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The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of <jats:italic>n<\/jats:italic>\u2009=\u200979 patients with spider phobia (discovery sample) and <jats:italic>n<\/jats:italic>\u2009=\u200969 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of &gt;30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of &gt;50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.<\/jats:p>","DOI":"10.1038\/s41398-024-02799-x","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T19:01:54Z","timestamp":1709838114000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Association between resting-state connectivity patterns in the defensive system network and treatment response in spider phobia\u2014a replication approach"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9264-5003","authenticated-orcid":false,"given":"Elisabeth J.","family":"Leehr","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian R.","family":"Seeger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9870-5599","authenticated-orcid":false,"given":"Joscha","family":"B\u00f6hnlein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"Gathmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Straube","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6940-3551","authenticated-orcid":false,"given":"Kati","family":"Roesmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Jungh\u00f6fer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Schwarzmeier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niklas","family":"Siminski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9970-2122","authenticated-orcid":false,"given":"Martin J.","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Till","family":"Langhammer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janik","family":"Goltermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8718-0128","authenticated-orcid":false,"given":"Dominik","family":"Grotegerd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2177-7161","authenticated-orcid":false,"given":"Susanne","family":"Meinert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6241-1492","authenticated-orcid":false,"given":"Nils R.","family":"Winter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0623-3759","authenticated-orcid":false,"given":"Udo","family":"Dannlowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-4012","authenticated-orcid":false,"given":"Ulrike","family":"Lueken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"2799_CR1","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.cpr.2015.08.004","volume":"42","author":"AG Loerinc","year":"2015","unstructured":"Loerinc AG, Meuret AE, Twohig MP, Rosenfield D, Bluett EJ, Craske MG. 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