Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial

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Non-phamacological strategies such as transcranial direct current stimulation (tDCS) and osteopathic manual therapy show promise, but their combined efficacy remains underexplored. This study aims to evaluate the effectiveness of combining active tDCS with physiotherapy compared to sham tDCS plus physiotherapy in patients with chronic migraine. Methods A single-center, single-blind randomized controlled trial was conducted at Sri Aurobindo University, India. A total of 160 participants with chronic migraine were randomized into two groups: Experimental Group A (Active tDCS + Cranio-cervical osteopathic therapy) and Control Group B (sham tDCS + Cranio-cervical osteopathic therapy). Interventions were delivered over six weeks (18 sessions). The outcomes were pain intensity measured by the Visual Analogue Scale (VAS), headache frequency and duration, pressure pain threshold (PPT), balance (MiniBESTest), quality of life (SF-36), Migraine Disability Assessment Score (MIDAS), Pittsburgh Sleep Quality Index (PSQI), Migraine Symptom Severity Score (MSSS). Statistical analyses employed ANCOVA and linear mixed-effects models with false discovery rate correction. Results Compared with controls, GroupA demonstrated significantly greater reduction in VAS (= 2.10, p < 0.001, d = 1.15), headache frequency (∆ = 1.85/week, p < 0.001) and duration (∆ =9.45 minutes/day, p < 0.001). Significant improvements were also observed in trapezius PPT, balance (+4.30 points, p < 0.001), quality of life, dsability and symptom severity. No between-group differences was noted for the sub-occipital PPT, anterior scalene PPT and PSQI. Conclusion Active tDCS combined with physiotherapy provides superior clinical benefits over sham stimulation, reducing migraine intensity, frequency, disability and improving function and qulaity of life. This multimodal approach addresses both central sensitization and peripheral dysfunction, support its role as an effective non-phamacological strategy in migrain management. Trial Registration Enrolled in the International Clinical Trials Registry on December 20, 2021 (CTRI/2021/12/038734). On July 18, 2020, the Sri Aurobindo Institute of Allied Health & Paramedical Sciences’ Research & Ethical Committee gave its approval. 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F1000Research 2026, 15 :84 ( https://doi.org/10.12688/f1000research.171391.1 ) 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 Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial [version 1; peer review: 1 approved with reservations] Deepti Agrawal Garg https://orcid.org/0000-0001-7428-3769 1 , Ritika Vyas https://orcid.org/0009-0002-9589-0175 2 , Arpita Gehlot 3 , [...] A Yashudas https://orcid.org/0000-0001-8180-8412 1 , Anmoldeep Kaur 4 , Kiran Arora 4 , Gurleen Kaur https://orcid.org/0000-0001-7351-8765 4 , Ramesh Chandra Patra https://orcid.org/0000-0001-5287-8833 1 , Anand Misra 3 Deepti Agrawal Garg https://orcid.org/0000-0001-7428-3769 1 , Ritika Vyas https://orcid.org/0009-0002-9589-0175 2 , [...] Arpita Gehlot 3 , A Yashudas https://orcid.org/0000-0001-8180-8412 1 , Anmoldeep Kaur 4 , Kiran Arora 4 , Gurleen Kaur https://orcid.org/0000-0001-7351-8765 4 , Ramesh Chandra Patra https://orcid.org/0000-0001-5287-8833 1 , Anand Misra 3 PUBLISHED 20 Jan 2026 Author details Author details 1 Physiotherapy Department, Lovely Professional University Faculty of Applied Medical Sciences, Phagwara, Punjab, 144411, India 2 Physiotherapy Department, Bhandari Group of Hospital and Institute, Indore, Madhya Pradesh, India 3 Allied Health & Paramedical Sciences, Sri Aurobindo Institute of Allied Health & Paramedical Sciences, Jabalpur, Madhya Predesh, India 4 Physiotherapy department, Khalsa Amritsar main campus, Amritsar, Punjab, India Deepti Agrawal Garg Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Ritika Vyas Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Arpita Gehlot Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing A Yashudas Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Anmoldeep Kaur Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Kiran Arora Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Gurleen Kaur Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Ramesh Chandra Patra Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Supervision, Validation, Writing – Original Draft Preparation Anand Misra Roles: Formal Analysis, Investigation, Methodology, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Migraine is a leading cause of disability worldwide, often complicated by cervical dysfunction and central sensitization. Non-phamacological strategies such as transcranial direct current stimulation (tDCS) and osteopathic manual therapy show promise, but their combined efficacy remains underexplored. This study aims to evaluate the effectiveness of combining active tDCS with physiotherapy compared to sham tDCS plus physiotherapy in patients with chronic migraine. Methods A single-center, single-blind randomized controlled trial was conducted at Sri Aurobindo University, India. A total of 160 participants with chronic migraine were randomized into two groups: Experimental Group A (Active tDCS + Cranio-cervical osteopathic therapy) and Control Group B (sham tDCS + Cranio-cervical osteopathic therapy). Interventions were delivered over six weeks (18 sessions). The outcomes were pain intensity measured by the Visual Analogue Scale (VAS), headache frequency and duration, pressure pain threshold (PPT), balance (MiniBESTest), quality of life (SF-36), Migraine Disability Assessment Score (MIDAS), Pittsburgh Sleep Quality Index (PSQI), Migraine Symptom Severity Score (MSSS). Statistical analyses employed ANCOVA and linear mixed-effects models with false discovery rate correction. Results Compared with controls, GroupA demonstrated significantly greater reduction in VAS (= 2.10, p < 0 . 001, d = 1.15), headache frequency (∆ = 1.85/week, p < 0 . 001) and duration (∆ =9.45 minutes/day, p < 0 . 001). Significant improvements were also observed in trapezius PPT, balance (+4.30 points, p < 0 . 001), quality of life, dsability and symptom severity. No between-group differences was noted for the sub-occipital PPT, anterior scalene PPT and PSQI. Conclusion Active tDCS combined with physiotherapy provides superior clinical benefits over sham stimulation, reducing migraine intensity, frequency, disability and improving function and qulaity of life. This multimodal approach addresses both central sensitization and peripheral dysfunction, support its role as an effective non-phamacological strategy in migrain management. Trial Registration Enrolled in the International Clinical Trials Registry on December 20, 2021 (CTRI/2021/12/038734). On July 18, 2020, the Sri Aurobindo Institute of Allied Health & Paramedical Sciences’ Research & Ethical Committee gave its approval. READ ALL READ LESS Keywords Chronic Migraine, transcranial direct current stimulation, physiotherapy, osteo- pathic manual techniques, non-pharmacological therapy Corresponding Author(s) Ramesh Chandra Patra ( [email protected] ) Close Corresponding author: Ramesh Chandra Patra Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2026 Agrawal Garg D 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: Agrawal Garg D, Vyas R, Gehlot A et al. Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial [version 1; peer review: 1 approved with reservations] . F1000Research 2026, 15 :84 ( https://doi.org/10.12688/f1000research.171391.1 ) First published: 20 Jan 2026, 15 :84 ( https://doi.org/10.12688/f1000research.171391.1 ) Latest published: 20 Jan 2026, 15 :84 ( https://doi.org/10.12688/f1000research.171391.1 ) 1 Introduction 1.1 Burden of migraine Migraine affects over one billion people worldwide and is the second leading cause of years lived with disability in those below 50 years of age, making it a highly incapacitating neurological condition. 1 According to Sic et al., frequent assaults lower quality of life and place a heavy financial burden on society due to missed output and medical expenses. 2 Clinical overlap with cervicogenic headache, which frequently manifests as cranial autonomic symptoms and neck pain, makes diagnosis more difficult and can result in incorrect classification and ineffective treatment. 3 So it’s important to address both cervical and cranial factors. By combining peripheral cervical biomechanic restoration with central modulation of cortical excitability, transcranial direct current stimulation (tDCS) in conjunction with cranio-cervical osteopathic techniques presents a novel strategy that reduces nociceptive input and central sensitization in a synergistic manner. 4 , 5 1.2 Pathophysiological considerations The trigeminovascular system, cerebral pain networks, and peripheral nociceptive inputs interact intricately in the neurological basis of migraine. Cross-sensitization between cranial and cervical nociceptors is facilitated by the convergence of afferents from the trigeminal nerve and upper cervical spinal nerves in the trigemino-cervical complex (TCC), a crucial relay structure. 5 By sensitizing neurons in the TCC and encouraging central hyperexcitability, continuous input from cervical structures like facet joints, muscles, or ligaments may make migraines worse. 6 Additional evidence connecting cervical deficits to altered cortical excitability and pain sensitivity in migraine and associated diseases comes from newly developed neuroimaging and neurochemical research. 7 These results lend credence to the idea that cervical afferents play a role in chronicity, allodynia, and migraine beginning. Additionally, the importance of neuro-immune interactions is becoming more well acknowledged. A feedback loop that prolongs pain and impairment is created when mechanical dysfunctions interact with inflammation, glial activation, and autonomic dysregulation. 4 Crucially, migraine chronification is also influenced by the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. The frequency and severity of headaches have been associated with dysregulated stress responses, which supports treatments that alter both the central and peripheral nervous systems. 2 When combined, these findings demonstrate the need for multimodal therapies that can concurrently address the neurophysiological, biomechanical, and autonomic factors that contribute to migraine. 1.3 Current non-pharmacological approaches in migraine 1.3.1 Manual therapy and osteopathic interventions Non-Pharmacological management strategies have gained increasing interest due to limitations of pharmacotherapy, including side effects, contraindications and medication overuse headaches. Osteopathic and manual therapy methods can enhance function and decrease nociceptive input, particularly in patients with cervical comorbidities. 4 , 8 In order to modulate cortical excitability, restore biomechanics, and attenuate both central sensitization and peripheral triggers, a novel approach combining transcranial direct current stimulation (tDCS) with cranio-cervical osteopathic interventions leverages both central and peripheral mechanisms. 4 , 5 Migraine frequency, severity, and related disability have all been shown to decrease with manual therapy. 8 By focusing on cranio-cervical structures, osteopathic manipulative treatments seek to normalize afferent input to the TCC, decrease mechanical dysfunction, and restore mobility. Due to their direct convergence with trigeminal afferents, there is evidence that modifications at the C2-C3 segments can be especially helpful. 9 Spinal and cranio-cervical treatments have been shown to be successful headache management techniques in recent studies. When it comes to cervicogenic headache, instrument-assisted soft tissue mobilization and spinal manipulation provide more advantages than each therapy alone. 10 Additionally, systematic evaluations show that manual treatment improves functional results, including mandibular mobility, and decreases discomfort in the craniomandibular and cervical regions. 11 According to Barsotti et al., 4 osteopathic therapies are mechanobiologically based and have the ability to affect central pain regulation and neuroimmune pathways. However, inconsistent results are a reflection of differences in study designs, patient characteristics and protocols. 12 1.3.2 Neuromodulation therapies Neuromodulation is now another effective non-pharmacological method for treating headaches. Low-amplitude electrical currents are used in transcranial direct current stimulation (tDCS), a non-invasive brain stimulation method, to alter cortical excitability and plasticity. Affecting central pain networks, anodal stimulation over motor or prefrontal cortices can lessen headache frequency and intensity. 1 The foundation for future efficacy trials is laid by preliminary safety and feasibility studies that show tDCS in conjunction with conservative therapies is both feasible and well tolerated in individuals with cervicogenic headaches. 13 By altering neuronal and muscle responses, other neuromodulatory techniques, including repetitive neuromuscular magnetic stimulation (rNMS), have also demonstrated promising outcomes in headache populations. 14 , 15 Despite these developments, the evidence is still preliminary, and the best stimulation regimens, treatment lengths, and patient subgroups with the highest potential for benefit have not yet been determined. Additionally, peripheral dysfunctions, which frequently coexist in migraine sufferers, are not immediately addressed by tDCS, despite the fact that it primarily treats cortical excitability. This drawback offers justification for combining neuromodulation with osteopathic and other peripheral therapies. 4 , 5 1.4 Rationale for a combined approach 1.4.1 Neurophysiological and biomechanical synergy Integrating tDCS with cranio-cervical osteopathic methods is a new treatment approach that takes advantage of the complementing central and peripheral modulation processes. While osteopathic therapies restore biomechanical function and decrease nociceptive drive from cervical tissues, tDCS affects cortical excitability and reconfiguration of the pain network. 13 , 14 According to Hong et al., and Sic et al., these modalities may work in concert to reduce peripheral stimuli and attenuate central sensitization. 2 , 16 Neuroplasticity plays a central role in this potential synergy. By enhancing cortical responsiveness to afferent input, tDCS may amplify the therapeutic effects of manual therapy, facilitating long-term modulation of pain pathways. Concurrently, cranio-cervical manipulations may reduces abnormal input into the TCC, therapy lowering the burden of nociceptive stimuli reaching sensitized cortical areas. 16 Additionally, by targeting stress-related processes connected to migraine chronification, these techniques may aid in the regulation of autonomic dysfunction and the HPA axis. 2 1.5 Evidence gap Despite strong theoretical underpinnings, evidence for the combined use of tDCS and osteopathic/manual therapy in migraine remains scarce. Current research typically assesses each modality separately. For instance, feasibility studies stress the safety of tDCS in conjunction with conservative treatment, 13 while systematic reviews highlight the advantages of manual therapy. 12 There aren’t enough studies, though, that examine their combined effectiveness directly. Furthermore, multimodal interventions that target both central and peripheral systems appear to be more beneficial than unimodal therapies, according to prior studies in relevant fields such cervico-vestibular rehabilitation following traumatic brain injury. 17 However, the additive or synergistic effects of combining tDCS with cranio-cervical osteopathic treatments in migraine have not yet been specifically investigated in a randomized controlled research. This disparity offers a great chance to develop mechanism-driven, individualized non-pharmacological treatment for migraineurs. 1.6 Study objective 1.6.1 Primary objective To evaluate the efficacy of combining tDCS with cranio-cervical osteopathic techniques in reducing migraine frequency and intensity compared to control interventions. 1.6.2 Secondary objective To assess improvements in headache-related disability, quality of life and cervical function. 2. Methodology 2.1 Study design and setting This single-center and single-blind randomized controlled trial was carried out from 2020 to 2022 at Sri Aurobindo University in Indore, Madhya Pradesh, India. It examined the efficacy of transcranial direct current stimulation (tDCS) in conjunction with traditional physiotherapy against placebo in patients who experienced chronic migraines. 2.1.1 Ethical approval and trial registration The current randomized controlled clinical study complied with the Declaration of Helsinki’s (World Medical Association, 2013) ethical guidelines for studies involving human subjects. Ethical approval was received from the Institutional Ethics Committee of Sri Aurobindo Medical College and P.G. Institute, Indore (Ethical No. SAIMS/IEC/2020/07/21: approval dated 18 July 2020). The study was prospectively registered with the Clinical Trials Registry of India (CTRI/2021/12/038734); dated 20 December 2021. Before being included, each participant was briefed on the goals, methods, possible hazards, and advantages of the study, and written informed consent was acquired. Parents or legal guardians were not required as all participants were adult above 18 years old. 2.2 Randomization and blinding A computer-generated sequence was used to randomly assign participants, and an independent researcher constructed sealed opaque envelopes to conceal the allocation. In order to minimize measurement bias, the study was single-blind, meaning that both participants and result assessors were blinded to group assignment. The institution’s outpatient clinic served as the source of recruitment. The CONSORT 2010 standards were followed in the reporting of this study. 2.3 Participant A total of 170 eligible individuals were selected from a total of 200 screened participants, and they were randomized into two groups: an experimental group (n = 85) and a control group (n = 85). There were 160 individuals in the final analysis, 80 in each group ( Figure 1 ). Inclusion Criteria comprised migraineurs with chronic migraines (>15 days per month) or episodic migraines (≤15 days per month). Additionally, it was recorded what percentage of subjects experienced aura compared to those who did not. People with migraines between the ages of 18 and 50 who indicated a desire to participate and had no coexisting medical conditions were included in the trial. The study also included participants who were able to keep their promises to attend the mandatory evaluation sessions and adhere to the intervention procedure. Exclusion Criteria included participants with neurological problems, musculoskeletal injuries, chronic pain issues, or those using drugs that could impair balance or pain perception. Additionally, individuals were not allowed to participate if they were pregnant, had severe physical problems, or were unable to follow the study’s rules. Figure 1. CONSORT flow diagram showing enrollment, allocation, duration of intervention and analyses. 2.4 Sample size calculation G*Power (v3.1.9.2) was used to determine the sample size based on preliminary Visual Analogue Scale (VAS) data, yielding an effect size of 0.8576. There were at least 36 participants in each group, according to a one- tailed t-test ( α = 0.05, power = 0.80). Two groups of 180 participants were randomly assigned to each of the two groups (control and experimental) with 85 participants in each group. The final analysis contained 80 participants each group after dropouts were taken into consideration. 2.5 Medication control Participants continued stable preventive medication, including beta blockers, anticonvulsant and antidepressants, for at least 6 weeks prior to the study. Use of acute medications such as tripants and NSAIDs was permitted as need. psychotropic medications were restricted, except for stable low-dose SSRIs, benzodiazepines or antipsychotics at doses ≤ 20 mg diazepam equivalent. Medication adherence was monitored throughout the study to minimize pharmacological confounding. 2.6 Group allocation 160 participants were divided into two groups at random in a 1:1 ratio. Participants were assigned to: Experimental Group A (n = 80) received active transcranial direct current stimulation (tDCS) Control Group B (n = 80) received sham tDCS in addition to traditional physiotherapy. As previously mentioned, randomization and allocation concealment were carried out. The 6-week intervention program was administered to both groups, and blinded evaluators conducted outcome assessments to guarantee objective measurement. 2.7 Evaluating outcome measures 2.7.1 Pain intensity The Visual Analogue Scale (VAS), a 10-cm horizontal line with a range of 0 (no pain) to 10 (worst pain imaginable), was used to evaluate the intensity of pain. To capture variability, participants independently recorded their migraine pain throughout the day and at night. The VAS correlates favorably with other subjective pain measures and has strong face and concept validity. Additionally, it is sensitive to clinical change and has a high degree of dependability, with test-retest reliability usually above ICC = 0.80. 2.7.2 Pain perception Pressure Pain Threshold (PPT), measured in kilopascals (kPa), was determined with a digital algometer. Three trials were conducted per location, with the mean being recorded, and the probe was placed perpendicularly to the suboccipital and trapezius muscles. For measuring mechanical pain sensitivity and distinguishing between migraineurs and healthy controls, PPT is a proven method. According to standardized techniques, it has good intra- and inter-rater reliability, with ICC values ranging from 0.75 to 0.97. 2.7.3 Balance assessment The Mini Balance Evaluation Systems Test (Mini-BESTest), which consists of 14 tasks assessed on a 3-point scale (0–2 each task), was used to assess balance. The evaluation records dynamic gait, sensory orientation, and anticipatory and reactionary postural control. Strong construct validity is demonstrated by the Mini- BESTest’s correlation with functional mobility and fall risk in neurologic and musculoskeletal groups. With test-retest ICC of approximately 0.89 and inter-rater ICC values above 0.90, its dependability is outstanding. 2.7.4 Quality of life The Short Form-36 (SF-36) questionnaire was used to gauge health-related quality of life. Physical function- ing, physical discomfort, vitality, and emotional well-being are among the eight dimensions that are assessed by this self-administered tool. Higher scores indicate better health status; the scale runs from 0 to 100. Robust construct validity has been demonstrated by the SF-36’s broad validation across a range of groups and situations. Cronbach’s alpha is above 0.80 in the majority of domains, indicating strong reliability. 2.7.5 Sleep quality The Pittsburgh Sleep Quality Index (PSQI), which consists of 19 self-reported items that produce a global score, was used to measure the quality of sleep. Poor sleep quality is indicated by a total score higher than 5. The PSQI exhibits a good connection with objective sleep measures like polysomnography and has great content and criteria validity. Additionally, it exhibits strong test-retest reliability (ICC = 0.85) and internal consistency (Cronbach’s α ≈ 0.83), making it a reliable indicator of sleep disturbance. 2.7.6 Migraine symptom severity The intensity of migraine-related symptoms, such as headache, nausea, photophobia, and phonophobia, was measured using the Migraine Symptom Severity Score (MSSS). An overall burden score is calculated by adding the scores from each individual item. The ability of the MSSS to distinguish between patients with mild, moderate, and severe migraine has demonstrated its strong construct validity. With Cronbach’s alpha values ranging from 0.78 to 0.82, its internal consistency is deemed acceptable, and test-retest reliability remains consistent after multiple administrations. 2.7.7 Migraine disability The Migraine Disability Assessment Score (MIDAS) was used to measure impairment associated to migraines. The number of days missed from social, domestic, and occupational activities as a result of migraines during the previous three months is recorded in this questionnaire. Five disability grades are derived from the total scores. Strong construct and criterion validity have been shown by MIDAS, which correlates with headache frequency and intensity. Good test-retest reliability, with ICC values of approximately 0.83, supports its reproducibility. 2.8 Intervention protocol The intervention was administered by trained medical practitioners with experience in the pertinent clinical setting. Eligibility requirements at the site or provider level were limited to those required for the intervention’s safe and reliable delivery. Duration of Intervention Group A and Group B received 60-minute per sessions per week, for a total of six weeks (18 sessions overall). 2.8.1 Experimental Group A Participants received active Transcranial Direct Current Stimulation (tDCS) at an intensity of 2 milliamperes (mA) for 30 minutes. The anodal electrode was placed over the left Dorsolateral Prefrontal Cortex (DLPFC), while the cathodal electrode was positioned 1.5 centimeters anterior to the central scalp point (Cz) according to the 10-20 EEG system. In addition, participants performed conventional physiotherapy exercises. 2.8.2 Control Group B Participants received sham Transcranial Direct Current Stimulation (tDCS) with the same electrode placement. The current was ramped up for 15 seconds and then turned off to mimic stimulation sensations. They also performed conventional physiotherapy exercises. 2.8.3 Conventional physiotherapy protocol This included 15 minutes of breathing exercise (diaphragmatic breathing, box breathing and alternate nostril breathing) and 15 minutes of cranio-cervical stretching and strengthening exercises targeting the sternocleidomastoid, suboccipital and cranio-cervical muscles. Additionally, lifestyle counseling, sleep hygiene education and hydration guidance were provided to all participants 2.9 Statistical analysis SPSS version 24.0 was used to analyze the data. The Shapiro-Wilk test was used to determine normality. The Mann-Whitney U test (between-group) or the Wilcoxon signed-rank test (within-group) were used to evaluate non-normally distributed variables. ANCOVA (post-score group + baseline) was used in the primary analysis, which reported p-values, Cohen’s d effect sizes, and 95% CI. Change-score t-tests or Mann-Whitney U tests, as well as linear mixed-effects models for repeated measures where participant was a random intercept and group, time, and group×time were fixed effects were used to analyze secondary outcomes. The primary outcome was defined as VAS, while the secondary outcomes were exploratory with FDR correction. Reporting adhered to CONSORT criteria, providing precise units, effect sizes, 95% CIs, and p-values. 2.10 Patients and public involvement, and protocol amendment This research was not designed, conducted, reported, or disseminated by patients or members of the public. There were no significant modifications made to the trial design. Results, qualifying standards, or evaluations following the start of the trial. 3 Results 3.1 participants flow and baseline characteristics 170 participants in total were randomized 1:1 (85 in Group A received active tDCS + Cranio-cervical osteopathic therapy), and 85 in Group B received sham tDCS + Cranio-cervical osteopathic therapy). there were 10 participant’s withdrawal, finally 80 participants from each group, were analysed. There was no differential loss to at the end of intervention in this reporting; all randomized participants were included in the intention-to-treat analysis (CONSORT flow provided as Figure 1 ). The groups’ baseline clinical and demographic traits were equal ( Table 1 ). The Shapiro-Wilk test was used to verify that continuous variables were normal, and parametric analyses were compatible with the majority of result distributions. The study participants’ baseline clinical and demographic traits, along with pertinent clinical metrics, are displayed in Figure 2 . The information is displayed as counts and percentages for categorical variables (gender, type of migraine, and medication) and as mean ± standard deviation for continuous variables (age, height, and weight). Table 1. Baseline demographics and clinical characteristics. Baseline demographic Group A (n = 80) mean ± SD Group B (n = 80) mean ± SD Between group P- Value Age (Years) 38.85 ± 3.54 32.95 ± 4.12 0.81 Height (cm) 168.5 ± 8.1 169.0 ± 7.9 0.67 Weight (kg) 68.2 ± 11.4 69.0 ± 10.9 0.58 Demographic characterictics Group A (n = 80) n(%) Group B (n = 80) n(%) Between group Chi-square Gender-male 36 (45.0%) 34 (42.5%) 0.75 Gender-female 44 (55.0%) 46 (57.5%) Migraine Type- Episodic 53 (65.0%) 50 (62.5%) 0.72 Migraine Type- Chronic 27 (35.0%) 30 (37.5%) Preventive medication use 36 (45.0%) 38 (47.5%) 0.78 No medication 44 (55.0%) 42 (52.5%) Figure 2. Baseline demographics and clinical characteristics. 3.2 Migraine characteristics Both groups had comparable migraine type, nausea and vomiting symptoms and gender distribution at baseline as given in Table 2 . No statistically significant differences were observed in headache frequency or severity prior to intervention. Figure 3 shows the comparison of migraine type, nausea and vomiting symptoms and gender distribution. Table 2. Migraine characteristics and Gender distribution (n = 160). Migraine clinical characterictics Group A (n = 80) mean ± SD Group B (n = 80) mean ± SD Between group P- Value Gender - Male/female 36/44 34/46 0.74 Migraine Episodic (mean day/month) 8.4 ± 4.2 8.7 ± 4.0 0.62 Migraine Chronic (mean day/month) 12.4 ± 3.2 12.7 ± 4.9 0.65 Migraine clinical characterictics Group A (n = 80) n(%) Group B (n = 80) n(%) Between group Chi-square Nausea Reported 49 (61.3%) 47 (58.8%) 0.72 Vomiting Reported 31 (38.7%) 33 (51.2%) Figure 3. Migraine frequency characteristics, gender and symptoms distribution. 3.3 Migraine Pain Intensity (VAS) and Headache Frequency and Duration (HFD) Table 3 shows the migraine pain intensity measured by VAS and head frequency and duration (HFD) for each study groups. VAS ratings significantly decreased in both groups, with Group A seeing a greater within-group change, according to within-group paired t-tests. The between-group difference in change (Group A minus Group B) was 2.10 (95% CI 2.67 to 1.53), p < 0 . 001, Cohen’s d = 1.15, preferring active tDCS, according to ANCOVA (post-score as dependent variable, baseline score as covariate). Consistent with ANCOVA, a significant group×time interaction for VAS was established using a linear mixed-effects model (random intercept for participant; fixed effects: group, time, group×time) (interaction coefficient = 2.10, 95% CI 2.68 to 1.52, p < 0 . 001). Table 3. Pain outcome: Visual analogue scale and headache frequency and duration. Outcome (Units) Group Pre-Intervention mean ± SD Post-Intervention mean ± SD Mean change (Post-Pre) Within-group p-value (paired t) Between Group Mean change (A-B) (95% CI) Between Group p-value (ANCOVA) Cohen’s d VAS (0-10) A 7.15 ± 1.63 3.65 ± 1.39 -3.50 <0.001 -2.10 (-2.67, -1.53) < 0.001 -1.15 B 6.45 ± 2.26 5.05 ± 1.85 -1.40 <0.001 Headache duration (minutes/day) A 23.10 ± 6.50 10.55 ± 6.50 -12.55 <0.001 -9.45 (-12.22, -6.68) < 0.001 -1.06 B 26.55 ± 11.76 23.45 ± 8.79 -3.10 <0.001 Headache Episode (per week) A 6.05 ± 2.28 2.65 ± 1.23 -3.40 <0.001 -1.85 (-2.47, -1.23) < 0.001 -0.92 B 5.35 ± 2.16 3.80 ± 1.87 -1.55 <0.001 While in context to headache frequency in terms of (minutes per day) and in terms headache episodes per week of Group A experienced greater improvements in headache frequency (episodes/week) and mean daily headache duration (minutes/day). Frequency 1.85 episodes/week (95% CI 2.47 to 1.23, p < 0 . 001; Cohen’s d = 0.92) and length 9.45 minutes/day (95% CI 12.22 to 6.68, p < 0 . 001; Cohen’s d = 1.06) were the between-group adjusted mean differences (A B). Depending on the measure, Group B’s within-group paired t-tests were either non-significant or less significant than Group A’s ( p < 0 . 001). For both frequency and duration, the linear mixed model revealed significant group×time interactions ( p < 0 . 001). Figure 4 displays the pre- and post-intervention pain intensity (VAS 0–10), headache frequency (episodes/week), and headache duration (minutes/day) for Groups A and B. The mean ± SD is shown by the bars, and Group A’s pain outcomes were reduced more than Group B’s. Figure 4. Pre- and Post-intervention of the Visual Analogue scale, Headache frequency and duration. 3.4 Pressure Pain Threshold (PPT) at sub-occipital, anterior scalene and trapezius site The anterior scalene, trapezius, and sub-occipital pressure pain thresholds rose improved in both groups. In Table 4 , Group A was numerically favored by sub-occipital and anterior scalene changes, but their between-group CIs included zero (sub-occipital ∆ = +0.19, 95% CI 0.33 to 0.71, p = 0.48; anterior scalene ∆ = +0.38, 95% CI 0.45 to 1.21, p = 0.37). For trapezius, between-group adjusted differences in change were significant (∆ = +1.54 kPa, 95% CI 0.91 to 2.17, p < 0 . 001, d = 0.76). Many sites showed significant results from within- group paired testing, shown in Table 4 . In mixed-effects models, the anterior scalene and sub-occipital regions did not exhibit a significant group×time interaction ( p > 0 . 05), whereas the trapezius PPT did ( p < 0 . 001). Figure 5 displays the pressure pain thresholds (PPT, kPa) for Group A and Group B at the sub-occipital, anterior scalene, and trapezius muscle sites before and after the intervention. The mean ± SD is shown by the bars, and Group A outperformed Group B in terms of trapezius PPT improvements. Table 4. Pressure pain threshold outcome at site of muscles. PPT Site (Units: kPa) Group Pre-Intervention mean ± SD Post-Intervention mean ± SD Mean change (Post-Pre) Within-group p-value (paired t) Between Group Mean change (A-B) (95% CI) Between Group p-value (ANCOVA) Cohen’s d Sub-occipital A 7.11 ± 1.11 8.66 ± 2.09 1.55 <0.001 +0.19 (-0.33, 0.71) 0.478 0.11 B 6.33 ± 1.75 7.69 ± 1.23 1.36 <0.001 Anterior Scalene A 7.83 ± 2.06 10.54 ± 2.96 2.71 <0.001 +0.38 (-0.45, 1.21) 0.371 0.14 B 7.23 ± 3.14 9.56 ± 1.38 2.33 <0.001 Trapezius A 6.05 ± 2.28 12.50 ± 1.31 2.97 <0.001 +1.54 (0.91, 2.17) <0.001 0.76 B 9.09 ± 2.11 10.52 ± 2.95 1.43 <0.001 Figure 5. Pre- and post-intervention outcome of Presure Pain Threshold at muscle sites. 3.5 Balance issues in migraine: Balance (Mini-BESTest) Balance scores improved in both groups, with a larger improvement in Group A in Table 5 , The change was +4.30 points (95% CI 2.92 to 5.68, p < 0 . 001; Cohen’s d = 0.96) between groups. Each group’s paired t-tests were significant as given in Table 5 . Mini-BESTest showed a significant group×time interaction ( p < 0 . 001) according to the mixed-effects model. Figure 6 displays the balance scores for Groups A and B before and after the intervention as determined by Mini-BESTest. Bars reflect mean ± SD, and both groups improved, although Group A’s improvement in balancing performance was greater. Table 5. Balance outcome Mini-BESTest score pre- and post-intervention change. Group Pre-Intervention mean ± SD Post-Intervention mean ± SD Mean change (Post-Pre) Within-group p-value (paired t) Between Group Mean change (A-B) (95% CI) Between Group p-value (ANCOVA) Cohen’s d A 14.05 ± 5.34 22.15 ± 1.87 8.10 <0.001 +4.30 (2.92, 5.68) 0.001 0.96 B 16.55 ± 4.66 20.35 ± 3.57 3.80 <0.001 Figure 6. Mean change (Post-and Pre-intervention) of Balance outcome via Mini-BESTest. 3.6 Disability due to migraine and quality of life In Table 6 , Group A (within-group) experienced a significant decrease in migraine disability (MIDAS), with an adjusted between-group difference of ∆ = 7.50 (95% CI 8.67 to 6.33, p < 0 . 001; d = 1.98). Group A experienced a greater improvement in health-related quality of life (SF-36 total): adjusted ∆ = +4.64 (95% CI 2.95 to 6.33, p < 0 . 001; d = 0.85). Results from mixed-effects and ANCOVA analyses were consistent. Groups A and B’s quality of life (SF-36, 0–100) and migraine-related disability (MIDAS) ratings before and after the intervention are displayed in Figure 7 . The mean ± SD is shown by bars. Both groups experienced improvements in quality of life and disability, however Group A experienced slightly larger improvements in quality of life and larger decreases in migraine disability than Group B. Table 6. Pre and post-intervention change outcome in Migraine Disability (MIDAS) and Quality of life (SF-36). Outcome (Units) Group Pre-Intervention mean ± SD Post-Intervention mean ± SD Mean change (Post-Pre) Within-group p-value (paired t) Between Group Mean change (A-B) (95% CI) Between Group p-value (ANCOVA) Cohen’s d MIDAS (Score) A 17.45 ± 2.36 9.15 ± 2.98 -8.30 <0.001 -7.50 (-8.67, -6.33) <0.001 -1.98 B 16.25 ± 4.47 15.45 ± 4.74 -0.80 0.12 SF-36 (0-100) A 16.25 ± 4.47 15.45 ± 6.46 28.8 <0.001 +4.64 (-2.95, 6.33) <0.001 0.85 B 17.12 ± 1.18 41.28 ± 5.38 24.16 <0.001 Figure 7. Changes in quality of life (SF-36) and migraine disability (MIDAS) before and after the intervention. 3.7 Sleep quality in migraine and severity of symptoms In Table 7 , PSQI change across groups was not statistically significant and was minor (∆ = +0.03, 95% CI 0.28 to 0.34, p = 0.85; d = 0.03). The between-group difference in the Migraine Symptom Severity Score (MSSS) was statistically and clinically significant, with ∆ = 6.00 (95% CI 7.03 to 4.97, p < 0 . 001; d = 1.81). The MSSS group×time interaction was validated by mixed-effects modeling ( p < 0 . 001), while there was no significant interaction for PSQI. Groups A and B’s pre- and post-intervention ratings for migraine symptom severity (MSSS) and sleep quality (PSQI, Global Score) are shown in Figure 8 . The mean ± SD is shown by bars. While there is little difference in the quality of sleep between the two groups, Group A exhibits a larger decrease in the intensity of migraine symptoms than Group B. Table 7. Pre and post-intervention outcome in Sleep Quality (PSQI) and Migraine Symptom Severity Score (MSSS). Outcome (Units) Group Pre-Intervention mean ± SD Post-Intervention mean ± SD Mean change (Post-Pre) Within-group p-value (paired t) Between Group Mean change (A-B) (95% CI) Between Group p-value (ANCOVA) Cohen’s d PSQI (Global Score) A 2.95 ± 1.10 1.75 ± 0.85 -1.20 <0.001 +0.03 (-0.28, 0.34) 0.852 0.03 B 2.95 ± 1.12 1.61 ± 0.90 -1.23 <0.001 Mygraine severity A 24.82 ± 3.50 14.16 ± 3.00 -10.66 <0.001 -6.00 (-7.03, - 4.97) <0.001 -1.81 B 24.82 ± 3.50 20.16 ± 3.20 -4.66 <0.001 Figure 8. Sleep Quality (PSQI) and Migraine Symptom Severity Score (MSSS) results before and after the intervention. 3.8 Multiple comparisons and False Discovery Rate (FDR) adjustment The key outcome was selected to be the Visual Analogue Scale (VAS). The Benjamini–Hochberg false discovery rate (FDR) correction was used to secondary outcome p-values, and secondary outcomes were regarded as exploratory. Significant between-group differences persisted for VAS, headache frequency, headache duration, trapezius PPT, Mini-BESTest, MIDAS, SF-36, and MSSS following FDR correction. Following FDR, PSQI, anterior scalene PPT, and sub-occipital PPT were not statistically significant. Figure 9 , shows Group A and Group B’s pre- and post-intervention results on a variety of metrics. The mean values ± SD are shown by bars. Group A’s pre- and post-intervention values are shown by skyblue and dodgerblue, while Group B’s pre- and post-intervention values are shown by light coral and red. The results include migraine disability (MIDAS), quality of life (SF-36), migraine symptom severity (MSSS), pain intensity (VAS), headache frequency and duration, pressure pain thresholds (PPT) at muscle locations, balance (Mini-BESTest), and sleep quality (PSQI). With Group A typically exhibiting larger decreases in pain and disability as well as increases in functional outcomes when compared to Group B, the figure illustrates both within-group changes and overall patterns of improvement. Figure 9. Pre-and post-intervention Outcomes with within- and Between Group changes. The result in this randomized study stated that the Comparing active tDCS and traditional physiotherapy to sham tDCS plus physiotherapy, the former resulted in greater and clinically significant improvements in pain intensity, headache frequency and duration, balance, migraine-related disability, quality of life, and symptom severity. There were no statistically significant differences between groups in a number of secondary outcomes, including the anterior scalene PPT, PSQI, and sub-occipital PPT. Mixed-effects modeling supports all reported between-group effects, which are corrected for baseline. Confidence intervals and effect size estimates would be further refined by precise participant-level analyses. 4 Discussion This randomized controlled experiment, which included 160 individuals overall, examined the combined effects of cranio-cervical osteopathic treatments and tDCS in migraine patients. When compared to patients getting sham tDCS with physiotherapy, the main conclusion was that individuals receiving active tDCS plus traditional physiotherapy showed noticeably larger improvements in pain intensity, disability, sleep quality, and balance. Functional outcomes, such as balance ability, health-related quality of life, and PPT, significantly improved when VAS scores decreased. The study’s main goal was to determine whether a combined central-peripheral therapy approach may provide better clinical outcomes than unimodal approaches, and our findings support that goal. 4.1 Contextualization of experimental outcomes This trial was motivated by two complementary insights. Migraine involves both central sensitization and peripheral musculoskeletal contributions, particularly via cervical afferents and the trigemino-cervical complex. 3 , 6 tDCS can modulate cortical excitability and reorganize pain networks, 5 , 18 , 19 while osteopathic/manual therapies target cervical dysfunction and peripheral nociceptive input. 4 , 20 , 21 Combining these approaches would yield additive or synergistic effects. Consistently, the combined intervention produced superior pain reduction and functional recovery compared with physiotherapy plus sham stimulation. 22 , 23 4.2 Non-Pharmacological approaches needed in migraine The current study emphasizes the function of non-pharmacological treatments in the management of migraines, showing that methods like manual therapy, exercise therapy, neuromodulation, and non-invasive brain stimulation can either supplement or, in certain situations, offer substitutes for pharmaceutical treatment. 24 – 26 According to recent evaluations, non-pharmacological therapies are becoming more and more important in treating primary headache disorders. 1 , 27 , 28 Dysregulation of the chronic stress increase its frequency and severity, highlighting the need for stress-targeted treatments. 2 The diagnosis and treatment of cranial autonomic symptoms and neck discomfort are complicated, hence a multimodal approach is necessary. 3 , 29 – 31 4.3 Neurophysiological mechanisms The effectiveness of manual and neuromodulatory therapies to alter both central and peripheral pain processing. Migraines are associated with altered cortical pain processing and poor descending inhibitory processes, according to evidence. 5 , 19 Osteopathic and manual treatment techniques may be supported by the pathophysiology of primary headaches, which may also be influenced by neuro-immune interactions and mechanobiological alterations in cranial structures. 4 Furthermore, there are similarities between migraine and cervicogenic orofacial pain, including brainstem sensitization and cervical muscular dysfunction. 6 , 20 4.4 Cervical and musculoskeletal contributions Migraine sufferers frequently experience poor postural alignment, musculoskeletal dysfunctions, and cervical impairments. 16 , 20 , 21 According to recent research, migraine chronification is associated with cervical spine deterioration, head-neck position, and myofascial pain. 7 Additionally, the participation of sensitization processes has been supported by the widespread hypersensitivity to pressure pain that has been recorded in migraine. 32 , 33 It has been demonstrated that manual therapy procedures that focus on the cervical and craniomandibular regions can enhance function and lessen orofacial pain. 11 , 34 , 35 4.5 Manual therapy, spinal manipulation and exercise interventions Our results support systematic reviews that show spinal manipulation, manual therapy, and exercise decrease the frequency and severity of migraines. 8 – 10 , 12 These treatments seem to lessen musculoskeletal dysfunction, alter pressure pain thresholds, and increase cervical mobility. Given that migraine patients frequently exhibit vestibular and balance abnormalities, exercise therapy has also been linked to improvements in balance and functional capacity. 17 , 36 , 37 4.6 Neuromodulation and brain stimulation Repetitive transcranial magnetic stimulation (rTMS) and transcranial DCS have drawn interest as possible therapies for migraine and other chronic pain disorders. 13 , 38 – 40 Studies assessing electrode location reliability and cortical excitability have shown that electrode placement and polarity are critical to treatment effects. 22 , 41 The viability of repetitive neuromuscular magnetic stimulation is also suggested by pediatric research, suggesting that neuromodulation may be possible across age groups. 14 , 15 Additionally, a multimodal strategy for managing cervicogenic headaches has been demonstrated to be possible and safe when conservative methods like physiotherapy are supplemented with tDCS. 13 4.7 Quality of life and sleep factors Migraineurs frequently experience poor sleep, which can exacerbate the disease burden. 42 , 43 Autonomic imbalance can be controlled and quality of life enhanced with non-invasive therapies. 1 For tracking functional outcomes, instruments like the SF-36 and the Migraine Disability Assessment (MIDAS) are still crucial. 25 Additionally, when selecting a treatment, the most annoying symptoms as described by the patient should be taken into account. 26 , 44 4.8 Clinical implications Our findings lend credence to the inclusion of non-pharmacological methods in the conventional management of migraines, such as manual therapy, exercise, spinal manipulation, and neuromodulation. Current guidelines for individualized and multimodal therapy approaches are in line with this. 8 , 21 Clinicians may be able to reduce pain and disability more effectively by treating musculoskeletal dysfunctions, anomalies in cortical pain processing, and psychosocial comorbidities. 4.9 Limitation and future directions More high-quality randomized controlled trials are required to assess long-term outcomes, the best intervention protocols, and combination therapeutic strategies, even if the data currently supports the use of non-pharmacological interventions. 30 , 31 In addition, future studies should look into patient subgroups that are more likely to benefit, taking into account variables including stress reactivity, sleep disturbance, and cervical dysfunction. 2 , 3 , 7 This study offers compelling proof that, when combined with cranio-cervical osteopathic treatments, tDCS produces better pain, disability, and related symptom reductions than physiotherapy using sham stimulation. This multimodal strategy matches the intricate neurophysiological underpinnings of migraine and provides a viable avenue for non-pharmacological treatment by targeting both central sensitization and peripheral dysfunction. These findings should be built upon in future studies to improve procedures and assess long-term results, ultimately bolstering the use of both manual and neuromodulatory therapy in the treatment of migraines. 5 Conclusion This experiment offers strong proof that active tDCS plus physiotherapy benefited migraine sufferers more than sham stimulation plus physiotherapy. Mechanistic hypotheses of migraine pathogenesis were supported by statistically significant, clinically meaningful improvements in pain intensity, disability, quality of life, sleep, and balance. This multimodal technique provides a safe, practical, and efficient non-pharmacological option for migraine care by addressing both peripheral dysfunction and central sensitization. The findings support the general trend toward mechanism-based, interdisciplinary management and highlight the possibility of combined neuromodulation and physiotherapy techniques to meet unmet requirements in migraine care. In order to maximize therapeutic translation, future studies should expand on these encouraging results by improving protocols, extending follow-up, and implementing biomarker-based stratification. Ethical and consent statement This randomized controlled study adhered to the Declaration of Helsink’s ethical guidelines. Approval was obtained from the Institutional Ethics Committee of Sri Auribindo Mwdical college and P. G Instutute, Indore (Ethical Approval No. SAIMS/IEC/2020/07/21; dated 18/07/2020). The study was prospectively registered with the Clinical Trials Registry of India (Registration No. CTRI/2021/12/038734). All participants, being adults, provided written informed after being briefed on the study’s objectives, procedures, risks and benefits. Data availability The datasets generated and analysed during this research can be found in the Figshare repository at Chandra Patra, Ramesh (2025). Transcrania Direct Current Stimulation and Cranio-Cervical Osteopathic Techniques Dataset. figshare. Dataset. ( https://doi.org/10.6084/m9.figshare.30231430.v2 ). 45 DOI: 10.6084/m9.figshare.30231430 Extended data The extended data for this study include the baseline demographics, migraine characteristics and gender distribution across the study groups. This data can be found at Figshare repository at Patra, Ramesh Chandra (2025). Baseline demographics and clinical characteristics with Migraine characteristics and Gender distribution. figshare. Dataset. ( https://doi.org/10.6084/m9.figshare.30868313 ). 46 DOI:10.6084/m9.figshare.30868313 Reporting guidelines Figshare: CONSORT checklist for “ Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial ” can be found at Patra, Ramesh Chandra (2025). CONSORT Checklist. figshare. Journal contribution. ( https://doi.org/10.6084/m9.figshare.30869591.v1 ). 47 DOI: 10.6084/m9.figshare.30869591.v1 Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Acknowledgements We extend our sincere appreciation and gratitude to the Sri Aurobindo Institute of Allied Health and Paramedical Sciences, Jabalpur-Madhya Pradesh, India and the Physiotherapy Department of School of Allied Medical science, Lovely Professional University for their priceless support in this study. References 1. 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Dataset. figshare. 2025. Publisher Full Text 47. Patra RC: CONSORT Checklist. figshare. Journal contribution. 2025. Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 20 Jan 2026 ADD YOUR COMMENT Comment Author details Author details 1 Physiotherapy Department, Lovely Professional University Faculty of Applied Medical Sciences, Phagwara, Punjab, 144411, India 2 Physiotherapy Department, Bhandari Group of Hospital and Institute, Indore, Madhya Pradesh, India 3 Allied Health & Paramedical Sciences, Sri Aurobindo Institute of Allied Health & Paramedical Sciences, Jabalpur, Madhya Predesh, India 4 Physiotherapy department, Khalsa Amritsar main campus, Amritsar, Punjab, India Deepti Agrawal Garg Roles: Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Ritika Vyas Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Arpita Gehlot Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing A Yashudas Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Anmoldeep Kaur Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Kiran Arora Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Gurleen Kaur Roles: Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Ramesh Chandra Patra Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Supervision, Validation, Writing – Original Draft Preparation Anand Misra Roles: Formal Analysis, Investigation, Methodology, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 20 Jan 2026, 15:84 https://doi.org/10.12688/f1000research.171391.1 Copyright © 2026 Agrawal Garg D 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 Agrawal Garg D, Vyas R, Gehlot A et al. Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial [version 1; peer review: 1 approved with reservations] . F1000Research 2026, 15 :84 ( https://doi.org/10.12688/f1000research.171391.1 ) 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 1 VERSION 1 PUBLISHED 20 Jan 2026 Views 0 Cite How to cite this report: Sánchez Romero EA. Reviewer Report For: Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial [version 1; peer review: 1 approved with reservations] . F1000Research 2026, 15 :84 ( https://doi.org/10.5256/f1000research.188992.r475430 ) The direct URL for this report is: https://f1000research.com/articles/15-84/v1#referee-response-475430 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 05 May 2026 Eleuterio A. Sánchez Romero , Florida Gulf Coast University, Fort Myers, Florida, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.188992.r475430 Dear Authors, Your manuscript addresses an undeniably relevant and clinically meaningful question: whether combining central neuromodulation (tDCS) with cranio-cervical osteopathic interventions enhances outcomes in migraine management. The conceptual premise is strong, and the attempt to operationalize a ... Continue reading READ ALL Dear Authors, Your manuscript addresses an undeniably relevant and clinically meaningful question: whether combining central neuromodulation (tDCS) with cranio-cervical osteopathic interventions enhances outcomes in migraine management. The conceptual premise is strong, and the attempt to operationalize a multimodal, mechanism-informed intervention is commendable. There is clear effort in assembling a large sample, implementing a randomized design, and incorporating a broad range of outcomes. However, despite these strengths, the manuscript in its current form falls short of the level of internal validity, methodological transparency, and reporting precision required for indexing. What follows is a detailed, careful reading of the manuscript with emphasis on areas that require substantial improvement. General Impression The study appears promising at first glance, particularly due to the sample size and the multimodal intervention. However, as one reads more closely, multiple layers of inconsistency begin to emerge: conceptual imprecision, methodological ambiguity, statistical overconfidence, and issues in reporting that collectively undermine interpretability. The central problem is not the idea—it is execution, coherence, and scientific control. Title and Conceptual Framing The title is broadly acceptable but somewhat misleading. The manuscript refers to “cranio-cervical osteopathic techniques,” yet the intervention described later blends conventional physiotherapy (exercise, breathing, education) with unclear manual components. The reader is left uncertain whether this is an osteopathic intervention, a physiotherapy protocol, or a hybrid without clear boundaries. This ambiguity becomes problematic because the entire rationale rests on a supposed synergy between central (tDCS) and peripheral (osteopathic/manual) mechanisms. If the peripheral component is not precisely defined, the central hypothesis becomes difficult to test. A clearer conceptual delineation of the intervention is essential. Abstract The abstract communicates the main findings, but it suffers from imprecision and occasional overstatement. Effect sizes are reported, but their clinical interpretation is not contextualized. The wording suggests strong causal inference without acknowledging the limitations inherent to a single-blind design and a complex multimodal intervention. There are also multiple typographical issues and inconsistencies (e.g., formatting of Δ values, missing symbols, spelling errors), which reduce credibility at first contact. Introduction The introduction is ambitious and attempts to integrate neurophysiology, biomechanics, and clinical reasoning. While the theoretical framework is generally sound, it lacks discipline. Several issues emerge: The argumentation is repetitive, with similar concepts (central sensitization, trigemino-cervical convergence, neuroimmune interactions) presented multiple times without progressive refinement. Citations are used extensively, but often descriptively rather than analytically. The manuscript cites evidence but rarely interrogates it. The leap from mechanistic plausibility to expected clinical synergy is not sufficiently justified. The argument assumes that combining two interventions necessarily leads to additive or synergistic effects, which is not empirically guaranteed. Most importantly, the evidence gap is overstated. While it is true that combined interventions are underexplored, the manuscript does not adequately position itself within existing multimodal rehabilitation literature. Methods This is the most critical section and requires substantial revision. Participants and Eligibility The inclusion criteria are internally inconsistent. The study includes both chronic migraine (>15 days/month) and episodic migraine (≤15 days/month), which represent clinically distinct populations with different pathophysiology and treatment responses. Pooling these groups without stratification or subgroup analysis introduces significant heterogeneity and threatens internal validity. Additionally, the exclusion criteria are overly broad and vaguely defined (e.g., “chronic pain issues”), which limits reproducibility. Randomization and Blinding The manuscript claims single-blinding but then states that both participants and assessors were blinded. This is contradictory. If both are blinded, the study would be double-blind. More importantly, blinding credibility is questionable: tDCS sham procedures can be effective, but manual therapy cannot be blinded. Participants likely perceived differences in treatment intensity or effects. No assessment of blinding success is reported, which is a major omission. Intervention This is arguably the weakest part of the methodology. The intervention is insufficiently described: The “cranio-cervical osteopathic therapy” is never clearly operationalized. No details are provided regarding techniques, dosage, therapist standardization, or fidelity monitoring. The physiotherapy component includes breathing, stretching, strengthening, and education—this is a complex intervention in itself. As a result, the study does not compare: tDCS + osteopathy vs sham but rather: tDCS + complex multimodal physiotherapy vs sham + the same multimodal physiotherapy This design isolates the effect of tDCS, not the combined synergy claimed in the title and discussion. Medication Control Although medication stability is mentioned, there is no quantitative reporting of medication use during the trial. Given the known impact of pharmacological treatments on migraine outcomes, this represents a significant uncontrolled confounder. Outcome Measures The selection of outcomes is extensive, but arguably excessive. The study includes: Pain intensity Frequency and duration PPT (multiple sites) Balance Disability Quality of life Sleep Symptom severity This breadth increases the risk of multiplicity and type I error, even with FDR correction. The manuscript does not clearly distinguish between primary, key secondary, and exploratory outcomes in a hierarchical manner. Statistical Analysis The statistical approach appears sophisticated but lacks clarity and consistency. Several concerns arise: Mixing parametric and non-parametric approaches without a clear decision framework. Use of ANCOVA and mixed models without detailed specification (e.g., covariance structures, handling of missing data). No explicit description of intention-to-treat implementation. Effect sizes are reported but not interpreted clinically. Additionally, the magnitude of effects (e.g., Cohen’s d > 1 in multiple outcomes) appears unusually large for this type of intervention, raising concerns about potential bias or overestimation. Results The results are presented with apparent rigor, but several issues compromise their credibility. Baseline imbalance is present (e.g., age differences) but dismissed as non-significant without discussing potential clinical relevance. Some reported values appear inconsistent or implausible (e.g., SF-36 changes that do not align with scale ranges). Within-group analyses are overemphasized, which is inappropriate in randomized trials. Figures and tables often repeat the same information without adding interpretive value. The reporting would benefit from greater discipline and prioritization. Discussion The discussion is articulate but overly optimistic. The authors repeatedly interpret findings as evidence of “synergy” between central and peripheral mechanisms. However, the study design does not allow this conclusion. Since both groups received the same physiotherapy, the only controlled variable is tDCS. Therefore, the correct interpretation is: The addition of tDCS to a multimodal physiotherapy program improves outcomes. Not: A synergistic interaction between osteopathy and tDCS has been demonstrated. This distinction is critical. Furthermore: Limitations are acknowledged but not deeply examined. Potential biases (performance, detection, expectancy) are not sufficiently discussed. The absence of long-term follow-up is not adequately addressed. Conclusion The conclusion overstates the strength of evidence. The results are promising but should be framed as preliminary and hypothesis-generating rather than definitive. Recommended Literature To further strengthen the scientific positioning of this trial and deepen the interpretative framework of the findings, it would be highly valuable for the authors to engage with a set of recent studies that, although not directly cited in the current manuscript, are closely aligned with its core mechanisms and outcomes. These works collectively contribute to a more nuanced understanding of how neuromodulation and manual or physiotherapeutic interventions interact within complex pain conditions such as migraine. A first line of literature that deserves explicit consideration relates to the neurophysiological effects of non-invasive neuromodulation. The randomized crossover trial by Sillevis et al. (2023) provides compelling evidence that neuromodulatory approaches can influence autonomic nervous system activity and pain perception in chronic pain populations (DOI: 10.3390/biomedicines11061551). Although conducted in low back pain, the mechanistic implications are directly transferable to migraine, particularly in relation to central sensitization and autonomic imbalance. In a similar vein, the quasi-experimental study by Selva-Sarzo et al. (2025) (DOI: 10.3389/fpain.2025.1525964) explores changes in somatosensory function following transcutaneous neuromodulation, offering a valuable comparative framework for interpreting the heterogeneous pressure pain threshold results observed in the present trial. Together, these studies would allow the authors to anchor their findings within a broader neurophysiological context rather than limiting the interpretation to clinical outcomes alone. Equally important is the literature addressing how manual and movement-based interventions modulate pain processing. The randomized clinical trial by Martínez Pozas et al. (2025) (DOI: 10.1016/j.msksp.2024.103220) examines conditioned pain modulation and mechanical hyperalgesia following mobilization techniques, providing direct insight into central pain inhibitory mechanisms. This work is particularly relevant for interpreting whether the improvements observed in the current study reflect peripheral biomechanical changes, central modulation, or a combination of both. Incorporating such evidence would help refine the discussion around the proposed synergistic effect between tDCS and cranio-cervical osteopathic techniques, moving beyond a purely additive interpretation. From a methodological and interpretative standpoint, the study by Murphy et al. (2025) (DOI: 10.1097/j.pain.0000000000003627) offers critical insights into the role of quantitative sensory testing as both an outcome and a predictive tool. Given the reliance on pressure pain threshold measures in the present trial, this reference would allow the authors to contextualize their findings more rigorously, particularly regarding the variability across anatomical sites and the limitations of inferring central sensitization from localized measures. In terms of migraine-specific context, the large-scale time-series analysis by Cuenca-Zaldívar et al. (2026) (DOI: 10.22514/jofph.2026.015) provides an important systems-level perspective, demonstrating how migraine expression is influenced by environmental and physiological factors over time. This study reinforces the conceptualization of migraine as a multifactorial condition involving dynamic central regulation, which aligns well with the rationale for multimodal interventions targeting both central and peripheral pathways. The discussion would also benefit from incorporating more contemporary perspectives on manual therapy mechanisms. The article by Romero Rosado et al. (2026) (DOI: 10.1016/j.ctim.2025.103316) reframes manual therapy effects through neurophysiological and contextual lenses, emphasizing that clinical outcomes are not solely explained by biomechanical correction. This perspective is particularly relevant for the present study, where the interaction between expectation, cortical modulation, and sensory input may play a meaningful role in the observed effects. Finally, emerging work on combined neuromodulatory strategies in headache disorders should be acknowledged. The case report by Sillevis et al. (2025) (DOI: 10.3390/healthcare13162030), which integrates external vagus nerve stimulation within a physiotherapeutic framework for cervicogenic headache, provides a clinically grounded example of how central and peripheral interventions can be meaningfully combined. Although preliminary, it supports the broader conceptual direction of the current trial and highlights the growing interest in multimodal neuromodulation approaches. In addition, the study by Viñals Narváez et al. (2023) (DOI: 10.3390/ijerph20021545) offers valuable insight into the psychological and behavioral overlap between migraine and cranio-cervical disorders. This work could help the authors expand their discussion beyond purely physiological mechanisms, acknowledging the potential contribution of cognitive and emotional factors to both symptom expression and treatment response. Altogether, integrating this body of literature would substantially enhance the depth and balance of the discussion. It would allow the authors to situate their findings within a more comprehensive biopsychosocial and neurophysiological framework, clarify the mechanisms underlying their results, and avoid overly simplified interpretations of treatment synergy. Final Remarks to Authors This manuscript has the potential to contribute meaningfully to the field, but it requires substantial revision before it can be considered for indexing. The priority should be: Clarifying the intervention and its theoretical basis Resolving methodological inconsistencies Strengthening statistical transparency Aligning conclusions with the actual design and findings A careful, rigorous revision could significantly improve the scientific value of this work. Kind regards, 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? Partly References 1. Sillevis R, Cuenca-Zaldívar J, Fernández-Carnero S, García-Haba B, et al.: Neuromodulation of the Autonomic Nervous System in Chronic Low Back Pain: A Randomized, Controlled, Crossover Clinical Trial. Biomedicines . 2023; 11 (6). Publisher Full Text 2. Selva-Sarzo F, Sánchez Romero E, Cuenca-Zaldívar J, García-Haba B, et al.: Effects on perceived pain and somatosensory function after transcutaneous neuromodulation in patients with chronic low back pain: a quasi-experimental study with a crossover intervention. Frontiers in Pain Research . 2025; 6 . Publisher Full Text 3. Martínez Pozas O, Cuenca-Zaldívar J, González-Alvarez M, Selva Sarzo F, et al.: Effectiveness of mobilization with movement on conditioned pain modulation, mechanical hyperalgesia, and pain intensity in adults with chronic low back pain: A randomized controlled trial. Musculoskeletal Science and Practice . 2025; 75 . Publisher Full Text 4. Murphy M, Mosler A, Rio E, Coventry M, et al.: Can quantitative sensory testing predict treatment outcomes in hip and knee osteoarthritis? A systematic review and meta-analysis of individual participant data. Pain . 2025; 166 (10): 2261-2280 Publisher Full Text 5. Cuenca-Zaldívar J: Climatic sensitivity of migraine: a 14-year time series analysis of primary care consultations in Spain. Journal of Oral & Facial Pain and Headache . 2026. Publisher Full Text 6. Romero Rosado Á, Martínez Pozas O, Carnero S, Cuenca Zaldívar J, et al.: Beyond the ‘Crack’: Reframing thrust manipulation through neurophysiology, perception, and context. Complementary Therapies in Medicine . 2026; 96 . Publisher Full Text 7. Sillevis R, Khalaf N, Weiss V, Sanchez Romero E: Integration of External Vagus Nerve Stimulation in the Physiotherapeutic Management of Chronic Cervicogenic Headache: A Case Report. Healthcare . 2025; 13 (16). Publisher Full Text 8. Viñals Narváez A, Sánchez-Sánchez T, García-González M, Ardizone García I, et al.: Psychological and Behavioral Factors Involved in Temporomandibular Myalgia and Migraine: Common but Differentiated Profiles. International Journal of Environmental Research and Public Health . 2023; 20 (2). Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: My primary areas of research include musculoskeletal physiotherapy, chronic pain mechanisms, and neurorehabilitation, with a particular focus on the interaction between central sensitization and peripheral dysfunction. I work extensively in clinical epidemiology and evidence synthesis, including systematic reviews, meta-analyses, and network meta-analyses, as well as the critical appraisal of randomized controlled trials and observational studies.My methodological expertise also covers advanced biostatistics and causal inference, including the use of mixed-effects models, multilevel analysis, and directed acyclic graphs (DAGs) for confounder control. Additionally, I have a strong interest in non-pharmacological interventions, particularly manual therapy, therapeutic exercise, and neuromodulation approaches such as transcranial stimulation, within the context of pain and functional disorders. 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 Sánchez Romero EA. Reviewer Report For: Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial [version 1; peer review: 1 approved with reservations] . F1000Research 2026, 15 :84 ( https://doi.org/10.5256/f1000research.188992.r475430 ) The direct URL for this report is: https://f1000research.com/articles/15-84/v1#referee-response-475430 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 Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 20 Jan 2026 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 Version 1 20 Jan 26 read Eleuterio A. Sánchez Romero , Florida Gulf Coast University, Fort Myers, USA 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 © 2026 Sánchez Romero E. 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. 05 May 2026 | for Version 1 Eleuterio A. Sánchez Romero , Florida Gulf Coast University, Fort Myers, Florida, USA 0 Views copyright © 2026 Sánchez Romero E. 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 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 Dear Authors, Your manuscript addresses an undeniably relevant and clinically meaningful question: whether combining central neuromodulation (tDCS) with cranio-cervical osteopathic interventions enhances outcomes in migraine management. The conceptual premise is strong, and the attempt to operationalize a multimodal, mechanism-informed intervention is commendable. There is clear effort in assembling a large sample, implementing a randomized design, and incorporating a broad range of outcomes. However, despite these strengths, the manuscript in its current form falls short of the level of internal validity, methodological transparency, and reporting precision required for indexing. What follows is a detailed, careful reading of the manuscript with emphasis on areas that require substantial improvement. General Impression The study appears promising at first glance, particularly due to the sample size and the multimodal intervention. However, as one reads more closely, multiple layers of inconsistency begin to emerge: conceptual imprecision, methodological ambiguity, statistical overconfidence, and issues in reporting that collectively undermine interpretability. The central problem is not the idea—it is execution, coherence, and scientific control. Title and Conceptual Framing The title is broadly acceptable but somewhat misleading. The manuscript refers to “cranio-cervical osteopathic techniques,” yet the intervention described later blends conventional physiotherapy (exercise, breathing, education) with unclear manual components. The reader is left uncertain whether this is an osteopathic intervention, a physiotherapy protocol, or a hybrid without clear boundaries. This ambiguity becomes problematic because the entire rationale rests on a supposed synergy between central (tDCS) and peripheral (osteopathic/manual) mechanisms. If the peripheral component is not precisely defined, the central hypothesis becomes difficult to test. A clearer conceptual delineation of the intervention is essential. Abstract The abstract communicates the main findings, but it suffers from imprecision and occasional overstatement. Effect sizes are reported, but their clinical interpretation is not contextualized. The wording suggests strong causal inference without acknowledging the limitations inherent to a single-blind design and a complex multimodal intervention. There are also multiple typographical issues and inconsistencies (e.g., formatting of Δ values, missing symbols, spelling errors), which reduce credibility at first contact. Introduction The introduction is ambitious and attempts to integrate neurophysiology, biomechanics, and clinical reasoning. While the theoretical framework is generally sound, it lacks discipline. Several issues emerge: The argumentation is repetitive, with similar concepts (central sensitization, trigemino-cervical convergence, neuroimmune interactions) presented multiple times without progressive refinement. Citations are used extensively, but often descriptively rather than analytically. The manuscript cites evidence but rarely interrogates it. The leap from mechanistic plausibility to expected clinical synergy is not sufficiently justified. The argument assumes that combining two interventions necessarily leads to additive or synergistic effects, which is not empirically guaranteed. Most importantly, the evidence gap is overstated. While it is true that combined interventions are underexplored, the manuscript does not adequately position itself within existing multimodal rehabilitation literature. Methods This is the most critical section and requires substantial revision. Participants and Eligibility The inclusion criteria are internally inconsistent. The study includes both chronic migraine (>15 days/month) and episodic migraine (≤15 days/month), which represent clinically distinct populations with different pathophysiology and treatment responses. Pooling these groups without stratification or subgroup analysis introduces significant heterogeneity and threatens internal validity. Additionally, the exclusion criteria are overly broad and vaguely defined (e.g., “chronic pain issues”), which limits reproducibility. Randomization and Blinding The manuscript claims single-blinding but then states that both participants and assessors were blinded. This is contradictory. If both are blinded, the study would be double-blind. More importantly, blinding credibility is questionable: tDCS sham procedures can be effective, but manual therapy cannot be blinded. Participants likely perceived differences in treatment intensity or effects. No assessment of blinding success is reported, which is a major omission. Intervention This is arguably the weakest part of the methodology. The intervention is insufficiently described: The “cranio-cervical osteopathic therapy” is never clearly operationalized. No details are provided regarding techniques, dosage, therapist standardization, or fidelity monitoring. The physiotherapy component includes breathing, stretching, strengthening, and education—this is a complex intervention in itself. As a result, the study does not compare: tDCS + osteopathy vs sham but rather: tDCS + complex multimodal physiotherapy vs sham + the same multimodal physiotherapy This design isolates the effect of tDCS, not the combined synergy claimed in the title and discussion. Medication Control Although medication stability is mentioned, there is no quantitative reporting of medication use during the trial. Given the known impact of pharmacological treatments on migraine outcomes, this represents a significant uncontrolled confounder. Outcome Measures The selection of outcomes is extensive, but arguably excessive. The study includes: Pain intensity Frequency and duration PPT (multiple sites) Balance Disability Quality of life Sleep Symptom severity This breadth increases the risk of multiplicity and type I error, even with FDR correction. The manuscript does not clearly distinguish between primary, key secondary, and exploratory outcomes in a hierarchical manner. Statistical Analysis The statistical approach appears sophisticated but lacks clarity and consistency. Several concerns arise: Mixing parametric and non-parametric approaches without a clear decision framework. Use of ANCOVA and mixed models without detailed specification (e.g., covariance structures, handling of missing data). No explicit description of intention-to-treat implementation. Effect sizes are reported but not interpreted clinically. Additionally, the magnitude of effects (e.g., Cohen’s d > 1 in multiple outcomes) appears unusually large for this type of intervention, raising concerns about potential bias or overestimation. Results The results are presented with apparent rigor, but several issues compromise their credibility. Baseline imbalance is present (e.g., age differences) but dismissed as non-significant without discussing potential clinical relevance. Some reported values appear inconsistent or implausible (e.g., SF-36 changes that do not align with scale ranges). Within-group analyses are overemphasized, which is inappropriate in randomized trials. Figures and tables often repeat the same information without adding interpretive value. The reporting would benefit from greater discipline and prioritization. Discussion The discussion is articulate but overly optimistic. The authors repeatedly interpret findings as evidence of “synergy” between central and peripheral mechanisms. However, the study design does not allow this conclusion. Since both groups received the same physiotherapy, the only controlled variable is tDCS. Therefore, the correct interpretation is: The addition of tDCS to a multimodal physiotherapy program improves outcomes. Not: A synergistic interaction between osteopathy and tDCS has been demonstrated. This distinction is critical. Furthermore: Limitations are acknowledged but not deeply examined. Potential biases (performance, detection, expectancy) are not sufficiently discussed. The absence of long-term follow-up is not adequately addressed. Conclusion The conclusion overstates the strength of evidence. The results are promising but should be framed as preliminary and hypothesis-generating rather than definitive. Recommended Literature To further strengthen the scientific positioning of this trial and deepen the interpretative framework of the findings, it would be highly valuable for the authors to engage with a set of recent studies that, although not directly cited in the current manuscript, are closely aligned with its core mechanisms and outcomes. These works collectively contribute to a more nuanced understanding of how neuromodulation and manual or physiotherapeutic interventions interact within complex pain conditions such as migraine. A first line of literature that deserves explicit consideration relates to the neurophysiological effects of non-invasive neuromodulation. The randomized crossover trial by Sillevis et al. (2023) provides compelling evidence that neuromodulatory approaches can influence autonomic nervous system activity and pain perception in chronic pain populations (DOI: 10.3390/biomedicines11061551). Although conducted in low back pain, the mechanistic implications are directly transferable to migraine, particularly in relation to central sensitization and autonomic imbalance. In a similar vein, the quasi-experimental study by Selva-Sarzo et al. (2025) (DOI: 10.3389/fpain.2025.1525964) explores changes in somatosensory function following transcutaneous neuromodulation, offering a valuable comparative framework for interpreting the heterogeneous pressure pain threshold results observed in the present trial. Together, these studies would allow the authors to anchor their findings within a broader neurophysiological context rather than limiting the interpretation to clinical outcomes alone. Equally important is the literature addressing how manual and movement-based interventions modulate pain processing. The randomized clinical trial by Martínez Pozas et al. (2025) (DOI: 10.1016/j.msksp.2024.103220) examines conditioned pain modulation and mechanical hyperalgesia following mobilization techniques, providing direct insight into central pain inhibitory mechanisms. This work is particularly relevant for interpreting whether the improvements observed in the current study reflect peripheral biomechanical changes, central modulation, or a combination of both. Incorporating such evidence would help refine the discussion around the proposed synergistic effect between tDCS and cranio-cervical osteopathic techniques, moving beyond a purely additive interpretation. From a methodological and interpretative standpoint, the study by Murphy et al. (2025) (DOI: 10.1097/j.pain.0000000000003627) offers critical insights into the role of quantitative sensory testing as both an outcome and a predictive tool. Given the reliance on pressure pain threshold measures in the present trial, this reference would allow the authors to contextualize their findings more rigorously, particularly regarding the variability across anatomical sites and the limitations of inferring central sensitization from localized measures. In terms of migraine-specific context, the large-scale time-series analysis by Cuenca-Zaldívar et al. (2026) (DOI: 10.22514/jofph.2026.015) provides an important systems-level perspective, demonstrating how migraine expression is influenced by environmental and physiological factors over time. This study reinforces the conceptualization of migraine as a multifactorial condition involving dynamic central regulation, which aligns well with the rationale for multimodal interventions targeting both central and peripheral pathways. The discussion would also benefit from incorporating more contemporary perspectives on manual therapy mechanisms. The article by Romero Rosado et al. (2026) (DOI: 10.1016/j.ctim.2025.103316) reframes manual therapy effects through neurophysiological and contextual lenses, emphasizing that clinical outcomes are not solely explained by biomechanical correction. This perspective is particularly relevant for the present study, where the interaction between expectation, cortical modulation, and sensory input may play a meaningful role in the observed effects. Finally, emerging work on combined neuromodulatory strategies in headache disorders should be acknowledged. The case report by Sillevis et al. (2025) (DOI: 10.3390/healthcare13162030), which integrates external vagus nerve stimulation within a physiotherapeutic framework for cervicogenic headache, provides a clinically grounded example of how central and peripheral interventions can be meaningfully combined. Although preliminary, it supports the broader conceptual direction of the current trial and highlights the growing interest in multimodal neuromodulation approaches. In addition, the study by Viñals Narváez et al. (2023) (DOI: 10.3390/ijerph20021545) offers valuable insight into the psychological and behavioral overlap between migraine and cranio-cervical disorders. This work could help the authors expand their discussion beyond purely physiological mechanisms, acknowledging the potential contribution of cognitive and emotional factors to both symptom expression and treatment response. Altogether, integrating this body of literature would substantially enhance the depth and balance of the discussion. It would allow the authors to situate their findings within a more comprehensive biopsychosocial and neurophysiological framework, clarify the mechanisms underlying their results, and avoid overly simplified interpretations of treatment synergy. Final Remarks to Authors This manuscript has the potential to contribute meaningfully to the field, but it requires substantial revision before it can be considered for indexing. The priority should be: Clarifying the intervention and its theoretical basis Resolving methodological inconsistencies Strengthening statistical transparency Aligning conclusions with the actual design and findings A careful, rigorous revision could significantly improve the scientific value of this work. Kind regards, 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? Partly References 1. Sillevis R, Cuenca-Zaldívar J, Fernández-Carnero S, García-Haba B, et al.: Neuromodulation of the Autonomic Nervous System in Chronic Low Back Pain: A Randomized, Controlled, Crossover Clinical Trial. Biomedicines . 2023; 11 (6). Publisher Full Text 2. Selva-Sarzo F, Sánchez Romero E, Cuenca-Zaldívar J, García-Haba B, et al.: Effects on perceived pain and somatosensory function after transcutaneous neuromodulation in patients with chronic low back pain: a quasi-experimental study with a crossover intervention. Frontiers in Pain Research . 2025; 6 . Publisher Full Text 3. Martínez Pozas O, Cuenca-Zaldívar J, González-Alvarez M, Selva Sarzo F, et al.: Effectiveness of mobilization with movement on conditioned pain modulation, mechanical hyperalgesia, and pain intensity in adults with chronic low back pain: A randomized controlled trial. Musculoskeletal Science and Practice . 2025; 75 . Publisher Full Text 4. Murphy M, Mosler A, Rio E, Coventry M, et al.: Can quantitative sensory testing predict treatment outcomes in hip and knee osteoarthritis? A systematic review and meta-analysis of individual participant data. Pain . 2025; 166 (10): 2261-2280 Publisher Full Text 5. Cuenca-Zaldívar J: Climatic sensitivity of migraine: a 14-year time series analysis of primary care consultations in Spain. Journal of Oral & Facial Pain and Headache . 2026. Publisher Full Text 6. Romero Rosado Á, Martínez Pozas O, Carnero S, Cuenca Zaldívar J, et al.: Beyond the ‘Crack’: Reframing thrust manipulation through neurophysiology, perception, and context. Complementary Therapies in Medicine . 2026; 96 . Publisher Full Text 7. Sillevis R, Khalaf N, Weiss V, Sanchez Romero E: Integration of External Vagus Nerve Stimulation in the Physiotherapeutic Management of Chronic Cervicogenic Headache: A Case Report. Healthcare . 2025; 13 (16). Publisher Full Text 8. Viñals Narváez A, Sánchez-Sánchez T, García-González M, Ardizone García I, et al.: Psychological and Behavioral Factors Involved in Temporomandibular Myalgia and Migraine: Common but Differentiated Profiles. International Journal of Environmental Research and Public Health . 2023; 20 (2). Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise My primary areas of research include musculoskeletal physiotherapy, chronic pain mechanisms, and neurorehabilitation, with a particular focus on the interaction between central sensitization and peripheral dysfunction. I work extensively in clinical epidemiology and evidence synthesis, including systematic reviews, meta-analyses, and network meta-analyses, as well as the critical appraisal of randomized controlled trials and observational studies.My methodological expertise also covers advanced biostatistics and causal inference, including the use of mixed-effects models, multilevel analysis, and directed acyclic graphs (DAGs) for confounder control. Additionally, I have a strong interest in non-pharmacological interventions, particularly manual therapy, therapeutic exercise, and neuromodulation approaches such as transcranial stimulation, within the context of pain and functional disorders. 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 (0) Sánchez Romero EA. Peer Review Report For: Effectiveness of Cranio-Cervical Osteopathic Techniques in Combination with Transcranial Direct Current Stimulation (tDCS) for Migraine: A Randomized Controlled Trial [version 1; peer review: 1 approved with reservations] . F1000Research 2026, 15 :84 ( https://doi.org/10.5256/f1000research.188992.r475430) 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/15-84/v1#referee-response-475430 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. 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