{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:23:23Z","timestamp":1785155003944,"version":"3.55.0"},"reference-count":105,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":139,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["101017884"],"award-info":[{"award-number":["101017884"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["773121"],"award-info":[{"award-number":["773121"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Parkinson\u2019s disease is characterized by progressive degeneration of dopaminergic neurons within the nigrostriatal pathway, leading to motor and non-motor deficits that become less responsive to chronic dopaminergic pharmacotherapy. Here, we examined whether a multimodal mobile digital intervention, DopApp\u2122, delivering adaptive daily training across sensorimotor, psychological and rehabilitation domains, can induce functional reorganization of thalamocortical motor and limbic networks and augment dopaminergic treatment effects in Parkinson\u2019s disease. To test this hypothesis, we conducted a pilot study in 42 levodopa-treated patients randomized to a 3-week DopApp\u2122 or placebo app intervention. Clinical, psychological and resting-state functional MRI assessments were acquired at baseline and post-treatment. Compared with the placebo group, the active group showed greater motor improvements, as assessed by total scores on the Movement Disorder Society-Unified Parkinson\u2019s Disease Rating Scale (MDS-UPDRS; P &amp;lt; 0.001; d = 1.22). These improvements were driven by gains in motor function (Part III: P &amp;lt; 0.001; d = 1.16) and activities of daily living (Part II: P &amp;lt; 0.05; d = 0.68). Depressive symptoms also improved during the intervention (Beck\u2019s Depression Inventory II: P &amp;lt; 0.05; d = 0.76), representing a parallel non-motor gain. Seed-based resting-state analyses revealed increased group-by-time connectivity within two parallel thalamocortical pathways. In the motor pathway, connectivity strengthened between the bilateral ventral lateral thalamic nuclei and primary motor cortex (PFDR &amp;lt; 0.05), correlating with motor improvement (MDS-UPDRS Part III: r = \u22120.72; P &amp;lt; 0.05). In parallel, increased connectivity was observed within the limbic circuit linking the anteroventral thalamus with medial prefrontal, posterior cingulate and hippocampal regions (PFDR &amp;lt; 0.05). Connectivity increases within this pathway correlated with improved depressive symptoms (r = \u22120.65; P &amp;lt; 0.01) and self-perceived daily function (MDS-UPDRS Part II: r = \u22120.66; P &amp;lt; 0.01). Additionally, engagement with specific app modules predicted domain-specific gains, and connectivity changes correlated with these improvements, suggesting a dose\u2013response relationship and parallel circuit-specific neuroplasticity. These findings provide preliminary evidence supporting the integration of scalable digital interventions into precision, drug-digital treatment paradigms for Parkinson\u2019s disease and related neurodegenerative disorders. Moreover, they represent a conceptual advance towards personalized care models that enhance drug efficacy and expand therapeutic impact beyond conventional clinical settings.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag148","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:44:11Z","timestamp":1777031051000},"source":"Crossref","is-referenced-by-count":1,"title":["Neural correlates of Parkinson\u2019s improvements after combined digital-levodopa therapy: a pilot study"],"prefix":"10.1093","volume":"8","author":[{"given":"Merav","family":"Catalogna","sequence":"first","affiliation":[{"name":"The Dina Recanati School of Medicine, Reichman University , Herzliya 4610101 ,","place":["Israel"]},{"name":"The Baruch Ivcher Institute for Brain, Cognition, and Technology, Baruch Ivcher School of Psychology, Reichman University , Herzliya 4610101 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nira","family":"Saporta","sequence":"additional","affiliation":[{"name":"Remepy Health Ltd , Scientific Department, Ramat Gan 5252247 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Tamir","sequence":"additional","affiliation":[{"name":"Remepy Health Ltd , Scientific Department, Ramat Gan 5252247 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shira","family":"Molcho","sequence":"additional","affiliation":[{"name":"Remepy Health Ltd , Scientific Department, Ramat Gan 5252247 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rotem","family":"Sivan Hoffmann","sequence":"additional","affiliation":[{"name":"Radiology Department, Meir Medical Center , Kfar Sava 4428164 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"De Picciotto","sequence":"additional","affiliation":[{"name":"Remepy Health Ltd , Scientific Department, Ramat Gan 5252247 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shai","family":"Erlich","sequence":"additional","affiliation":[{"name":"Remepy Health Ltd , Scientific Department, Ramat Gan 5252247 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Oren","sequence":"additional","affiliation":[{"name":"Remepy Health Ltd , Scientific Department, Ramat Gan 5252247 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahar","family":"Shelly","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rambam Medical Center , Haifa 3109601 ,","place":["Israel"]},{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa 3200003 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Amedi","sequence":"additional","affiliation":[{"name":"The Dina Recanati School of Medicine, Reichman University , Herzliya 4610101 ,","place":["Israel"]},{"name":"The Baruch Ivcher Institute for Brain, Cognition, and Technology, Baruch Ivcher School of Psychology, Reichman University , Herzliya 4610101 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"issue":"7","key":"2026052008313905400_fcag148-B1","doi-asserted-by":"crossref","first-page":"e464","DOI":"10.1016\/S2666-7568(24)00094-1","article-title":"Temporal trends in the prevalence of Parkinson\u2019s disease from 1980 to 2023: A systematic review and meta-analysis","volume":"5","author":"Zhu","year":"2024","journal-title":"Lancet Healthy Longev."},{"issue":"24","key":"2026052008313905400_fcag148-B2","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1056\/NEJMoa033447","article-title":"Levodopa and the progression of Parkinson\u2019s disease","volume":"351","author":"Fahn","year":"2004","journal-title":"N Engl J Med"},{"issue":"1","key":"2026052008313905400_fcag148-B3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1080\/14737175.2023.2176220","article-title":"Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach","volume":"23","author":"Lees","year":"2023","journal-title":"Expert Rev Neurother."},{"key":"2026052008313905400_fcag148-B4","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1016\/j.parkreldis.2020.09.024","article-title":"Unmet needs in Parkinson disease: Motor and non-motor","volume":"80","author":"LeWitt","year":"2020","journal-title":"Parkinsonism Relat Disord."},{"key":"2026052008313905400_fcag148-B5","doi-asserted-by":"crossref","first-page":"j1951","DOI":"10.1136\/bmj.j1951","article-title":"Parkinson\u2019s disease: Summary of updated NICE guidance","volume":"358","author":"Rogers","year":"2017","journal-title":"BMJ"},{"issue":"1","key":"2026052008313905400_fcag148-B6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1468-1331.2012.03866.x","article-title":"Summary of the recommendations of the EFNS\/MDS-ES review on therapeutic management of Parkinson\u2019s 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