics Committee of Thammasat University (Medicine) has granted approval for this medical research study (MTU-EC-PS-1-304/64) with an approval date from December 24, 2021 to December 23, 2022. It is in full compliance with international guidelines such as the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). This study protocol outlined a double-blinded randomized controlled clinical trial (RCT) and pilot study design conducted at a single center, focusing on evaluating the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) who experience cognitive dysfunction when compared to the control group, while both experimental and control groups were under the standard pharmacological treatment for depressive disorder. The present study was conducted during the Coronavirus Disease (COVID-19) pandemic. The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients To this This trial was registered with the Human Research Ethics Committee of Thammasat University (Medicine), which approved the study (approval code: MTU-EC-PS-1-304/64) for the period from December 24, 2021, to December 23, 2022. The study adhered fully to international ethical guidelines, including the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). The research protocol detailed a double-blinded, randomized controlled trial (RCT) and pilot study conducted at a single center. The study aimed to evaluate the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) and cognitive dysfunction, compared to a control group. Both the experimental and control groups received standard pharmacological treatment for depressive disorders. This study was conducted during the Coronavirus Disease (COVID-19) pandemic, necessitating modifications due to safety concerns and social distancing measures. As a result, the study was adapted to a pilot design with 30 participants in each group. The preliminary findings are intended to guide and inform future large-scale research on the effects of electroacupuncture on cognitive dysfunction in patients with MDD. To enhance research transparency and public accessibility, the authors registered the study with the Thai Clinical Trials Registry (www.clinicaltrials.in.th), under the identifier NCT06239740, certified on February 2, 2024. 2. About the sample size, how the authors calculated the sample size? In according the previous study, or just set as a pilot study? I think a scientific hypothesis should be added to identify the current sample size is enough to get the conclusion. Answer: The authors have titled their research "Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial" and have provided details regarding the sample size in the Methods section as follows: "The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients." Initially, the study was designed as a randomized controlled trial (RCT) with a larger sample size, calculated based on statistical power analyses derived from previous studies on similar interventions for cognitive dysfunction in major depressive disorder (MDD). However, due to the unforeseen challenges posed by the COVID-19 pandemic, including safety concerns and the necessity for social distancing, the study was adapted to a pilot study with 30 participants per group. This adjusted sample size is intended to provide preliminary estimates of effect size and variability, which are crucial for designing adequately powered studies in the future. As stated by Totton, N., Lin, J., Julious, S. et al. in their review "A Review of Sample Sizes for UK Pilot and Feasibility Studies on the ISRCTN Registry from 2013 to 2020" (Pilot Feasibility Stud 9, 188, 2023; https://doi.org/10.1186/s40814-023-01416-w), the median sample size per arm in pilot and feasibility studies from 2013 to 2020 was found to be 30 participants. 3. How to identify the cognitive dysfunction in MDD patients? The criteria should be issued in the revised manuscript. Answer: In our study, we used the PHQ-9 to assess subjective cognitive complaints, specifically focusing on item 7, which inquires about difficulties related to concentration and memory. Item 7 asks, "Trouble concentrating on things, such as reading the newspaper or watching television." The authors have revised and added these details in the manuscript. The manuscript was changed from A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-516 or DSM-IV-TR criteria,17 and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptom was screened using the 7th item of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9),18 which assesses experiencing trouble concentrating or cognitive problems (e.g., reading or watching TV). To this : A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-5 16 or DSM-IV-TR criteria 17 , and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptoms were screened using item 7 of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9) 18 , which assesses difficulties with concentration or cognitive problems. The question in item 7 reads, "Trouble concentrating on things, such as reading the newspaper or watching television." 4. How the double blinded protocol work? I noticed that the real EA treatment protocol and the sham one are totally different, so how the authors blind the operation during the experiment should be calefied The details of the double-blinded protocol are provided in the Methods section as follows: "This study was a double-blinded RCT. All participants and assessors were unaware of group assignments. Before treatment began, participants were unable to distinguish whether they were in the real acupuncture or sham group. They were placed in separate, quiet units on different days." In detail, to prevent any interaction between the experimental and control groups, their appointments were scheduled on different days. The control group was only required to attend the initial session and the follow-up at week 10, during which they were kept in a separate room from the experimental group. This scheduling strategy effectively minimized the possibility of participants from both groups meeting. In summary, the researchers intentionally designed the study to ensure that participants, assessors (who are psychologists), and researchers responsible for statistical data analysis were blinded. 5. About the discussion section, some citations are focused on cerebral ischemia, I think more citations in relevance of cognitive dysfunction should be citated. The discussion about cognitive dysfunction was added in the manuscript Cognitive impairment in patients with depressive disorder is linked to inflammation. When inflammation occurs in the central nervous system, known as neuroinflammation, it triggers the production of pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), chemokines, small-molecule messengers such as prostaglandins and nitric oxide (NO), as well as reactive oxygen species from innate immune cells in the CNS. This oxidative stress is associated with damage to DNA, RNA, lipids, and proteins, with pyramidal neurons in the hippocampus being particularly sensitive to energy deficits. This vulnerability contributes to cognitive impairment. Moreover, oxidative stress leads to a decrease in the expression and function of tropomyosin receptor kinase B (Trk B), a receptor that is crucial for brain-derived neurotrophic factor (BDNF), which plays an essential role in promoting brain plasticity. Competing Interests: none Close Report a concern COMMENT ON THIS REPORT Version 2 VERSION 2 PUBLISHED 01 Jul 2024 Revised Views 0 Cite How to cite this report: Li SX. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.168555.r297844 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v2#referee-response-297844 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 18 Jul 2024 Su-Xia Li , National Institute on Drug Dependence and Beijing Key laboratory of Drug Dependence Research, Peking University, Beijing, China Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.168555.r297844 I think that most of the reviewer's concerns have been addressed. As for the explanation for “Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of ... Continue reading READ ALL I think that most of the reviewer's concerns have been addressed. As for the explanation for “Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable?”. Authors explanation is not reasonable. Firstly, the baseline subjective cognitive function in the control group were not less severe than those in the experimental group, it is comparable. Secondly, the idea of ceiling effect is also unreasonable and inappropriate. In fact, authors have not explained anything for this problem. Additionally, in the Discussion section, the author should also discuss in depth the reasons for the lack of improvement in all objective indicators. In the abstract, the author used different words to describe the drug treatment taken by the two groups of subjects. In the main text, the two groups were actually the same, and it was suggested to use the same words to describe them. In the Table 2, the number of patients in CG totally 27 who took SSRIs, Instead, the number of patients who took Sertraline, Fluoxetine and Escitalopram combined was 28 In the Table 3, both EG (n=30) and CG (n=30) should be placed in the correct position, corresponding to their respective data. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Psychiatry，Depression I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Li SX. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.168555.r297844 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v2#referee-response-297844 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 15 Aug 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 15 Aug 2024 Author Response Response to Reviewers 1. Reviewer Comment : "I think that most of the reviewer's concerns have been addressed. As for the explanation for ‘Many measures of cognitive function did not differ ... Continue reading Response to Reviewers 1. Reviewer Comment : "I think that most of the reviewer's concerns have been addressed. As for the explanation for ‘Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable?’" Response : The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Therefore, we have added the following explanation to the Discussion section: “However, even though the researcher tried to design sham acupuncture using very small and short needles, believing they might not have any effect at the acupuncture points, the points used were He gu points, which could influence the placebo effect. Therefore, designing sham acupuncture should avoid using actual acupuncture points, as this may better differentiate between the two groups.” 2. Reviewer Comment : "Additionally, in the Discussion section, the author should also discuss in depth the reasons for the lack of improvement in all objective indicators." Response : The authors have expanded the Discussion section to provide a more in-depth explanation of the low-dose regimen and its effects on neurotropins, as follows: “ Due to its ability to stimulate the expression of GSK-3β/PP2A, acupuncture can enhance neurogenesis in the hippocampus. This results in improved cerebral blood flow in the ischemic cortex, hippocampus, and striatum. Additionally, acupuncture increases the levels of neurotrophic factors such as BDNF and VEGF (brain-derived neurotrophic factor and vascular endothelial growth factor). BDNF and VEGF play crucial roles in stimulating neurogenesis, promoting the formation of new neurons, and facilitating neuronal migration in neurogenic areas. Moreover, VEGF itself is a significant contributor to the angiogenic process. [1] During ischemic conditions in the brain, the body naturally responds by promoting the formation of new blood vessels, serving as an essential neuroprotective factor. [2] Electroacupuncture has been shown to stimulate the release of VEGF, which can be detected in peripheral blood, and to increase cerebral blood flow and cerebral blood volume. This also improves motor function in patients with ischemic stroke. [3] Additionally, experiments on rats have demonstrated that acupuncture can stimulate the release of nitric oxide (NO) and reduce the release of angiotensin II, leading to greater dilation of cerebral blood vessels. [4, 5] When the release of these substances is stimulated, it is found that the half-life of BDNF in the brain is unknown. However, the half-life of nerve growth factor (NGF), a neurotrophin of similar size and charge, is reported to be less than one hour. [6] Since BDNF and NGF both activate the Trk family of receptors, it is likely that the half-life of BDNF is also on the order of hours. Therefore, electroacupuncture should be administered relatively frequently to maintain effective levels of BDNF or VEGF. It is recommended to apply the treatment at a high dose, which means more than twice a week. This may explain why the researcher's study did not yield significant results. ” References : 1. Kim, Y.R., et al., Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One, 2014. 9(2): p. e90000 DOI: 10.1371/journal.pone.0090000. 2. Vallon, M., et al., Developmental and pathological angiogenesis in the central nervous system. Cell Mol Life Sci, 2014. 71(18): p. 3489-506 DOI: 10.1007/s00018-014-1625-0. 3. Zheng, C., et al., A randomized controlled trial comparing electroacupuncture with manual acupuncture for motor function recovery after ischemic stroke. European Journal of Integrative Medicine, 2018. 22: p. 76-80. 4. Kim, J.H., et al., Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice. PLoS One, 2013. 8(2): p. e56736 DOI: 10.1371/journal.pone.0056736. 5. Li, J., et al., Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats. BMC Complement Altern Med, 2014. 14: p. 441 DOI: 10.1186/1472-6882-14-441. 6. Krewson, C.E. and W.M. Saltzman, Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res, 1996. 727(1-2): p. 169-81 DOI: 10.1016/0006-8993(96)00378-2. 3. Reviewer Comment : "In the abstract, the author used different words to describe the drug treatment taken by the two groups of subjects. In the main text, the two groups were actually the same, and it was suggested to use the same words to describe them." Response : The authors have revised the abstract for consistency. It now reads: “Participants were divided into two groups: the electroacupuncture group combined with standard pharmacological treatment (EG; n=30) and the control group receiving standard pharmacological treatment with placebo acupuncture (CG; n=30).” 4. Reviewer Comment : "In Table 2, the number of patients in CG totally 27 who took SSRIs. Instead, the number of patients who took Sertraline, Fluoxetine, and Escitalopram combined was 28." Response : The authors have added the following note under Table 2 to clarify: “ Note: Some patients received multiple types of antidepressants concurrently or in combination with other drug classes such as benzodiazepines or antipsychotics. Some patients did not receive SSRIs as the primary medication but were prescribed other types of antidepressants. The medication administration followed the guidelines set by the American Psychological Association (2019) in the Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. ” 5. Reviewer Comment : "In Table 3, both EG (n=30) and CG (n=30) should be placed in the correct position, corresponding to their respective data." Response : The authors have corrected the placement of EG (n=30) and CG (n=30) at the header of Table 3. Response to Reviewers 1. Reviewer Comment : "I think that most of the reviewer's concerns have been addressed. As for the explanation for ‘Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable?’" Response : The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Therefore, we have added the following explanation to the Discussion section: “However, even though the researcher tried to design sham acupuncture using very small and short needles, believing they might not have any effect at the acupuncture points, the points used were He gu points, which could influence the placebo effect. Therefore, designing sham acupuncture should avoid using actual acupuncture points, as this may better differentiate between the two groups.” 2. Reviewer Comment : "Additionally, in the Discussion section, the author should also discuss in depth the reasons for the lack of improvement in all objective indicators." Response : The authors have expanded the Discussion section to provide a more in-depth explanation of the low-dose regimen and its effects on neurotropins, as follows: “ Due to its ability to stimulate the expression of GSK-3β/PP2A, acupuncture can enhance neurogenesis in the hippocampus. This results in improved cerebral blood flow in the ischemic cortex, hippocampus, and striatum. Additionally, acupuncture increases the levels of neurotrophic factors such as BDNF and VEGF (brain-derived neurotrophic factor and vascular endothelial growth factor). BDNF and VEGF play crucial roles in stimulating neurogenesis, promoting the formation of new neurons, and facilitating neuronal migration in neurogenic areas. Moreover, VEGF itself is a significant contributor to the angiogenic process. [1] During ischemic conditions in the brain, the body naturally responds by promoting the formation of new blood vessels, serving as an essential neuroprotective factor. [2] Electroacupuncture has been shown to stimulate the release of VEGF, which can be detected in peripheral blood, and to increase cerebral blood flow and cerebral blood volume. This also improves motor function in patients with ischemic stroke. [3] Additionally, experiments on rats have demonstrated that acupuncture can stimulate the release of nitric oxide (NO) and reduce the release of angiotensin II, leading to greater dilation of cerebral blood vessels. [4, 5] When the release of these substances is stimulated, it is found that the half-life of BDNF in the brain is unknown. However, the half-life of nerve growth factor (NGF), a neurotrophin of similar size and charge, is reported to be less than one hour. [6] Since BDNF and NGF both activate the Trk family of receptors, it is likely that the half-life of BDNF is also on the order of hours. Therefore, electroacupuncture should be administered relatively frequently to maintain effective levels of BDNF or VEGF. It is recommended to apply the treatment at a high dose, which means more than twice a week. This may explain why the researcher's study did not yield significant results. ” References : 1. Kim, Y.R., et al., Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One, 2014. 9(2): p. e90000 DOI: 10.1371/journal.pone.0090000. 2. Vallon, M., et al., Developmental and pathological angiogenesis in the central nervous system. Cell Mol Life Sci, 2014. 71(18): p. 3489-506 DOI: 10.1007/s00018-014-1625-0. 3. Zheng, C., et al., A randomized controlled trial comparing electroacupuncture with manual acupuncture for motor function recovery after ischemic stroke. European Journal of Integrative Medicine, 2018. 22: p. 76-80. 4. Kim, J.H., et al., Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice. PLoS One, 2013. 8(2): p. e56736 DOI: 10.1371/journal.pone.0056736. 5. Li, J., et al., Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats. BMC Complement Altern Med, 2014. 14: p. 441 DOI: 10.1186/1472-6882-14-441. 6. Krewson, C.E. and W.M. Saltzman, Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res, 1996. 727(1-2): p. 169-81 DOI: 10.1016/0006-8993(96)00378-2. 3. Reviewer Comment : "In the abstract, the author used different words to describe the drug treatment taken by the two groups of subjects. In the main text, the two groups were actually the same, and it was suggested to use the same words to describe them." Response : The authors have revised the abstract for consistency. It now reads: “Participants were divided into two groups: the electroacupuncture group combined with standard pharmacological treatment (EG; n=30) and the control group receiving standard pharmacological treatment with placebo acupuncture (CG; n=30).” 4. Reviewer Comment : "In Table 2, the number of patients in CG totally 27 who took SSRIs. Instead, the number of patients who took Sertraline, Fluoxetine, and Escitalopram combined was 28." Response : The authors have added the following note under Table 2 to clarify: “ Note: Some patients received multiple types of antidepressants concurrently or in combination with other drug classes such as benzodiazepines or antipsychotics. Some patients did not receive SSRIs as the primary medication but were prescribed other types of antidepressants. The medication administration followed the guidelines set by the American Psychological Association (2019) in the Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. ” 5. Reviewer Comment : "In Table 3, both EG (n=30) and CG (n=30) should be placed in the correct position, corresponding to their respective data." Response : The authors have corrected the placement of EG (n=30) and CG (n=30) at the header of Table 3. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 15 Aug 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 15 Aug 2024 Author Response Response to Reviewers 1. Reviewer Comment : "I think that most of the reviewer's concerns have been addressed. As for the explanation for ‘Many measures of cognitive function did not differ ... Continue reading Response to Reviewers 1. Reviewer Comment : "I think that most of the reviewer's concerns have been addressed. As for the explanation for ‘Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable?’" Response : The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Therefore, we have added the following explanation to the Discussion section: “However, even though the researcher tried to design sham acupuncture using very small and short needles, believing they might not have any effect at the acupuncture points, the points used were He gu points, which could influence the placebo effect. Therefore, designing sham acupuncture should avoid using actual acupuncture points, as this may better differentiate between the two groups.” 2. Reviewer Comment : "Additionally, in the Discussion section, the author should also discuss in depth the reasons for the lack of improvement in all objective indicators." Response : The authors have expanded the Discussion section to provide a more in-depth explanation of the low-dose regimen and its effects on neurotropins, as follows: “ Due to its ability to stimulate the expression of GSK-3β/PP2A, acupuncture can enhance neurogenesis in the hippocampus. This results in improved cerebral blood flow in the ischemic cortex, hippocampus, and striatum. Additionally, acupuncture increases the levels of neurotrophic factors such as BDNF and VEGF (brain-derived neurotrophic factor and vascular endothelial growth factor). BDNF and VEGF play crucial roles in stimulating neurogenesis, promoting the formation of new neurons, and facilitating neuronal migration in neurogenic areas. Moreover, VEGF itself is a significant contributor to the angiogenic process. [1] During ischemic conditions in the brain, the body naturally responds by promoting the formation of new blood vessels, serving as an essential neuroprotective factor. [2] Electroacupuncture has been shown to stimulate the release of VEGF, which can be detected in peripheral blood, and to increase cerebral blood flow and cerebral blood volume. This also improves motor function in patients with ischemic stroke. [3] Additionally, experiments on rats have demonstrated that acupuncture can stimulate the release of nitric oxide (NO) and reduce the release of angiotensin II, leading to greater dilation of cerebral blood vessels. [4, 5] When the release of these substances is stimulated, it is found that the half-life of BDNF in the brain is unknown. However, the half-life of nerve growth factor (NGF), a neurotrophin of similar size and charge, is reported to be less than one hour. [6] Since BDNF and NGF both activate the Trk family of receptors, it is likely that the half-life of BDNF is also on the order of hours. Therefore, electroacupuncture should be administered relatively frequently to maintain effective levels of BDNF or VEGF. It is recommended to apply the treatment at a high dose, which means more than twice a week. This may explain why the researcher's study did not yield significant results. ” References : 1. Kim, Y.R., et al., Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One, 2014. 9(2): p. e90000 DOI: 10.1371/journal.pone.0090000. 2. Vallon, M., et al., Developmental and pathological angiogenesis in the central nervous system. Cell Mol Life Sci, 2014. 71(18): p. 3489-506 DOI: 10.1007/s00018-014-1625-0. 3. Zheng, C., et al., A randomized controlled trial comparing electroacupuncture with manual acupuncture for motor function recovery after ischemic stroke. European Journal of Integrative Medicine, 2018. 22: p. 76-80. 4. Kim, J.H., et al., Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice. PLoS One, 2013. 8(2): p. e56736 DOI: 10.1371/journal.pone.0056736. 5. Li, J., et al., Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats. BMC Complement Altern Med, 2014. 14: p. 441 DOI: 10.1186/1472-6882-14-441. 6. Krewson, C.E. and W.M. Saltzman, Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res, 1996. 727(1-2): p. 169-81 DOI: 10.1016/0006-8993(96)00378-2. 3. Reviewer Comment : "In the abstract, the author used different words to describe the drug treatment taken by the two groups of subjects. In the main text, the two groups were actually the same, and it was suggested to use the same words to describe them." Response : The authors have revised the abstract for consistency. It now reads: “Participants were divided into two groups: the electroacupuncture group combined with standard pharmacological treatment (EG; n=30) and the control group receiving standard pharmacological treatment with placebo acupuncture (CG; n=30).” 4. Reviewer Comment : "In Table 2, the number of patients in CG totally 27 who took SSRIs. Instead, the number of patients who took Sertraline, Fluoxetine, and Escitalopram combined was 28." Response : The authors have added the following note under Table 2 to clarify: “ Note: Some patients received multiple types of antidepressants concurrently or in combination with other drug classes such as benzodiazepines or antipsychotics. Some patients did not receive SSRIs as the primary medication but were prescribed other types of antidepressants. The medication administration followed the guidelines set by the American Psychological Association (2019) in the Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. ” 5. Reviewer Comment : "In Table 3, both EG (n=30) and CG (n=30) should be placed in the correct position, corresponding to their respective data." Response : The authors have corrected the placement of EG (n=30) and CG (n=30) at the header of Table 3. Response to Reviewers 1. Reviewer Comment : "I think that most of the reviewer's concerns have been addressed. As for the explanation for ‘Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable?’" Response : The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Therefore, we have added the following explanation to the Discussion section: “However, even though the researcher tried to design sham acupuncture using very small and short needles, believing they might not have any effect at the acupuncture points, the points used were He gu points, which could influence the placebo effect. Therefore, designing sham acupuncture should avoid using actual acupuncture points, as this may better differentiate between the two groups.” 2. Reviewer Comment : "Additionally, in the Discussion section, the author should also discuss in depth the reasons for the lack of improvement in all objective indicators." Response : The authors have expanded the Discussion section to provide a more in-depth explanation of the low-dose regimen and its effects on neurotropins, as follows: “ Due to its ability to stimulate the expression of GSK-3β/PP2A, acupuncture can enhance neurogenesis in the hippocampus. This results in improved cerebral blood flow in the ischemic cortex, hippocampus, and striatum. Additionally, acupuncture increases the levels of neurotrophic factors such as BDNF and VEGF (brain-derived neurotrophic factor and vascular endothelial growth factor). BDNF and VEGF play crucial roles in stimulating neurogenesis, promoting the formation of new neurons, and facilitating neuronal migration in neurogenic areas. Moreover, VEGF itself is a significant contributor to the angiogenic process. [1] During ischemic conditions in the brain, the body naturally responds by promoting the formation of new blood vessels, serving as an essential neuroprotective factor. [2] Electroacupuncture has been shown to stimulate the release of VEGF, which can be detected in peripheral blood, and to increase cerebral blood flow and cerebral blood volume. This also improves motor function in patients with ischemic stroke. [3] Additionally, experiments on rats have demonstrated that acupuncture can stimulate the release of nitric oxide (NO) and reduce the release of angiotensin II, leading to greater dilation of cerebral blood vessels. [4, 5] When the release of these substances is stimulated, it is found that the half-life of BDNF in the brain is unknown. However, the half-life of nerve growth factor (NGF), a neurotrophin of similar size and charge, is reported to be less than one hour. [6] Since BDNF and NGF both activate the Trk family of receptors, it is likely that the half-life of BDNF is also on the order of hours. Therefore, electroacupuncture should be administered relatively frequently to maintain effective levels of BDNF or VEGF. It is recommended to apply the treatment at a high dose, which means more than twice a week. This may explain why the researcher's study did not yield significant results. ” References : 1. Kim, Y.R., et al., Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One, 2014. 9(2): p. e90000 DOI: 10.1371/journal.pone.0090000. 2. Vallon, M., et al., Developmental and pathological angiogenesis in the central nervous system. Cell Mol Life Sci, 2014. 71(18): p. 3489-506 DOI: 10.1007/s00018-014-1625-0. 3. Zheng, C., et al., A randomized controlled trial comparing electroacupuncture with manual acupuncture for motor function recovery after ischemic stroke. European Journal of Integrative Medicine, 2018. 22: p. 76-80. 4. Kim, J.H., et al., Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice. PLoS One, 2013. 8(2): p. e56736 DOI: 10.1371/journal.pone.0056736. 5. Li, J., et al., Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats. BMC Complement Altern Med, 2014. 14: p. 441 DOI: 10.1186/1472-6882-14-441. 6. Krewson, C.E. and W.M. Saltzman, Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res, 1996. 727(1-2): p. 169-81 DOI: 10.1016/0006-8993(96)00378-2. 3. Reviewer Comment : "In the abstract, the author used different words to describe the drug treatment taken by the two groups of subjects. In the main text, the two groups were actually the same, and it was suggested to use the same words to describe them." Response : The authors have revised the abstract for consistency. It now reads: “Participants were divided into two groups: the electroacupuncture group combined with standard pharmacological treatment (EG; n=30) and the control group receiving standard pharmacological treatment with placebo acupuncture (CG; n=30).” 4. Reviewer Comment : "In Table 2, the number of patients in CG totally 27 who took SSRIs. Instead, the number of patients who took Sertraline, Fluoxetine, and Escitalopram combined was 28." Response : The authors have added the following note under Table 2 to clarify: “ Note: Some patients received multiple types of antidepressants concurrently or in combination with other drug classes such as benzodiazepines or antipsychotics. Some patients did not receive SSRIs as the primary medication but were prescribed other types of antidepressants. The medication administration followed the guidelines set by the American Psychological Association (2019) in the Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. ” 5. Reviewer Comment : "In Table 3, both EG (n=30) and CG (n=30) should be placed in the correct position, corresponding to their respective data." Response : The authors have corrected the placement of EG (n=30) and CG (n=30) at the header of Table 3. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Schnyer RN. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.168555.r297843 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v2#referee-response-297843 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 16 Jul 2024 Rosa N Schnyer , School of Nursing, The University of Texas, Austin, Texas, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.168555.r297843 Although most comments from the reviewers have been addressed, the authors still describe the study as a double-blind study. It is not, or rather, it is impossible to assess if it fact the double blind worked. Please add a clause ... Continue reading READ ALL Although most comments from the reviewers have been addressed, the authors still describe the study as a double-blind study. It is not, or rather, it is impossible to assess if it fact the double blind worked. Please add a clause to explain how blinding was neither assessed and may not have been necessarily accomplished. It is important not to claim that a study is double, unless this has been effectively established. The authors need to remove the double blind statement, and explain that they set to conduct a double-blind study but since blinding wasn't assessed they cannot be sure that acupuncturists were in fact blind. Blinding of the treatment providers is not essential to the conclusions of the study but a caveat needs to be included. Thank you Competing Interests: No competing interests were disclosed. Reviewer Expertise: Acupuncture, depression, pain, women's health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Schnyer RN. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.168555.r297843 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v2#referee-response-297843 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 17 May 2024 Views 0 Cite How to cite this report: Li SX. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.161025.r282200 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v1#referee-response-282200 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 11 Jun 2024 Su-Xia Li , National Institute on Drug Dependence and Beijing Key laboratory of Drug Dependence Research, Peking University, Beijing, China Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.161025.r282200 1. The treatment plan for the two groups of patients in the Abstract is different from the description in the Methods section. 2. A healthy control group should be included in the study protocol. On the one hand, does ... Continue reading READ ALL 1. The treatment plan for the two groups of patients in the Abstract is different from the description in the Methods section. 2. A healthy control group should be included in the study protocol. On the one hand, does the cognitive function of patients with MDD differ from that of healthy controls at baseline. On the other hand, after treatment, whether the cognitive function of patients is restored, and how much differences between healthy controls and patients with depression. These can only be achieved in the presence of a healthy control group. 3. For the electroacupuncture group, the authors needed to describe the entire treatment process in detail. Such as the duration of each treatment, how many days consecutive per week, the specific depth of the acupuncture therapy, and how strong the current intensity is? 4. How does the Sham group work？The authors need to describe in detail the specific operation of the sham acupuncture control group, how long the acupuncture of He gu point lasted for each treatment, and how many consecutive days were in the first week and the 10th week. The specific depth of the acupuncture therapy, and how strong the current intensity is? 5. For the comparison of the two groups of indicators at the end point, the existence of time effect should be considered. It is unreasonable and unscientific to use a simple t -test between two groups. 6. Authors defined that at baseline is T0, at the ten-week intervention is T10. However, in Results section, baseline is described as T1. The author's description of the same event should be uniform. 7. Abbreviations in the table should be explained at the bottom of the table. 8. Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable? Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Psychiatry，Depression I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Li SX. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.161025.r282200 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v1#referee-response-282200 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 26 Jun 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 26 Jun 2024 Author Response - According to the review comment, the revision of abstract was made. Page 2 Line 4-8 in abstract - Thank you for your advice. We agree that a healthy control should ... Continue reading - According to the review comment, the revision of abstract was made. Page 2 Line 4-8 in abstract - Thank you for your advice. We agree that a healthy control should be included in experimental studies aiming to assess the safety and efficacy of new interventions and medications. However, a literature review on the use of electroacupuncture has provided evidence of its safety and efficacy in treating patients with schizophrenia, brain injury, and stroke who have cognitive impairment. The researchers aimed to study the effects of electroacupuncture on specific cognitive functions in subjects experiencing cognitive dysfunction associated with MDD. Including healthy controls without subjective cognitive complaints in this study might not address the research question adequately. Therefore, we recruited MDD patients with cognitive dysfunction receiving sham acupuncture and standard treatment as a comparator instead. - According to the review comment, the revision was made in the method / intervention session. (page 4, Line 12-31) - Due to the outcome from this pilot study (n=30 per group), the data had a non-normal distribution. A comparison between the electroacupuncture and control groups was conducted using the Mann-Whitney U test, which compared the median differences of the outcomes. Differences between groups were calculated by comparing baseline (T1) and endpoint (T10) values. Page 6 Line 16 -According to the review comment about the Base line , the revision was made as T1.(Page 6 line 11) - All abbreviations in the table were explained at the bottom of all tables. (table 1 and table 3 ) - According to Sham setting : The authors hypothesized that the reason many measures of cognitive function did not differ between the two groups after 10 weeks of treatment was due to two factors: firstly, the baseline subjective cognitive function in the control group were less severe than those in the experimental group; and secondly, the ceiling effect, as the baseline scores of executive function, subjective cognitive complaints, and quality of life were relatively high in both groups. These points have been addressed in the discussion section. - According to the review comment, the revision of abstract was made. Page 2 Line 4-8 in abstract - Thank you for your advice. We agree that a healthy control should be included in experimental studies aiming to assess the safety and efficacy of new interventions and medications. However, a literature review on the use of electroacupuncture has provided evidence of its safety and efficacy in treating patients with schizophrenia, brain injury, and stroke who have cognitive impairment. The researchers aimed to study the effects of electroacupuncture on specific cognitive functions in subjects experiencing cognitive dysfunction associated with MDD. Including healthy controls without subjective cognitive complaints in this study might not address the research question adequately. Therefore, we recruited MDD patients with cognitive dysfunction receiving sham acupuncture and standard treatment as a comparator instead. - According to the review comment, the revision was made in the method / intervention session. (page 4, Line 12-31) - Due to the outcome from this pilot study (n=30 per group), the data had a non-normal distribution. A comparison between the electroacupuncture and control groups was conducted using the Mann-Whitney U test, which compared the median differences of the outcomes. Differences between groups were calculated by comparing baseline (T1) and endpoint (T10) values. Page 6 Line 16 -According to the review comment about the Base line , the revision was made as T1.(Page 6 line 11) - All abbreviations in the table were explained at the bottom of all tables. (table 1 and table 3 ) - According to Sham setting : The authors hypothesized that the reason many measures of cognitive function did not differ between the two groups after 10 weeks of treatment was due to two factors: firstly, the baseline subjective cognitive function in the control group were less severe than those in the experimental group; and secondly, the ceiling effect, as the baseline scores of executive function, subjective cognitive complaints, and quality of life were relatively high in both groups. These points have been addressed in the discussion section. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 26 Jun 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 26 Jun 2024 Author Response - According to the review comment, the revision of abstract was made. Page 2 Line 4-8 in abstract - Thank you for your advice. We agree that a healthy control should ... Continue reading - According to the review comment, the revision of abstract was made. Page 2 Line 4-8 in abstract - Thank you for your advice. We agree that a healthy control should be included in experimental studies aiming to assess the safety and efficacy of new interventions and medications. However, a literature review on the use of electroacupuncture has provided evidence of its safety and efficacy in treating patients with schizophrenia, brain injury, and stroke who have cognitive impairment. The researchers aimed to study the effects of electroacupuncture on specific cognitive functions in subjects experiencing cognitive dysfunction associated with MDD. Including healthy controls without subjective cognitive complaints in this study might not address the research question adequately. Therefore, we recruited MDD patients with cognitive dysfunction receiving sham acupuncture and standard treatment as a comparator instead. - According to the review comment, the revision was made in the method / intervention session. (page 4, Line 12-31) - Due to the outcome from this pilot study (n=30 per group), the data had a non-normal distribution. A comparison between the electroacupuncture and control groups was conducted using the Mann-Whitney U test, which compared the median differences of the outcomes. Differences between groups were calculated by comparing baseline (T1) and endpoint (T10) values. Page 6 Line 16 -According to the review comment about the Base line , the revision was made as T1.(Page 6 line 11) - All abbreviations in the table were explained at the bottom of all tables. (table 1 and table 3 ) - According to Sham setting : The authors hypothesized that the reason many measures of cognitive function did not differ between the two groups after 10 weeks of treatment was due to two factors: firstly, the baseline subjective cognitive function in the control group were less severe than those in the experimental group; and secondly, the ceiling effect, as the baseline scores of executive function, subjective cognitive complaints, and quality of life were relatively high in both groups. These points have been addressed in the discussion section. - According to the review comment, the revision of abstract was made. Page 2 Line 4-8 in abstract - Thank you for your advice. We agree that a healthy control should be included in experimental studies aiming to assess the safety and efficacy of new interventions and medications. However, a literature review on the use of electroacupuncture has provided evidence of its safety and efficacy in treating patients with schizophrenia, brain injury, and stroke who have cognitive impairment. The researchers aimed to study the effects of electroacupuncture on specific cognitive functions in subjects experiencing cognitive dysfunction associated with MDD. Including healthy controls without subjective cognitive complaints in this study might not address the research question adequately. Therefore, we recruited MDD patients with cognitive dysfunction receiving sham acupuncture and standard treatment as a comparator instead. - According to the review comment, the revision was made in the method / intervention session. (page 4, Line 12-31) - Due to the outcome from this pilot study (n=30 per group), the data had a non-normal distribution. A comparison between the electroacupuncture and control groups was conducted using the Mann-Whitney U test, which compared the median differences of the outcomes. Differences between groups were calculated by comparing baseline (T1) and endpoint (T10) values. Page 6 Line 16 -According to the review comment about the Base line , the revision was made as T1.(Page 6 line 11) - All abbreviations in the table were explained at the bottom of all tables. (table 1 and table 3 ) - According to Sham setting : The authors hypothesized that the reason many measures of cognitive function did not differ between the two groups after 10 weeks of treatment was due to two factors: firstly, the baseline subjective cognitive function in the control group were less severe than those in the experimental group; and secondly, the ceiling effect, as the baseline scores of executive function, subjective cognitive complaints, and quality of life were relatively high in both groups. These points have been addressed in the discussion section. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Schnyer RN. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.161025.r282194 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v1#referee-response-282194 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Jun 2024 Rosa N Schnyer , School of Nursing, The University of Texas, Austin, Texas, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.161025.r282194 The authors set out to conduct a rigorous, double-blind RCT on the effect electro-acupuncture on cognitive symptoms in major depressive disorder. The subject is highly relevant clinically and the study is timely, as it is critical to identify strategies to ... Continue reading READ ALL The authors set out to conduct a rigorous, double-blind RCT on the effect electro-acupuncture on cognitive symptoms in major depressive disorder. The subject is highly relevant clinically and the study is timely, as it is critical to identify strategies to manage cognitive and mood symptoms which affect a large segment of the population worldwide. There are some key issues that need to be addressed in the reporting of the results, some critical considerations in future proposals on this subject: Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of the interventions, training of the acupuncture providers, etc. is incomplete. For example, there is no description of the needling parameters or the intensity / frequency of the electrostimulation Double-Blind: You state that the EG group received EA at 13 points: 10 scalp and 3 body points-weekly 10 weeks while the CG Control, received Brief needling at LI 4 Hegu for 10 weeks. You state that acupuncturists were also blinded, but given the design of the study, it is unlikely that acupuncturists were indeed blinding, when considering the electro protocol vs the sham protocol. Trained acupuncturists would know the difference in point selection, and it’s unlikely that they would not question shallow needling at Hegu as an effective treatment for cognitive symptoms and / or depression. You also didn’t assess after the study. whether the participants were in fact blinded to treatment, or whether the blinding work for either participants or providers. In the future consider exploring other well proven control for EA, for example by not attempting to blind the acupuncturist and using in the control group a small selection of non-acupuncture points connected to EA for which the wires have been cut but tapped to appear as if the machines work the same as the EG group. Population description and use of medication (Table 2): One major concern with this study, is the inclusion of patients who are on a variety of psychotropic medications that have effects beyond antidepressant treatment. There doesn’t seem to be explicit consideration for the way in which some of these medications may impact cognitive deficits, and thus confound treatment effects. Although the idea of using a naturalistic sample that reflects the complex and varied population experiencing comorbid cognitive symptoms and depression, who are on multiple and different medication regimes is closer to the real world practice in clinical setting, the sample is too small to identify a differential response to treatment, which may be confounded by different medication combinations. This is a limitation of the study that needs to be explicitly included in the discussion section. In the future, if conducting a naturalistic trial, you may need a much larger number of patients with these characteristics to detect conclusive differences between groups. Or in a smaller study, limit acupuncture as an augmentation of one specific class of medications only. Conclusions and Discussion: Your conclusions don’t reflect the results of the analysis; the scores for the CG overall are lower at week 1 and therefore it is possible that this cohort had less severe cognitive decline. Nevertheless, the difference of drop on score of 11.8 in EG vs 18.5 in CG (6.7 seconds) between week 1 and 10 doesn’t seem to be a significant enough difference between EG and CG. Therefore it is hard to conclude in the discussion section that “Findings from the study indicate that electrical stimulation acupuncture can significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group”. The reduction is not significant when compared to CG. Other minor: Provide consistency when describing the trial: it has been conducted, and is not waiting to be conducted (use of pats vs future verb tense) Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Acupuncture, depression, pain, women's health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Schnyer RN. Reviewer Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.161025.r282194 ) The direct URL for this report is: https://f1000research.com/articles/13-479/v1#referee-response-282194 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 26 Jun 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 26 Jun 2024 Author Response Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of ... Continue reading Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of the interventions, training of the acupuncture providers, etc. is incomplete. For example, there is no description of the needling parameters or the intensity / frequency of the electrostimulation - According to the review comment, the STRICTA 2010 checklist was done and attached in the “Data availability” section. Double-Blind: You state that the EG group received EA at 13 points: 10 scalp and 3 body points-weekly 10 weeks while the CG Control, received Brief needling at LI 4 Hegu for 10 weeks. You state that acupuncturists were also blinded, but given the design of the study, it is unlikely that acupuncturists were indeed blinding, when considering the electro protocol vs the sham protocol. Trained acupuncturists would know the difference in point selection, and it’s unlikely that they would not question shallow needling at Hegu as an effective treatment for cognitive symptoms and / or depression. You also didn’t assess after the study. whether the participants were in fact blinded to treatment, or whether the blinding work for either participants or providers. In the future consider exploring other well proven control for EA, for example by not attempting to blind the acupuncturist and using in the control group a small selection of non-acupuncture points connected to EA for which the wires have been cut but tapped to appear as if the machines work the same as the EG group. -According to the review comment about double blind the revision was made as follows; This study was double-blinded RCT. All participants and assessors were unaware of group assignments. at page 5 Line 4 -Thank you for your advice about blinding assessment after the intervention: We agree that assessing the blinding of all participants and providers is beneficial after the experimental phase to reduce bias. However, the authors will incorporate this into future studies for improvement. -Thank you for your advice. about the sham acupuncture The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Population description and use of medication (Table 2): One major concern with this study, is the inclusion of patients who are on a variety of psychotropic medications that have effects beyond antidepressant treatment. There doesn’t seem to be explicit consideration for the way in which some of these medications may impact cognitive deficits, and thus confound treatment effects. Although the idea of using a naturalistic sample that reflects the complex and varied population experiencing comorbid cognitive symptoms and depression, who are on multiple and different medication regimes is closer to the real world practice in clinical setting, the sample is too small to identify a differential response to treatment, which may be confounded by different medication combinations. This is a limitation of the study that needs to be explicitly included in the discussion section. In the future, if conducting a naturalistic trial, you may need a much larger number of patients with these characteristics to detect conclusive differences between groups. Or in a smaller study, limit acupuncture as an augmentation of one specific class of medications only. - According to the review comment, the authors are also concerned about small sample size and confounding factors such as the potential impact of various medications on cognitive deficits. We have included this issue in the study limitations as follows: (page 16 Line 28-41) Furthermore, findings from the present study indicate that electroacupuncture might be able to alleviate subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, compared to the control group. However, the clinical significance of the outcomes of electroacupuncture remains unclear. The authors did not include a healthy control group, focusing instead on patients with MDD who had subjective complaints and were receiving standard pharmacological treatment. The present study aimed to see how these patients responded to adjunctive electroacupuncture. Patients with MDD often receive various psychotropic drugs, such as benzodiazepines and antipsychotics, which can affect cognitive function and serve as confounding factors. Previous research suggested that acupuncture can influence cognitive function, so the study focused on its use as an adjunctive treatment in real-world settings. Future studies may include a much larger number of patients with these characteristics to detect conclusive differences between groups, or in a smaller study, limit acupuncture as an augmentation of one specific class of medications Conclusions and Discussion: Your conclusions don’t reflect the results of the analysis; the scores for the CG overall are lower at week 1 and therefore it is possible that this cohort had less severe cognitive decline. Nevertheless, the difference of drop on score of 11.8 in EG vs 18.5 in CG (6.7 seconds) between week 1 and 10 doesn’t seem to be a significant enough difference between EG and CG. Therefore it is hard to conclude in the discussion section that “Findings from the study indicate that electrical stimulation acupuncture can significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group”. The reduction is not significant when compared to CG. - According to the review comment, the authors are aware of the interpretation of results, which has limitations in generalizability from statistical significance to clinical significance. Therefore, the authors have addressed this issue in the discussion and limitations sections as follow: (page 14 Line 13) Findings from the study indicate that electroacupuncture can statically significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group. -The revision was made by employing past tense. Thank you Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of the interventions, training of the acupuncture providers, etc. is incomplete. For example, there is no description of the needling parameters or the intensity / frequency of the electrostimulation - According to the review comment, the STRICTA 2010 checklist was done and attached in the “Data availability” section. Double-Blind: You state that the EG group received EA at 13 points: 10 scalp and 3 body points-weekly 10 weeks while the CG Control, received Brief needling at LI 4 Hegu for 10 weeks. You state that acupuncturists were also blinded, but given the design of the study, it is unlikely that acupuncturists were indeed blinding, when considering the electro protocol vs the sham protocol. Trained acupuncturists would know the difference in point selection, and it’s unlikely that they would not question shallow needling at Hegu as an effective treatment for cognitive symptoms and / or depression. You also didn’t assess after the study. whether the participants were in fact blinded to treatment, or whether the blinding work for either participants or providers. In the future consider exploring other well proven control for EA, for example by not attempting to blind the acupuncturist and using in the control group a small selection of non-acupuncture points connected to EA for which the wires have been cut but tapped to appear as if the machines work the same as the EG group. -According to the review comment about double blind the revision was made as follows; This study was double-blinded RCT. All participants and assessors were unaware of group assignments. at page 5 Line 4 -Thank you for your advice about blinding assessment after the intervention: We agree that assessing the blinding of all participants and providers is beneficial after the experimental phase to reduce bias. However, the authors will incorporate this into future studies for improvement. -Thank you for your advice. about the sham acupuncture The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Population description and use of medication (Table 2): One major concern with this study, is the inclusion of patients who are on a variety of psychotropic medications that have effects beyond antidepressant treatment. There doesn’t seem to be explicit consideration for the way in which some of these medications may impact cognitive deficits, and thus confound treatment effects. Although the idea of using a naturalistic sample that reflects the complex and varied population experiencing comorbid cognitive symptoms and depression, who are on multiple and different medication regimes is closer to the real world practice in clinical setting, the sample is too small to identify a differential response to treatment, which may be confounded by different medication combinations. This is a limitation of the study that needs to be explicitly included in the discussion section. In the future, if conducting a naturalistic trial, you may need a much larger number of patients with these characteristics to detect conclusive differences between groups. Or in a smaller study, limit acupuncture as an augmentation of one specific class of medications only. - According to the review comment, the authors are also concerned about small sample size and confounding factors such as the potential impact of various medications on cognitive deficits. We have included this issue in the study limitations as follows: (page 16 Line 28-41) Furthermore, findings from the present study indicate that electroacupuncture might be able to alleviate subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, compared to the control group. However, the clinical significance of the outcomes of electroacupuncture remains unclear. The authors did not include a healthy control group, focusing instead on patients with MDD who had subjective complaints and were receiving standard pharmacological treatment. The present study aimed to see how these patients responded to adjunctive electroacupuncture. Patients with MDD often receive various psychotropic drugs, such as benzodiazepines and antipsychotics, which can affect cognitive function and serve as confounding factors. Previous research suggested that acupuncture can influence cognitive function, so the study focused on its use as an adjunctive treatment in real-world settings. Future studies may include a much larger number of patients with these characteristics to detect conclusive differences between groups, or in a smaller study, limit acupuncture as an augmentation of one specific class of medications Conclusions and Discussion: Your conclusions don’t reflect the results of the analysis; the scores for the CG overall are lower at week 1 and therefore it is possible that this cohort had less severe cognitive decline. Nevertheless, the difference of drop on score of 11.8 in EG vs 18.5 in CG (6.7 seconds) between week 1 and 10 doesn’t seem to be a significant enough difference between EG and CG. Therefore it is hard to conclude in the discussion section that “Findings from the study indicate that electrical stimulation acupuncture can significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group”. The reduction is not significant when compared to CG. - According to the review comment, the authors are aware of the interpretation of results, which has limitations in generalizability from statistical significance to clinical significance. Therefore, the authors have addressed this issue in the discussion and limitations sections as follow: (page 14 Line 13) Findings from the study indicate that electroacupuncture can statically significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group. -The revision was made by employing past tense. Thank you Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 26 Jun 2024 Muthita Phanasathit , Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand 26 Jun 2024 Author Response Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of ... Continue reading Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of the interventions, training of the acupuncture providers, etc. is incomplete. For example, there is no description of the needling parameters or the intensity / frequency of the electrostimulation - According to the review comment, the STRICTA 2010 checklist was done and attached in the “Data availability” section. Double-Blind: You state that the EG group received EA at 13 points: 10 scalp and 3 body points-weekly 10 weeks while the CG Control, received Brief needling at LI 4 Hegu for 10 weeks. You state that acupuncturists were also blinded, but given the design of the study, it is unlikely that acupuncturists were indeed blinding, when considering the electro protocol vs the sham protocol. Trained acupuncturists would know the difference in point selection, and it’s unlikely that they would not question shallow needling at Hegu as an effective treatment for cognitive symptoms and / or depression. You also didn’t assess after the study. whether the participants were in fact blinded to treatment, or whether the blinding work for either participants or providers. In the future consider exploring other well proven control for EA, for example by not attempting to blind the acupuncturist and using in the control group a small selection of non-acupuncture points connected to EA for which the wires have been cut but tapped to appear as if the machines work the same as the EG group. -According to the review comment about double blind the revision was made as follows; This study was double-blinded RCT. All participants and assessors were unaware of group assignments. at page 5 Line 4 -Thank you for your advice about blinding assessment after the intervention: We agree that assessing the blinding of all participants and providers is beneficial after the experimental phase to reduce bias. However, the authors will incorporate this into future studies for improvement. -Thank you for your advice. about the sham acupuncture The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Population description and use of medication (Table 2): One major concern with this study, is the inclusion of patients who are on a variety of psychotropic medications that have effects beyond antidepressant treatment. There doesn’t seem to be explicit consideration for the way in which some of these medications may impact cognitive deficits, and thus confound treatment effects. Although the idea of using a naturalistic sample that reflects the complex and varied population experiencing comorbid cognitive symptoms and depression, who are on multiple and different medication regimes is closer to the real world practice in clinical setting, the sample is too small to identify a differential response to treatment, which may be confounded by different medication combinations. This is a limitation of the study that needs to be explicitly included in the discussion section. In the future, if conducting a naturalistic trial, you may need a much larger number of patients with these characteristics to detect conclusive differences between groups. Or in a smaller study, limit acupuncture as an augmentation of one specific class of medications only. - According to the review comment, the authors are also concerned about small sample size and confounding factors such as the potential impact of various medications on cognitive deficits. We have included this issue in the study limitations as follows: (page 16 Line 28-41) Furthermore, findings from the present study indicate that electroacupuncture might be able to alleviate subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, compared to the control group. However, the clinical significance of the outcomes of electroacupuncture remains unclear. The authors did not include a healthy control group, focusing instead on patients with MDD who had subjective complaints and were receiving standard pharmacological treatment. The present study aimed to see how these patients responded to adjunctive electroacupuncture. Patients with MDD often receive various psychotropic drugs, such as benzodiazepines and antipsychotics, which can affect cognitive function and serve as confounding factors. Previous research suggested that acupuncture can influence cognitive function, so the study focused on its use as an adjunctive treatment in real-world settings. Future studies may include a much larger number of patients with these characteristics to detect conclusive differences between groups, or in a smaller study, limit acupuncture as an augmentation of one specific class of medications Conclusions and Discussion: Your conclusions don’t reflect the results of the analysis; the scores for the CG overall are lower at week 1 and therefore it is possible that this cohort had less severe cognitive decline. Nevertheless, the difference of drop on score of 11.8 in EG vs 18.5 in CG (6.7 seconds) between week 1 and 10 doesn’t seem to be a significant enough difference between EG and CG. Therefore it is hard to conclude in the discussion section that “Findings from the study indicate that electrical stimulation acupuncture can significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group”. The reduction is not significant when compared to CG. - According to the review comment, the authors are aware of the interpretation of results, which has limitations in generalizability from statistical significance to clinical significance. Therefore, the authors have addressed this issue in the discussion and limitations sections as follow: (page 14 Line 13) Findings from the study indicate that electroacupuncture can statically significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group. -The revision was made by employing past tense. Thank you Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of the interventions, training of the acupuncture providers, etc. is incomplete. For example, there is no description of the needling parameters or the intensity / frequency of the electrostimulation - According to the review comment, the STRICTA 2010 checklist was done and attached in the “Data availability” section. Double-Blind: You state that the EG group received EA at 13 points: 10 scalp and 3 body points-weekly 10 weeks while the CG Control, received Brief needling at LI 4 Hegu for 10 weeks. You state that acupuncturists were also blinded, but given the design of the study, it is unlikely that acupuncturists were indeed blinding, when considering the electro protocol vs the sham protocol. Trained acupuncturists would know the difference in point selection, and it’s unlikely that they would not question shallow needling at Hegu as an effective treatment for cognitive symptoms and / or depression. You also didn’t assess after the study. whether the participants were in fact blinded to treatment, or whether the blinding work for either participants or providers. In the future consider exploring other well proven control for EA, for example by not attempting to blind the acupuncturist and using in the control group a small selection of non-acupuncture points connected to EA for which the wires have been cut but tapped to appear as if the machines work the same as the EG group. -According to the review comment about double blind the revision was made as follows; This study was double-blinded RCT. All participants and assessors were unaware of group assignments. at page 5 Line 4 -Thank you for your advice about blinding assessment after the intervention: We agree that assessing the blinding of all participants and providers is beneficial after the experimental phase to reduce bias. However, the authors will incorporate this into future studies for improvement. -Thank you for your advice. about the sham acupuncture The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Population description and use of medication (Table 2): One major concern with this study, is the inclusion of patients who are on a variety of psychotropic medications that have effects beyond antidepressant treatment. There doesn’t seem to be explicit consideration for the way in which some of these medications may impact cognitive deficits, and thus confound treatment effects. Although the idea of using a naturalistic sample that reflects the complex and varied population experiencing comorbid cognitive symptoms and depression, who are on multiple and different medication regimes is closer to the real world practice in clinical setting, the sample is too small to identify a differential response to treatment, which may be confounded by different medication combinations. This is a limitation of the study that needs to be explicitly included in the discussion section. In the future, if conducting a naturalistic trial, you may need a much larger number of patients with these characteristics to detect conclusive differences between groups. Or in a smaller study, limit acupuncture as an augmentation of one specific class of medications only. - According to the review comment, the authors are also concerned about small sample size and confounding factors such as the potential impact of various medications on cognitive deficits. We have included this issue in the study limitations as follows: (page 16 Line 28-41) Furthermore, findings from the present study indicate that electroacupuncture might be able to alleviate subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, compared to the control group. However, the clinical significance of the outcomes of electroacupuncture remains unclear. The authors did not include a healthy control group, focusing instead on patients with MDD who had subjective complaints and were receiving standard pharmacological treatment. The present study aimed to see how these patients responded to adjunctive electroacupuncture. Patients with MDD often receive various psychotropic drugs, such as benzodiazepines and antipsychotics, which can affect cognitive function and serve as confounding factors. Previous research suggested that acupuncture can influence cognitive function, so the study focused on its use as an adjunctive treatment in real-world settings. Future studies may include a much larger number of patients with these characteristics to detect conclusive differences between groups, or in a smaller study, limit acupuncture as an augmentation of one specific class of medications Conclusions and Discussion: Your conclusions don’t reflect the results of the analysis; the scores for the CG overall are lower at week 1 and therefore it is possible that this cohort had less severe cognitive decline. Nevertheless, the difference of drop on score of 11.8 in EG vs 18.5 in CG (6.7 seconds) between week 1 and 10 doesn’t seem to be a significant enough difference between EG and CG. Therefore it is hard to conclude in the discussion section that “Findings from the study indicate that electrical stimulation acupuncture can significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group”. The reduction is not significant when compared to CG. - According to the review comment, the authors are aware of the interpretation of results, which has limitations in generalizability from statistical significance to clinical significance. Therefore, the authors have addressed this issue in the discussion and limitations sections as follow: (page 14 Line 13) Findings from the study indicate that electroacupuncture can statically significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group. -The revision was made by employing past tense. Thank you Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 4 VERSION 4 PUBLISHED 17 May 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 4 (revision) 23 Dec 24 Version 3 (revision) 15 Aug 24 read Version 2 (revision) 01 Jul 24 read read Version 1 17 May 24 read read Rosa N Schnyer , The University of Texas, Austin, USA Su-Xia Li , National Institute on Drug Dependence and Beijing Key laboratory of Drug Dependence Research, Peking University, Beijing, China Min Cai , The Fourth Military Medical University, Shaanxi, China Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Cai M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 28 Nov 2024 | for Version 3 Min Cai , The Fourth Military Medical University, Shaanxi, China 0 Views copyright © 2024 Cai M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In the manuscript titled “Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial”, Yindee Boontra et al. reported a randomized controlled trial to investigate the role of EA on cognitive symptoms and quality of life in patients suffered from MDD. Some concerns still need to be issued before the conclusion can be got. 1. About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This is totally not be approved in current ethic protocol. 2. About the sample size, how the authors calculated the sample size? In according the previous study, or just set as a pilot study? I think a scientific hypothesis should be added to identify the current sample size is enough to get the conclusion. 3. How to identify the cognitive dysfunction in MDD patients? The criteria should be issued in the revised manuscript. 4. How the double blinded protocol work? I noticed that the real EA treatment protocol and the sham one are totally different, so how the authors blind the operation during the experiment should be calefied 5. About the discussion section, some citations are focused on cerebral ischemia, I think more citations in relevance of cognitive dysfunction should be citated. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 23 Dec 2024 Muthita Phanasathit, Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand About the trial registration of this study, I noted that the authors registered this trial at February 2, 2024, however, they started to enrolled participants from December 24, 2021. This is totally not be approved in current ethic protocol. Thank you for your valuable feedback regarding the ethics committee approval for our study. We would like to clarify that our research was approved by the Human Research Ethics Committee of Thammasat University (Medicine) on December 24, 2021 (MTU-EC-PS-1-304/64), prior to the data collection phase. This approval adhered to international ethical standards. Regarding the registration of our clinical trial to enhance research transparency and public accessibility, the authors also registered the study in the Thai Clinical Trials Registry (www.clinicaltrials.in.th) with the identifier NCT06239740, which was certified on February 2, 2024. The Manuscript was change from : (First paragraph of Methods) This trial was registered to the ClinicalTrials.gov (NCT06239740), with a registration date of February 2, 2024 and the Human Research Ethics Committee of Thammasat University (Medicine) has granted approval for this medical research study (MTU-EC-PS-1-304/64) with an approval date from December 24, 2021 to December 23, 2022. It is in full compliance with international guidelines such as the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). This study protocol outlined a double-blinded randomized controlled clinical trial (RCT) and pilot study design conducted at a single center, focusing on evaluating the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) who experience cognitive dysfunction when compared to the control group, while both experimental and control groups were under the standard pharmacological treatment for depressive disorder. The present study was conducted during the Coronavirus Disease (COVID-19) pandemic. The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients To this This trial was registered with the Human Research Ethics Committee of Thammasat University (Medicine), which approved the study (approval code: MTU-EC-PS-1-304/64) for the period from December 24, 2021, to December 23, 2022. The study adhered fully to international ethical guidelines, including the Declaration of Helsinki, The Belmont Report, CIOMS Guidelines, and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP). The research protocol detailed a double-blinded, randomized controlled trial (RCT) and pilot study conducted at a single center. The study aimed to evaluate the impact of electroacupuncture on specific cognitive functions in individuals with major depressive disorder (MDD) and cognitive dysfunction, compared to a control group. Both the experimental and control groups received standard pharmacological treatment for depressive disorders. This study was conducted during the Coronavirus Disease (COVID-19) pandemic, necessitating modifications due to safety concerns and social distancing measures. As a result, the study was adapted to a pilot design with 30 participants in each group. The preliminary findings are intended to guide and inform future large-scale research on the effects of electroacupuncture on cognitive dysfunction in patients with MDD. To enhance research transparency and public accessibility, the authors registered the study with the Thai Clinical Trials Registry (www.clinicaltrials.in.th), under the identifier NCT06239740, certified on February 2, 2024. 2. About the sample size, how the authors calculated the sample size? In according the previous study, or just set as a pilot study? I think a scientific hypothesis should be added to identify the current sample size is enough to get the conclusion. Answer: The authors have titled their research "Effects of Electroacupuncture on Cognitive Symptoms in Major Depressive Disorder: A Pilot Study and Randomized Controlled Trial" and have provided details regarding the sample size in the Methods section as follows: "The study was adapted to a pilot study with 30 samples per group due to safety concerns and social distancing measures. The preliminary outcomes aim to inform and guide future main research on the effects of electroacupuncture on cognitive dysfunction in MDD patients." Initially, the study was designed as a randomized controlled trial (RCT) with a larger sample size, calculated based on statistical power analyses derived from previous studies on similar interventions for cognitive dysfunction in major depressive disorder (MDD). However, due to the unforeseen challenges posed by the COVID-19 pandemic, including safety concerns and the necessity for social distancing, the study was adapted to a pilot study with 30 participants per group. This adjusted sample size is intended to provide preliminary estimates of effect size and variability, which are crucial for designing adequately powered studies in the future. As stated by Totton, N., Lin, J., Julious, S. et al. in their review "A Review of Sample Sizes for UK Pilot and Feasibility Studies on the ISRCTN Registry from 2013 to 2020" (Pilot Feasibility Stud 9, 188, 2023; https://doi.org/10.1186/s40814-023-01416-w), the median sample size per arm in pilot and feasibility studies from 2013 to 2020 was found to be 30 participants. 3. How to identify the cognitive dysfunction in MDD patients? The criteria should be issued in the revised manuscript. Answer: In our study, we used the PHQ-9 to assess subjective cognitive complaints, specifically focusing on item 7, which inquires about difficulties related to concentration and memory. Item 7 asks, "Trouble concentrating on things, such as reading the newspaper or watching television." The authors have revised and added these details in the manuscript. The manuscript was changed from A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-516 or DSM-IV-TR criteria,17 and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptom was screened using the 7th item of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9),18 which assesses experiencing trouble concentrating or cognitive problems (e.g., reading or watching TV). To this : A total of 60 eligible participants, aged between 18 and 55 years, with cognitive symptoms resulting from MDD, were recruited from the psychiatry outpatient clinic at Thammasat University Hospital. All participants with MDD and low suicidal risk, diagnosed according to the DSM-5 16 or DSM-IV-TR criteria 17 , and currently receiving standard treatment for at least 3 months from psychiatrists and psychiatric residents, were included. The subjective cognitive symptoms were screened using item 7 of the Thai version of the Patient Health Questionnaire (Thai-PHQ-9) 18 , which assesses difficulties with concentration or cognitive problems. The question in item 7 reads, "Trouble concentrating on things, such as reading the newspaper or watching television." 4. How the double blinded protocol work? I noticed that the real EA treatment protocol and the sham one are totally different, so how the authors blind the operation during the experiment should be calefied The details of the double-blinded protocol are provided in the Methods section as follows: "This study was a double-blinded RCT. All participants and assessors were unaware of group assignments. Before treatment began, participants were unable to distinguish whether they were in the real acupuncture or sham group. They were placed in separate, quiet units on different days." In detail, to prevent any interaction between the experimental and control groups, their appointments were scheduled on different days. The control group was only required to attend the initial session and the follow-up at week 10, during which they were kept in a separate room from the experimental group. This scheduling strategy effectively minimized the possibility of participants from both groups meeting. In summary, the researchers intentionally designed the study to ensure that participants, assessors (who are psychologists), and researchers responsible for statistical data analysis were blinded. 5. About the discussion section, some citations are focused on cerebral ischemia, I think more citations in relevance of cognitive dysfunction should be citated. The discussion about cognitive dysfunction was added in the manuscript Cognitive impairment in patients with depressive disorder is linked to inflammation. When inflammation occurs in the central nervous system, known as neuroinflammation, it triggers the production of pro-inflammatory cytokines, tumor necrosis factor-a (TNF-a), chemokines, small-molecule messengers such as prostaglandins and nitric oxide (NO), as well as reactive oxygen species from innate immune cells in the CNS. This oxidative stress is associated with damage to DNA, RNA, lipids, and proteins, with pyramidal neurons in the hippocampus being particularly sensitive to energy deficits. This vulnerability contributes to cognitive impairment. Moreover, oxidative stress leads to a decrease in the expression and function of tropomyosin receptor kinase B (Trk B), a receptor that is crucial for brain-derived neurotrophic factor (BDNF), which plays an essential role in promoting brain plasticity. View more View less Competing Interests none reply Respond Report a concern Cai M. Peer Review Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.170190.r326928) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-479/v3#referee-response-326928 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Li S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 Jul 2024 | for Version 2 Su-Xia Li , National Institute on Drug Dependence and Beijing Key laboratory of Drug Dependence Research, Peking University, Beijing, China 0 Views copyright © 2024 Li S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I think that most of the reviewer's concerns have been addressed. As for the explanation for “Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable?”. Authors explanation is not reasonable. Firstly, the baseline subjective cognitive function in the control group were not less severe than those in the experimental group, it is comparable. Secondly, the idea of ceiling effect is also unreasonable and inappropriate. In fact, authors have not explained anything for this problem. Additionally, in the Discussion section, the author should also discuss in depth the reasons for the lack of improvement in all objective indicators. In the abstract, the author used different words to describe the drug treatment taken by the two groups of subjects. In the main text, the two groups were actually the same, and it was suggested to use the same words to describe them. In the Table 2, the number of patients in CG totally 27 who took SSRIs, Instead, the number of patients who took Sertraline, Fluoxetine and Escitalopram combined was 28 In the Table 3, both EG (n=30) and CG (n=30) should be placed in the correct position, corresponding to their respective data. Competing Interests No competing interests were disclosed. Reviewer Expertise Psychiatry，Depression I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 15 Aug 2024 Muthita Phanasathit, Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand Response to Reviewers 1. Reviewer Comment : "I think that most of the reviewer's concerns have been addressed. As for the explanation for ‘Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable?’" Response : The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Therefore, we have added the following explanation to the Discussion section: “However, even though the researcher tried to design sham acupuncture using very small and short needles, believing they might not have any effect at the acupuncture points, the points used were He gu points, which could influence the placebo effect. Therefore, designing sham acupuncture should avoid using actual acupuncture points, as this may better differentiate between the two groups.” 2. Reviewer Comment : "Additionally, in the Discussion section, the author should also discuss in depth the reasons for the lack of improvement in all objective indicators." Response : The authors have expanded the Discussion section to provide a more in-depth explanation of the low-dose regimen and its effects on neurotropins, as follows: “ Due to its ability to stimulate the expression of GSK-3β/PP2A, acupuncture can enhance neurogenesis in the hippocampus. This results in improved cerebral blood flow in the ischemic cortex, hippocampus, and striatum. Additionally, acupuncture increases the levels of neurotrophic factors such as BDNF and VEGF (brain-derived neurotrophic factor and vascular endothelial growth factor). BDNF and VEGF play crucial roles in stimulating neurogenesis, promoting the formation of new neurons, and facilitating neuronal migration in neurogenic areas. Moreover, VEGF itself is a significant contributor to the angiogenic process. [1] During ischemic conditions in the brain, the body naturally responds by promoting the formation of new blood vessels, serving as an essential neuroprotective factor. [2] Electroacupuncture has been shown to stimulate the release of VEGF, which can be detected in peripheral blood, and to increase cerebral blood flow and cerebral blood volume. This also improves motor function in patients with ischemic stroke. [3] Additionally, experiments on rats have demonstrated that acupuncture can stimulate the release of nitric oxide (NO) and reduce the release of angiotensin II, leading to greater dilation of cerebral blood vessels. [4, 5] When the release of these substances is stimulated, it is found that the half-life of BDNF in the brain is unknown. However, the half-life of nerve growth factor (NGF), a neurotrophin of similar size and charge, is reported to be less than one hour. [6] Since BDNF and NGF both activate the Trk family of receptors, it is likely that the half-life of BDNF is also on the order of hours. Therefore, electroacupuncture should be administered relatively frequently to maintain effective levels of BDNF or VEGF. It is recommended to apply the treatment at a high dose, which means more than twice a week. This may explain why the researcher's study did not yield significant results. ” References : 1. Kim, Y.R., et al., Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One, 2014. 9(2): p. e90000 DOI: 10.1371/journal.pone.0090000. 2. Vallon, M., et al., Developmental and pathological angiogenesis in the central nervous system. Cell Mol Life Sci, 2014. 71(18): p. 3489-506 DOI: 10.1007/s00018-014-1625-0. 3. Zheng, C., et al., A randomized controlled trial comparing electroacupuncture with manual acupuncture for motor function recovery after ischemic stroke. European Journal of Integrative Medicine, 2018. 22: p. 76-80. 4. Kim, J.H., et al., Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice. PLoS One, 2013. 8(2): p. e56736 DOI: 10.1371/journal.pone.0056736. 5. Li, J., et al., Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats. BMC Complement Altern Med, 2014. 14: p. 441 DOI: 10.1186/1472-6882-14-441. 6. Krewson, C.E. and W.M. Saltzman, Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain Res, 1996. 727(1-2): p. 169-81 DOI: 10.1016/0006-8993(96)00378-2. 3. Reviewer Comment : "In the abstract, the author used different words to describe the drug treatment taken by the two groups of subjects. In the main text, the two groups were actually the same, and it was suggested to use the same words to describe them." Response : The authors have revised the abstract for consistency. It now reads: “Participants were divided into two groups: the electroacupuncture group combined with standard pharmacological treatment (EG; n=30) and the control group receiving standard pharmacological treatment with placebo acupuncture (CG; n=30).” 4. Reviewer Comment : "In Table 2, the number of patients in CG totally 27 who took SSRIs. Instead, the number of patients who took Sertraline, Fluoxetine, and Escitalopram combined was 28." Response : The authors have added the following note under Table 2 to clarify: “ Note: Some patients received multiple types of antidepressants concurrently or in combination with other drug classes such as benzodiazepines or antipsychotics. Some patients did not receive SSRIs as the primary medication but were prescribed other types of antidepressants. The medication administration followed the guidelines set by the American Psychological Association (2019) in the Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. ” 5. Reviewer Comment : "In Table 3, both EG (n=30) and CG (n=30) should be placed in the correct position, corresponding to their respective data." Response : The authors have corrected the placement of EG (n=30) and CG (n=30) at the header of Table 3. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Li SX. Peer Review Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.168555.r297844) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-479/v2#referee-response-297844 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Schnyer R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 16 Jul 2024 | for Version 2 Rosa N Schnyer , School of Nursing, The University of Texas, Austin, Texas, USA 0 Views copyright © 2024 Schnyer R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Although most comments from the reviewers have been addressed, the authors still describe the study as a double-blind study. It is not, or rather, it is impossible to assess if it fact the double blind worked. Please add a clause to explain how blinding was neither assessed and may not have been necessarily accomplished. It is important not to claim that a study is double, unless this has been effectively established. The authors need to remove the double blind statement, and explain that they set to conduct a double-blind study but since blinding wasn't assessed they cannot be sure that acupuncturists were in fact blind. Blinding of the treatment providers is not essential to the conclusions of the study but a caveat needs to be included. Thank you Competing Interests No competing interests were disclosed. Reviewer Expertise Acupuncture, depression, pain, women's health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Schnyer RN. Peer Review Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.168555.r297843) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-479/v2#referee-response-297843 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Li S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 11 Jun 2024 | for Version 1 Su-Xia Li , National Institute on Drug Dependence and Beijing Key laboratory of Drug Dependence Research, Peking University, Beijing, China 0 Views copyright © 2024 Li S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 1. The treatment plan for the two groups of patients in the Abstract is different from the description in the Methods section. 2. A healthy control group should be included in the study protocol. On the one hand, does the cognitive function of patients with MDD differ from that of healthy controls at baseline. On the other hand, after treatment, whether the cognitive function of patients is restored, and how much differences between healthy controls and patients with depression. These can only be achieved in the presence of a healthy control group. 3. For the electroacupuncture group, the authors needed to describe the entire treatment process in detail. Such as the duration of each treatment, how many days consecutive per week, the specific depth of the acupuncture therapy, and how strong the current intensity is? 4. How does the Sham group work？The authors need to describe in detail the specific operation of the sham acupuncture control group, how long the acupuncture of He gu point lasted for each treatment, and how many consecutive days were in the first week and the 10th week. The specific depth of the acupuncture therapy, and how strong the current intensity is? 5. For the comparison of the two groups of indicators at the end point, the existence of time effect should be considered. It is unreasonable and unscientific to use a simple t -test between two groups. 6. Authors defined that at baseline is T0, at the ten-week intervention is T10. However, in Results section, baseline is described as T1. The author's description of the same event should be uniform. 7. Abbreviations in the table should be explained at the bottom of the table. 8. Many measures of cognitive function did not differ between the two groups after 10 weeks of treatment. Is it because the settings of the sham group are unreasonable? Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Psychiatry，Depression I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 26 Jun 2024 Muthita Phanasathit, Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand - According to the review comment, the revision of abstract was made. Page 2 Line 4-8 in abstract - Thank you for your advice. We agree that a healthy control should be included in experimental studies aiming to assess the safety and efficacy of new interventions and medications. However, a literature review on the use of electroacupuncture has provided evidence of its safety and efficacy in treating patients with schizophrenia, brain injury, and stroke who have cognitive impairment. The researchers aimed to study the effects of electroacupuncture on specific cognitive functions in subjects experiencing cognitive dysfunction associated with MDD. Including healthy controls without subjective cognitive complaints in this study might not address the research question adequately. Therefore, we recruited MDD patients with cognitive dysfunction receiving sham acupuncture and standard treatment as a comparator instead. - According to the review comment, the revision was made in the method / intervention session. (page 4, Line 12-31) - Due to the outcome from this pilot study (n=30 per group), the data had a non-normal distribution. A comparison between the electroacupuncture and control groups was conducted using the Mann-Whitney U test, which compared the median differences of the outcomes. Differences between groups were calculated by comparing baseline (T1) and endpoint (T10) values. Page 6 Line 16 -According to the review comment about the Base line , the revision was made as T1.(Page 6 line 11) - All abbreviations in the table were explained at the bottom of all tables. (table 1 and table 3 ) - According to Sham setting : The authors hypothesized that the reason many measures of cognitive function did not differ between the two groups after 10 weeks of treatment was due to two factors: firstly, the baseline subjective cognitive function in the control group were less severe than those in the experimental group; and secondly, the ceiling effect, as the baseline scores of executive function, subjective cognitive complaints, and quality of life were relatively high in both groups. These points have been addressed in the discussion section. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Li SX. Peer Review Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.161025.r282200) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-479/v1#referee-response-282200 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Schnyer R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Jun 2024 | for Version 1 Rosa N Schnyer , School of Nursing, The University of Texas, Austin, Texas, USA 0 Views copyright © 2024 Schnyer R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors set out to conduct a rigorous, double-blind RCT on the effect electro-acupuncture on cognitive symptoms in major depressive disorder. The subject is highly relevant clinically and the study is timely, as it is critical to identify strategies to manage cognitive and mood symptoms which affect a large segment of the population worldwide. There are some key issues that need to be addressed in the reporting of the results, some critical considerations in future proposals on this subject: Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of the interventions, training of the acupuncture providers, etc. is incomplete. For example, there is no description of the needling parameters or the intensity / frequency of the electrostimulation Double-Blind: You state that the EG group received EA at 13 points: 10 scalp and 3 body points-weekly 10 weeks while the CG Control, received Brief needling at LI 4 Hegu for 10 weeks. You state that acupuncturists were also blinded, but given the design of the study, it is unlikely that acupuncturists were indeed blinding, when considering the electro protocol vs the sham protocol. Trained acupuncturists would know the difference in point selection, and it’s unlikely that they would not question shallow needling at Hegu as an effective treatment for cognitive symptoms and / or depression. You also didn’t assess after the study. whether the participants were in fact blinded to treatment, or whether the blinding work for either participants or providers. In the future consider exploring other well proven control for EA, for example by not attempting to blind the acupuncturist and using in the control group a small selection of non-acupuncture points connected to EA for which the wires have been cut but tapped to appear as if the machines work the same as the EG group. Population description and use of medication (Table 2): One major concern with this study, is the inclusion of patients who are on a variety of psychotropic medications that have effects beyond antidepressant treatment. There doesn’t seem to be explicit consideration for the way in which some of these medications may impact cognitive deficits, and thus confound treatment effects. Although the idea of using a naturalistic sample that reflects the complex and varied population experiencing comorbid cognitive symptoms and depression, who are on multiple and different medication regimes is closer to the real world practice in clinical setting, the sample is too small to identify a differential response to treatment, which may be confounded by different medication combinations. This is a limitation of the study that needs to be explicitly included in the discussion section. In the future, if conducting a naturalistic trial, you may need a much larger number of patients with these characteristics to detect conclusive differences between groups. Or in a smaller study, limit acupuncture as an augmentation of one specific class of medications only. Conclusions and Discussion: Your conclusions don’t reflect the results of the analysis; the scores for the CG overall are lower at week 1 and therefore it is possible that this cohort had less severe cognitive decline. Nevertheless, the difference of drop on score of 11.8 in EG vs 18.5 in CG (6.7 seconds) between week 1 and 10 doesn’t seem to be a significant enough difference between EG and CG. Therefore it is hard to conclude in the discussion section that “Findings from the study indicate that electrical stimulation acupuncture can significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group”. The reduction is not significant when compared to CG. Other minor: Provide consistency when describing the trial: it has been conducted, and is not waiting to be conducted (use of pats vs future verb tense) Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? No source data required Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Acupuncture, depression, pain, women's health I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 26 Jun 2024 Muthita Phanasathit, Department of Psychiatry, Thammasat University, Pathum Thani, 12120, Thailand Protocols: Please refer to and incorporate the STRICTA guidelines and include the checklist https://stricta.info/ STRICTA Standards for Reporting Clinical Trials of Acupuncture, which is an official extension of the CONSORT criteria. Description of the interventions, training of the acupuncture providers, etc. is incomplete. For example, there is no description of the needling parameters or the intensity / frequency of the electrostimulation - According to the review comment, the STRICTA 2010 checklist was done and attached in the “Data availability” section. Double-Blind: You state that the EG group received EA at 13 points: 10 scalp and 3 body points-weekly 10 weeks while the CG Control, received Brief needling at LI 4 Hegu for 10 weeks. You state that acupuncturists were also blinded, but given the design of the study, it is unlikely that acupuncturists were indeed blinding, when considering the electro protocol vs the sham protocol. Trained acupuncturists would know the difference in point selection, and it’s unlikely that they would not question shallow needling at Hegu as an effective treatment for cognitive symptoms and / or depression. You also didn’t assess after the study. whether the participants were in fact blinded to treatment, or whether the blinding work for either participants or providers. In the future consider exploring other well proven control for EA, for example by not attempting to blind the acupuncturist and using in the control group a small selection of non-acupuncture points connected to EA for which the wires have been cut but tapped to appear as if the machines work the same as the EG group. -According to the review comment about double blind the revision was made as follows; This study was double-blinded RCT. All participants and assessors were unaware of group assignments. at page 5 Line 4 -Thank you for your advice about blinding assessment after the intervention: We agree that assessing the blinding of all participants and providers is beneficial after the experimental phase to reduce bias. However, the authors will incorporate this into future studies for improvement. -Thank you for your advice. about the sham acupuncture The authors believe that sham acupuncture lacks efficacy and, due to safety concerns, aim to minimize injury and unnecessary infection risks from acupuncture needle insertion at non-acupuncture points connected to EA through wires. Population description and use of medication (Table 2): One major concern with this study, is the inclusion of patients who are on a variety of psychotropic medications that have effects beyond antidepressant treatment. There doesn’t seem to be explicit consideration for the way in which some of these medications may impact cognitive deficits, and thus confound treatment effects. Although the idea of using a naturalistic sample that reflects the complex and varied population experiencing comorbid cognitive symptoms and depression, who are on multiple and different medication regimes is closer to the real world practice in clinical setting, the sample is too small to identify a differential response to treatment, which may be confounded by different medication combinations. This is a limitation of the study that needs to be explicitly included in the discussion section. In the future, if conducting a naturalistic trial, you may need a much larger number of patients with these characteristics to detect conclusive differences between groups. Or in a smaller study, limit acupuncture as an augmentation of one specific class of medications only. - According to the review comment, the authors are also concerned about small sample size and confounding factors such as the potential impact of various medications on cognitive deficits. We have included this issue in the study limitations as follows: (page 16 Line 28-41) Furthermore, findings from the present study indicate that electroacupuncture might be able to alleviate subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, compared to the control group. However, the clinical significance of the outcomes of electroacupuncture remains unclear. The authors did not include a healthy control group, focusing instead on patients with MDD who had subjective complaints and were receiving standard pharmacological treatment. The present study aimed to see how these patients responded to adjunctive electroacupuncture. Patients with MDD often receive various psychotropic drugs, such as benzodiazepines and antipsychotics, which can affect cognitive function and serve as confounding factors. Previous research suggested that acupuncture can influence cognitive function, so the study focused on its use as an adjunctive treatment in real-world settings. Future studies may include a much larger number of patients with these characteristics to detect conclusive differences between groups, or in a smaller study, limit acupuncture as an augmentation of one specific class of medications Conclusions and Discussion: Your conclusions don’t reflect the results of the analysis; the scores for the CG overall are lower at week 1 and therefore it is possible that this cohort had less severe cognitive decline. Nevertheless, the difference of drop on score of 11.8 in EG vs 18.5 in CG (6.7 seconds) between week 1 and 10 doesn’t seem to be a significant enough difference between EG and CG. Therefore it is hard to conclude in the discussion section that “Findings from the study indicate that electrical stimulation acupuncture can significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group”. The reduction is not significant when compared to CG. - According to the review comment, the authors are aware of the interpretation of results, which has limitations in generalizability from statistical significance to clinical significance. Therefore, the authors have addressed this issue in the discussion and limitations sections as follow: (page 14 Line 13) Findings from the study indicate that electroacupuncture can statically significantly reduce subjective cognitive complaints in individuals with mild to moderate depressive symptoms and cognitive issues, when compared to the control group. -The revision was made by employing past tense. Thank you View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Schnyer RN. Peer Review Report For: Effects of electroacupuncture on cognitive symptoms in major depressive disorder: a pilot study and randomized controlled trial [version 4; peer review: 1 approved, 2 approved with reservations] . F1000Research 2024, 13 :479 ( https://doi.org/10.5256/f1000research.161025.r282194) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-479/v1#referee-response-282194 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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