{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T20:30:07Z","timestamp":1773865807084,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,16]]},"group-title":"Psychiatry and Clinical Psychology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Tobacco use is a leading cause of mortality in schizophrenia, but treatments are partially effective. Default mode network (DMN) pathology is linked to tobacco use in schizophrenia, and transcranial magnetic stimulation (TMS) applied to the DMN affects craving in schizophrenia. To advance TMS therapeutics for tobacco use in schizophrenia, we used TMS experiments to 1) determine optimal stimulation parameters then 2) compare our optimal parameters against a well-established, effective TMS intervention for craving.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In Protocol Optimization TMS, nicotine-using individuals with schizophrenia (n=10) received single sessions of DMN-targeted TMS with pre\/post neuroimaging and craving assessment. Neuroimaging analysis revealed bilateral parietal DMN connectivity was associated with craving change. In Comparative Effectiveness TMS (n=62), nicotine-using individuals with schizophrenia and non-psychosis controls participated in a crossover study comparing DMN-targeted and left dorsolateral prefrontal cortex (DLFPC)-targeted TMS with pre\/post neuroimaging and craving assessment. Mixed effects models were used to determine effects of target, group, and relationship between craving change and connectivity change.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In Protocol Optimization TMS, increased craving was associated with increased bilateral parietal DMN connectivity (mean pFDR&lt;0.012, r=0.60). In Comparative Effectiveness TMS, both interventions reduced craving (DLPFC: p=0.0015; DMN: p=0.0054) and bilateral parietal DMN connectivity (DLPFC: p=0.024; DMN: p=0.022). There was an interaction of bilateral parietal DMN connectivity change, group, and age (p=0.001) where connectivity change was associated with craving change in older individuals with schizophrenia (p=0.041) but not other groups.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Bilateral parietal DMN connectivity is a novel mechanism underlying craving in schizophrenia that can be engaged for therapeutic benefit.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.14.26348404","type":"posted-content","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T01:15:24Z","timestamp":1773710124000},"source":"Crossref","is-referenced-by-count":0,"title":["A Novel Therapeutic Mechanism for Nicotine Craving in Schizophrenia"],"prefix":"10.64898","author":[{"given":"Heather Burrell","family":"Ward","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jillian G.","family":"Connolly","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia H.","family":"Blyth","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Vandekar","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baxter P.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Halko","sequence":"additional","affiliation":[{"name":"McLean Hospital and Harvard Medical School, Belmont, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catie","family":"Chang","sequence":"additional","affiliation":[{"name":"Departments of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary","family":"Tindle","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center and Geriatric Research Education and Clinical Centers, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. Elliot","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, University of Texas Health Houston and McGovern Medical School, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Eden","family":"Evins","sequence":"additional","affiliation":[{"name":"Center for Addiction Medicine and Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Heckers","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Roscoe O.","family":"Brady","sequence":"additional","affiliation":[{"name":"McLean Hospital and Harvard Medical School, Belmont, MA, USA"},{"name":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026031806050523000_2026.03.14.26348404v1.1","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.177.3.212"},{"key":"2026031806050523000_2026.03.14.26348404v1.2","doi-asserted-by":"publisher","DOI":"10.1080\/00048670802653372"},{"key":"2026031806050523000_2026.03.14.26348404v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-clinpsy-032813-153657"},{"issue":"1","key":"2026031806050523000_2026.03.14.26348404v1.4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1176\/appi.ps.202000032","article-title":"Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES","volume":"72","year":"2021","journal-title":"Psychiatr Serv"},{"key":"2026031806050523000_2026.03.14.26348404v1.5","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.824878"},{"key":"2026031806050523000_2026.03.14.26348404v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.804055"},{"key":"2026031806050523000_2026.03.14.26348404v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.04.251"},{"issue":"1","key":"2026031806050523000_2026.03.14.26348404v1.8","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1080\/15504263.2018.1526432","article-title":"Increased Connectivity Between the Nucleus Accumbens and the Default Mode Network in Patients With Schizophrenia During Cigarette Cravings","volume":"15","year":"2019","journal-title":"J Dual Diagn"},{"key":"2026031806050523000_2026.03.14.26348404v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809141106"},{"key":"2026031806050523000_2026.03.14.26348404v1.10","doi-asserted-by":"crossref","unstructured":"Ward HB , Blyth SH , Vandekar S , Rogers BP , Yildiz G , Connolly JG , et al. Defining and Engaging a Novel rTMS Target for Nicotine Craving in Psychotic Disorders. medRxiv. 2025.","DOI":"10.1101\/2025.09.24.25334160"},{"key":"2026031806050523000_2026.03.14.26348404v1.11","doi-asserted-by":"crossref","unstructured":"Mehta DD , Praecht A , Ward HB , Sanches M , Sorkhou M , Tang VM , et al. A systematic review and meta-analysis of neuromodulation therapies for substance use disorders. Neuropsychopharmacology. 2023.","DOI":"10.1038\/s41386-023-01776-0"},{"issue":"7","key":"2026031806050523000_2026.03.14.26348404v1.12","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1111\/add.15624","article-title":"Efficacy of non-invasive brain stimulation interventions in reducing smoking frequency in patients with nicotine dependence: a systematic review and network meta-analysis of randomized controlled trials","volume":"117","year":"2022","journal-title":"Addiction"},{"key":"2026031806050523000_2026.03.14.26348404v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-022-01453-8"},{"key":"2026031806050523000_2026.03.14.26348404v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s00406-013-0446-8"},{"key":"2026031806050523000_2026.03.14.26348404v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2018.11.036"},{"key":"2026031806050523000_2026.03.14.26348404v1.16","doi-asserted-by":"crossref","unstructured":"Freitas C , Perez J , Knobel M , Tormos JM , Oberman L , Eldaief M , et al. Changes in cortical plasticity across the lifespan. Front Aging Neurosci. 2011;3:5.","DOI":"10.3389\/fnagi.2011.00005"},{"issue":"2","key":"2026031806050523000_2026.03.14.26348404v1.17","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.brs.2017.01.003","article-title":"Priming theta burst stimulation enhances motor cortex plasticity in young but not old adults","volume":"10","year":"2017","journal-title":"Brain Stimul"},{"key":"2026031806050523000_2026.03.14.26348404v1.18","doi-asserted-by":"crossref","unstructured":"Young-Bernier M , Tanguay AN , Davidson PS , Tremblay F . Short-latency afferent inhibition is a poor predictor of individual susceptibility to rTMS-induced plasticity in the motor cortex of young and older adults. Front Aging Neurosci. 2014;6:182.","DOI":"10.3389\/fnagi.2014.00182"},{"key":"2026031806050523000_2026.03.14.26348404v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.15195"},{"key":"2026031806050523000_2026.03.14.26348404v1.20","doi-asserted-by":"publisher","DOI":"10.1089\/brain.2011.0019"},{"key":"2026031806050523000_2026.03.14.26348404v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2012.04.028"},{"key":"2026031806050523000_2026.03.14.26348404v1.22","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1992.sp019243"},{"key":"2026031806050523000_2026.03.14.26348404v1.23","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199711100-00024"},{"key":"2026031806050523000_2026.03.14.26348404v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/0168-5597(89)90030-0"},{"key":"2026031806050523000_2026.03.14.26348404v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2004.04.020"},{"key":"2026031806050523000_2026.03.14.26348404v1.26","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.54.4.956"},{"key":"2026031806050523000_2026.03.14.26348404v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1113103109"},{"key":"2026031806050523000_2026.03.14.26348404v1.28","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.59.12.1162"},{"key":"2026031806050523000_2026.03.14.26348404v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2006.10.026"},{"key":"2026031806050523000_2026.03.14.26348404v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300780"},{"key":"2026031806050523000_2026.03.14.26348404v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301618"},{"issue":"1","key":"2026031806050523000_2026.03.14.26348404v1.32","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41398-020-0775-0","article-title":"Neural substrates of smoking and reward cue reactivity in smokers: a meta-analysis of fMRI studies","volume":"10","year":"2020","journal-title":"Transl Psychiatry"},{"key":"2026031806050523000_2026.03.14.26348404v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.12.024"},{"key":"2026031806050523000_2026.03.14.26348404v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.12.034"},{"key":"2026031806050523000_2026.03.14.26348404v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2012.02.020"},{"key":"2026031806050523000_2026.03.14.26348404v1.36","doi-asserted-by":"crossref","first-page":"109919","DOI":"10.1016\/j.drugalcdep.2023.109919","article-title":"Negative affect and craving during abstinence from smoking are both linked to default mode network connectivity","volume":"249","year":"2023","journal-title":"Drug Alcohol Depend"},{"key":"2026031806050523000_2026.03.14.26348404v1.37","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-011-2221-8"},{"key":"2026031806050523000_2026.03.14.26348404v1.38","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5129-06.2007"},{"key":"2026031806050523000_2026.03.14.26348404v1.39","doi-asserted-by":"publisher","DOI":"10.1001\/jama.284.20.2606"},{"key":"2026031806050523000_2026.03.14.26348404v1.40","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.61.11.1107"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.14.26348404","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T13:05:21Z","timestamp":1773839121000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.03.14.26348404"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":40,"URL":"https:\/\/doi.org\/10.64898\/2026.03.14.26348404","relation":{},"subject":[],"published":{"date-parts":[[2026,3,16]]},"subtype":"preprint"}}