{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T10:53:23Z","timestamp":1782471203406,"version":"3.54.5"},"update-to":[{"DOI":"10.12688\/f1000research.171975.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000}}],"reference-count":31,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The DAM Foundation","award":["SDAM_FOR701626"],"award-info":[{"award-number":["SDAM_FOR701626"]}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns5:p>Background Chronic migraine is frequently refractory to available preventive therapies. Image-guided cryoneurolysis of the greater occipital nerve (CryoGON) may provide longer-lasting relief than conventional greater occipital nerve (GON) blocks. This Stage 1 Registered Report describes a prospective, exploratory study evaluating whether response to a conventional GON block predicts subsequent response to CryoGON, and assesses open-label safety, tolerability, feasibility and efficacy of CryoGON. Methods The study is planned as a single-site, investigator-initiated, open-label clinical investigation. Adults with chronic migraine will complete a \u226528-day electronic baseline diary before receiving bilateral conventional GON blocks, followed by a \u226528-day observation. Eligible participants then undergo navigation-guided CryoGON with 12-week follow-up. The primary endpoint is the association between change in moderate-to-severe headache days after GON block (weeks 1\u20134) and after CryoGON (weeks 9\u201312). Key secondary endpoints estimate the diagnostic performance of GON-block response applying a \u226530% reduction threshold for treatment effect to identify CryoGON responders, including sensitivity, specificity and predictive values. Additional endpoints include change in migraine days, patient-reported global impression of change, Migraine-Specific Quality of Life Questionnaire v2.1, procedure tolerability, technical success, and safety (treatment-emergent adverse events and adverse device effects). Women of childbearing potential, including pregnant and breastfeeding participants, are eligible for participation. Discussion This study will provide the first systematic evaluation of whether a simple, widely available GON block can guide patient selection for CryoGON and will generate foundational open-label data on its clinical performance and safety. Findings will inform the design and justification of a subsequent sham-controlled trial. Trial registration and approvals The study will preregister at ClinicalTrials.gov. and obtain all necessary ethical approvals before study initiation. Sponsor: St. Olav\u2019s University Hospital, Trondheim, Norway. Funding: Stiftelsen Dam (grant SDAM_FOR701626).<\/ns5:p>","DOI":"10.12688\/f1000research.171975.2","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T04:14:06Z","timestamp":1770178446000},"page":"1157","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Stage 1 Registered Report:\u00a0 Rationale, design and study protocol for a prospective, exploratory study Predicting Response to image-Guided Cryoneurolysis of the Greater Occipital Nerve (CryoGON) in Chronic Migraine Using a Conventional Greater Occipital Nerve Block."],"prefix":"10.12688","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2295-123X","authenticated-orcid":false,"given":"Tore","family":"Wergeland","sequence":"first","affiliation":[{"name":"Norwegian Centre for Headache Research (NorHEAD) Trondheim Norwegian University of Science and Technology (NTNU)"},{"name":"Department of neurology and neurophysiology Trondheim St Olav\u2019s University Hospital"},{"name":"Department of Neuromedicine and Movement Sciences Trondheim Norwegian University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2763-6343","authenticated-orcid":false,"given":"Melanie Rae","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Public Health and Nursing Trondheim Norwegian University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Aschehoug","sequence":"additional","affiliation":[{"name":"Department of neurology and neurophysiology Trondheim St Olav\u2019s University Hospital"},{"name":"Department of Neuromedicine and Movement Sciences Trondheim Norwegian University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise Rystad","family":"\u00d8ie","sequence":"additional","affiliation":[{"name":"Norwegian Centre for Headache Research (NorHEAD) Trondheim Norwegian University of Science and Technology (NTNU)"},{"name":"Department of neurology and neurophysiology Trondheim St Olav\u2019s University Hospital"},{"name":"Department of Neuromedicine and Movement Sciences Trondheim Norwegian University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Devik","sequence":"additional","affiliation":[{"name":"Department of Neurology Namsos Nord Tr\u00f8ndelag Trust"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha Brakestad","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Neurology Molde Molde Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sverre","family":"Myren","sequence":"additional","affiliation":[{"name":"Department of Neuromedicine and Movement Sciences Trondheim Norwegian University of Science and Technology"},{"name":"Department of Neurology \u00c5lesund \u00c5lesund Hospital"},{"name":"Department of Health Sciences in \u00c5lesund \u00c5lesund Norwegian University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erling Andreas","family":"Tronvik","sequence":"additional","affiliation":[{"name":"Norwegian Centre for Headache Research (NorHEAD) Trondheim Norwegian University of Science and Technology (NTNU)"},{"name":"Department of neurology and neurophysiology Trondheim St Olav\u2019s University Hospital"},{"name":"Department of Neuromedicine and Movement Sciences Trondheim Norwegian University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Fossum","family":"Bratbak","sequence":"additional","affiliation":[{"name":"Norwegian Centre for Headache Research (NorHEAD) Trondheim Norwegian University of Science and Technology (NTNU)"},{"name":"Department of Neuromedicine and Movement Sciences Trondheim Norwegian University of Science and Technology"},{"name":"Department of Neurosurgery Trondheim St Olav's University Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s10194-024-01795-2","article-title":"GBD2021: headache disorders and global lost health - a focus on children, and a view forward.","volume":"25","author":"T Steiner","year":"2024","journal-title":"J. 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Journal contribution."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T10:44:11Z","timestamp":1782470651000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,4]]},"references-count":31,"URL":"https:\/\/doi.org\/10.12688\/f1000research.171975.2","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/f1000research.171975.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.196068.r486407","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.196068.r488434","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.196068.r458946","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.196068.r488434","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.196068.r486407","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.196068.r458946","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,4]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.189650.r434098, Nathaniel M. Schuster, University of California, San Diego, CA, 11 Dec 2025, version 1, 2 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v1#referee-response-434098","order":0,"name":"referee-response-434098","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Tore Wergeland<\/b>; \n<i>Posted: 01 Feb 2026<\/i>; Thank you for your thoughtful comments.  We agree with the reviewer that both the short-term abortive effect of a conventional greater occipital nerve (GON) block, in addition to its longer-term impact on headache frequency, could be scientifically and clinically informative when evaluating its predictive value for CryoGON outcomes.  However, in the current study, treatment response is defined as the change in moderate-to-severe headache days derived from prospective headache diaries, reflecting a preventive rather than abortive treatment framework. Because participants may receive the conventional GON block on headache-free days, the study design does not permit a systematic assessment of short-term abortive effects within the first several hours following injection.  To partially address short-term effects of a conventional GON block, we have added collection of the Patient Global Impression of Improvement (PGI-I) on day 1 (the day following the conventional block procedure). The manuscript has been updated to include this as an endpoint. In addition, we will document the presence or absence of headache at the time of the procedure and, when applicable, the participant-reported duration of headache following the injection. These data may be explored in post hoc analyses, if deemed feasible.  Extending the observation period following the conventional GON block to 12 weeks in order to assess longer-term predictive effects was considered. However, this would substantially prolong study participation and require prolonged stability of preventive treatments, which was not deemed feasible within the current design. The present study therefore focuses on the association between short-term changes in headache frequency following GON block (weeks 1\u20134) and subsequent response to CryoGON (weeks 9\u201312), with the aim of generating foundational data to inform the design of future studies specifically addressing these clinically relevant timing questions.","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2#referee-comment-15379","order":1,"name":"referee-comment-15379","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.189650.r441857, Gulcin Babaoglu, Ankara Bilkent City Hospital, Ankara, 08 Jan 2026, version 1, 2 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v1#referee-response-441857","order":2,"name":"referee-response-441857","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Tore Wergeland<\/b>; \n<i>Posted: 01 Feb 2026<\/i>; \n<i>Thank you for your comments. We address them in the following: <\/i>  1. When the inclusion and exclusion criteria are considered together, a situation arises that requires clarification regarding the inclusion of patients receiving onabotulinumtoxinA (Botox) treatment.  Inclusion Criterion 5 requires that patients using Botox must have completed at least three consecutive PREEMPT injection cycles and be on a stable regimen.  Exclusion Criterion 1 excludes patients who have received injections to the occipital or suboccipital region within the last 12 weeks prior to baseline.  The PREEMPT protocol anatomically includes injections to the occipital region and is administered at 12-week intervals.  Inclusion Criterion 6 requires that no changes be made in the dose or frequency of preventive treatments.  Assessment:  The concurrent application of these criteria appears likely to create practical difficulties in enrolling patients who are on stable Botox treatment. Even in cases where patients are considered non-responders after three injection cycles, this situation needs to be explicitly stated in the protocol. In summary, regardless of response status, patients receiving PREEMPT treatment may overlap with the exclusion window.  \n<i><b>Response:<\/b> <\/i> \n<i>You are correct, and we thank the reviewer for identifying this inconsistency. Exclusion criterion 1 was intended to exclude other occipital or suboccipital injections, but not onabotulinumtoxinA administered according to the PREEMPT protocol. This has now been explicitly clarified in the exclusion criteria. Patients receiving PREEMPT treatment are eligible provided they are on a stable regimen and meet all other inclusion criteria, irrespective of response status.<\/i>  2. The primary objective of the study is to investigate whether the response to a conventional GON block is associated with the response following CryoGON, and thereby to assess whether the GON block can serve as a potential clinical guidance tool for CryoGON.  However, the open-label design of the study and the invasive nature of both interventions necessitate a cautious interpretative framework when evaluating the findings. An observed association between GON block response and CryoGON response may reflect a shared physiological mechanism; however, it may also reflect patients\u2019 general tendency to respond to interventional treatments, treatment expectation, or individual response characteristics.  In this context, the continuous response relationship evaluated using linear regression essentially demonstrates an association between the responses to the two treatments. The use of this association as a clinical prediction or decision-making tool is limited to the prespecified dichotomous response analyses and remains exploratory in nature.  In summary, patients with a strong placebo response are more likely to respond to both interventions (\u201cplacebo consistency\u201d or expectation effect).  \n<i><b>Response:<\/b> We agree with the reviewer that, given the open-label design and the invasive nature of both interventions, any observed association between response to conventional GON block and CryoGON must be interpreted with caution. An observed relationship may reflect shared physiological mechanisms, but may also reflect non-specific factors such as treatment expectation or individual response propensity (\u201cplacebo consistency\u201d).<\/i> \n<i>Accordingly, the primary analysis is explicitly framed as an assessment of association rather than causal prediction. The dichotomised responder analyses are intended to explore potential clinical utility in a hypothesis-generating manner, and not to establish a definitive decision rule. This limitation has been clarified in the Discussion section of the manuscript.<\/i>    3. The CryoGON procedure is described in the protocol in a generally clear manner and provides a sufficient foundation with respect to clinical applicability and safety of the intervention. However, within the context of a protocol publication, a more explicit description of certain technical details related to interventional standardization and reproducibility across different centers could strengthen the methodological rigor of the study.  In particular, referencing only the instructions for use (IFU) may create ambiguity regarding which aspects of the procedure are fixed and which may vary depending on the operator or clinical conditions.  \n<i><b>Response:&nbsp;<\/b>We have now clarified that core procedural elements will be standardized prior to study initiation in the manuscript. An operation form capturing predefined procedural parameters will be completed for each procedure, and any deviations will be documented and reported. This approach is intended to enhance reproducibility while allowing documentation of clinically necessary variations.<\/i>   4. In the secondary analyses, it is planned to dichotomize the response to the GON block using a fixed threshold such as \u226530% and to calculate sensitivity and specificity.  While this approach is clinically intuitive, categorizing a continuous variable based on a single threshold may result in loss of information and may not fully reflect the predictive performance of the GON block across all possible thresholds  \n<i><b>Response:<\/b> We agree that dichotomising a continuous outcome may result in loss of information. This is why the primary analysis evaluates the association between responses to the two interventions as continuous variables using linear regression. The dichotomised responder analyses (30%, 50%, and PGI-C\u2013based thresholds) are prespecified secondary analyses intended to explore potential clinical applicability across commonly used responder definitions.<\/i>","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2#referee-comment-15380","order":3,"name":"referee-comment-15380","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.196068.r458946, Nourhan Abdelmohsen Taha, Ain Shams University, Cairo, Cairo Governorate, 27 Feb 2026, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2#referee-response-458946","order":4,"name":"referee-response-458946","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.196068.r486407, Faraidoon Haghdoost, The George Institute for Global Health, Sydney, New South Wales, 19 Jun 2026, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2#referee-response-486407","order":5,"name":"referee-response-486407","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.196068.r488434, Dagmareier Beier, Odense University Hospital, Odense C, 26 Jun 2026, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/14-1157\/v2#referee-response-488434","order":6,"name":"referee-response-488434","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The DAM Foundation\r\nSDAM_FOR701626. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":7,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}