Target variability and stability for precision fMRI-guided TMS of the amygdala circuitry in a clinical trial for PTSD

Target variability and stability of neuroimaging-guided transcranial magnetic stimulation of the amygdala circuitry for posttraumatic stress disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Target variability and stability of neuroimaging-guided transcranial magnetic stimulation of the amygdala circuitry for posttraumatic stress disorder Sanne van Rooij, Cecilia Hinojosa, Patlapa Sompolpong, Malin Au, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8321466/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Background: Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation therapy that is applied across psychiatric conditions to modulate specific neural circuits and improve clinical symptoms. While functional magnetic resonance imaging (fMRI)-guided personalized TMS targets are increasingly used, there are critical unresolved methodological, neurobiological, and clinical questions. Addressing topographic variability, stability, and associations with clinical outcomes is essential for advancing clinical development and scalable precision neuromodulation. Methods: A precision neurocircuitry-based fMRI-guided TMS approach was developed to treat disorders of the amygdala. In a randomized clinical trial for posttraumatic stress disorder (PTSD; n=50), topographic variability and stability of patient-specific right dorsolateral prefrontal cortex (rDLPFC) targets with the strongest functional connectivity to the right amygdala were analyzed. Results: There was significant target variability between participants and between targeting methods, but target stability was observed after engaging the amygdala circuitry with behavioral threat-related tasks. Target topography did not change after 20 sessions of sham TMS. However, after active TMS (1Hz, 36,000 pulses) target topography was significantly different. A larger change in the medial-anterior direction correlated with greater PTSD symptom improvement. Conclusions: Target variability and stability for fMRI-guided TMS of the amygdala circuitry is demonstrated, supporting the use of patient-specific targeting strategies for TMS. A clinical change in PTSD symptoms was associated with greater change in target topography, which suggests neuroplastic adaptations in the targeted networks and a possible treatment-dependent shift towards more medial prefrontal control over amygdala regulation. These findings are important for fMRI-guided precision neuromodulation therapy development, particularly for the amygdala circuitry. Biological sciences/Neuroscience/Neural circuits Health sciences/Diseases/Psychiatric disorders/Post-traumatic stress disorder transcranial magnetic stimulation (TMS) neuronavigation resting state functional connectivity (rs-FC) functional magnetic resonance imaging (fMRI) precision psychiatry threat neurocircuitry Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations The authors declare potential competing interests as follows: Dr. van Rooij is a consultant for Skyland Trail, Motif Neuro, and is compensated as the chair of the DSMB for a NIMH sponsored study. Dr. Riva-Posse has received consulting fees from LivaNova, Abbott, Johnson and Johnson, and Motif Neuro. Dr. Rauch receives royalties from Oxford University Press and American Psychological Association Press and served on an advisory board for Otsuka Pharmaceuticals and the Anxiety and Depression Association of America. Dr. Holtzheimer receives royalties from Oxford University Press and UpToDate. All other authors declare no conflicts of interest, financial or otherwise. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. William M. McDonald, M.D. was a member of the American Psychiatric Association (APA) Council on Research representing ECT and Neuromodulation Therapies until 2024. He has received funding from NIMH and NIA. Dr. McDonald is compensated as the chair of the DSMB for an NIA and NIMH sponsored multicenter study. He is on the boards of Skyland Trail and 3Keys. He is on the editorial boards of the American Journal of Geriatric Psychiatry, Brain Stimulation and Personalized Medicine in Psychiatry. He is compensated for his role as a Deputy Editor of the American Journal of Psychiatry. He received honorarium from the Lurie Endowed Psychiatric Lecture Series, University of Cincinnati College of Medicine (2023) and expenses for grand rounds at the University of Texas, Austin (2023). He has endowed chair funded by the JB Fuqua Foundation and is an employee of Emory School of Medicine. All other authors declare no conflicts of interest, financial or otherwise.Dr. Camprodon is on the scientific advisory board for Flow Neuroscience, and Grey Matter Neuroscience, and is a consultant for Neuroelectrics and Fisher Wallace. All other authors declare no conflicts of interest, financial or otherwise. Supplementary Files BPSvanRooijSupplementalMaterials.docx Supplemental Materials Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8321466","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":559412901,"identity":"b2f906f4-07ae-4a32-af87-7853b6524454","order_by":0,"name":"Sanne van Rooij","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/klEQVRIiWNgGAWjYPADAzY5GJOxgVgtxqRqYWBIhKnEqUW+/eyxBx8YDsubM/A+fPChgC+9X+zwsc88DDayGw7gcMmZvHTDGQyHDXc2sBsbzjBgy505Oy15Ng9DmjFOLQw5ZtJABYwbDrCxSfMAtWy4nWPMzMNwOBGXFvn+N2bSfxjS7GFa0u0hWv7j1MJwA2gLA4NNIkxLgoE0WMsBnFoMbrwxk+wxsEnecJiNGeQXwxm305IZ5xgkG8/E6bAcM4kfFRK2G463MT748OeYPP/s5MMMbyrsZPtwOQwaCAwMzGDWMTDJxGOATzkqqAGTjD+I1zEKRsEoGAXDHwAASt9Sao5kcbQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0160-7248","institution":"Emory University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Sanne","middleName":"van","lastName":"Rooij","suffix":""},{"id":559412902,"identity":"498e7dcc-d335-41b7-96aa-a128f28c765a","order_by":1,"name":"Cecilia Hinojosa","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences; University of New Mexico, Department of Psychology","correspondingAuthor":false,"prefix":"","firstName":"Cecilia","middleName":"","lastName":"Hinojosa","suffix":""},{"id":559412903,"identity":"0f8a55fe-3450-442d-9b80-42606d905709","order_by":2,"name":"Patlapa Sompolpong","email":"","orcid":"","institution":"Emory University Laney Graduate School, Graduate Division of Biological and Biomedical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Patlapa","middleName":"","lastName":"Sompolpong","suffix":""},{"id":559412904,"identity":"e2071171-e152-4037-9485-7238c70c5f8e","order_by":3,"name":"Malin Au","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences; Amsterdam University Medical Center, Department of Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Malin","middleName":"","lastName":"Au","suffix":""},{"id":559412905,"identity":"c5da2bb5-b55c-4612-bbc8-6748904eee05","order_by":4,"name":"Lois Teye-Botchway","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences","correspondingAuthor":false,"prefix":"","firstName":"Lois","middleName":"","lastName":"Teye-Botchway","suffix":""},{"id":559412906,"identity":"125615da-caf1-4333-b56a-e9f696f7b244","order_by":5,"name":"Timothy Ely","email":"","orcid":"https://orcid.org/0000-0002-5690-5234","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"","lastName":"Ely","suffix":""},{"id":559412907,"identity":"b4cb8530-31f3-4fe5-b515-8eeb788b52c4","order_by":6,"name":"Gregory Job","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences","correspondingAuthor":false,"prefix":"","firstName":"Gregory","middleName":"","lastName":"Job","suffix":""},{"id":559412908,"identity":"e4807ac1-c63a-49d8-90ad-9c050787eaf3","order_by":7,"name":"Sean Minton","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sean","middleName":"","lastName":"Minton","suffix":""},{"id":559412909,"identity":"bfba767c-8815-4187-bbd0-48cf69ab08bb","order_by":8,"name":"Ryan Langhinrichsen-Rohling","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Langhinrichsen-Rohling","suffix":""},{"id":559412910,"identity":"2fb15244-b95a-4415-8962-12d88bc59844","order_by":9,"name":"Patricio Riva-Posse","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences","correspondingAuthor":false,"prefix":"","firstName":"Patricio","middleName":"","lastName":"Riva-Posse","suffix":""},{"id":559412911,"identity":"c367c579-2f66-4c21-a44c-e6bd38148736","order_by":10,"name":"Joshua Lukemire","email":"","orcid":"","institution":"Emory University Rollins School of Public Health, Department of Biostatistics and Bioinformatics","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Lukemire","suffix":""},{"id":559412912,"identity":"7e1d589b-94c0-4955-a5d9-5f06f5c95d9d","order_by":11,"name":"Kerry Ressler","email":"","orcid":"https://orcid.org/0000-0002-5158-1103","institution":"McLean Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kerry","middleName":"","lastName":"Ressler","suffix":""},{"id":559412913,"identity":"9a3c86ff-2609-4f6c-b88f-a8cb47611f76","order_by":12,"name":"Nadine Kaslow","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nadine","middleName":"","lastName":"Kaslow","suffix":""},{"id":559412914,"identity":"071d4103-def0-49e8-ad30-0045f66b9ea9","order_by":13,"name":"Sheila Rauch","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences; Joseph Maxwell Cleland Atlanta VA Healthcare System","correspondingAuthor":false,"prefix":"","firstName":"Sheila","middleName":"","lastName":"Rauch","suffix":""},{"id":559412915,"identity":"6d8d04c6-3740-44ca-bf25-d0cb05ec9d16","order_by":14,"name":"Tanja Jovanovic","email":"","orcid":"https://orcid.org/0000-0002-6456-0053","institution":"Wayne State University","correspondingAuthor":false,"prefix":"","firstName":"Tanja","middleName":"","lastName":"Jovanovic","suffix":""},{"id":559412916,"identity":"97e6de39-7319-4c57-9117-ea14ef3f70ba","order_by":15,"name":"Paul Holtzheimer","email":"","orcid":"","institution":"National Center for PTSD; Dartmouth Geisel School of Medicine, Departments of Psychiatry and Surgery","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"Holtzheimer","suffix":""},{"id":559412917,"identity":"aebaaaa9-fdbb-4be9-a1ac-d0f963dd7639","order_by":16,"name":"Vince Calhoun","email":"","orcid":"https://orcid.org/0000-0001-9058-0747","institution":"Georgia State University","correspondingAuthor":false,"prefix":"","firstName":"Vince","middleName":"","lastName":"Calhoun","suffix":""},{"id":559412918,"identity":"2d291dc7-55ce-4a3f-b4c3-6fc865fea6ae","order_by":17,"name":"William McDonald","email":"","orcid":"","institution":"Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"McDonald","suffix":""},{"id":559412919,"identity":"9a741219-646b-4146-9318-897faedff779","order_by":18,"name":"Joan Camprodon","email":"","orcid":"","institution":"Massachusetts General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Joan","middleName":"","lastName":"Camprodon","suffix":""}],"badges":[],"createdAt":"2025-12-09 22:35:12","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8321466/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-8321466/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101148853,"identity":"e07f95cb-1ea9-42f3-850a-fe900be1ac76","added_by":"auto","created_at":"2026-01-26 15:27:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":208716,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT diagram and study overview\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA CONSORT diagram and schematic overview of the clinical trial (\u003ca href=\"https://clinicaltrials.gov/study/NCT04563078\"\u003ehttps://clinicaltrials.gov/study/NCT04563078\u003c/a\u003e). A total of 1,251 participants were assessed for eligibility, 63 were randomized and 50 participants were randomized to two weeks (20 sessions) of 1Hz active or sham TMS. Prior to the first TMS session, an functional magnetic resonance imaging (fMRI) scan was collected. On the scan day, two resting state fMRI scans were collected, one before and after functional engagement of the threat neurocircuitry using fMRI paradigms. The fMRI paradigms included \u0026nbsp;social threat processing (left), contextual response inhibition using the Stop Signal Anticipation Task (middle) and fear conditioning (right). The social threat processing task is based on our previous work with trauma-exposed civilians (11,12,37). Participants passively viewed blocks of fearful and neutral face stimuli, with emotion condition randomly interleaved. Contextual response inhibition was measured with the Stop Signal Anticipation Task (SSAT) following our prior work with trauma-exposed civilians(38). In this task, participants are instructed to stop a moving bar by pressing a button but withhold their response in instances when the bar stops on its own. Contextual cues indicate the chance that the bar stops on its own, allowing for a measure of contextual inhibition. Third, participants completed a\u003cem\u003e Fear Conditioning \u003c/em\u003etask, also previously used in our research with trauma-exposed civilians.(39) This paradigm was used to measure fear learning by pairing an aversive sound with a yellow or blue lamp. The TMS target used for the clinical trial was defined based on the first resting state scan using positive resting state functional connectivity. Usable targets were available for n=46 and used to measure varability between subjects (Question, Q1). For our analyses of variability between methods (Q2), the anti-correlated or negative target was calculated (n=46). To measure stability of the target (Q3), the target was again defined after engagement of the threat neurocircuitry (n=44 with usable data). After completing 20 session of active or sham TMS (n=47), another fMRI scan was collected. The target was again defined and compared with the pre-TMS target to analyze the effect of active versus sham TMS (Q4) on target topography (n=22, active; n=19, sham).\u003c/p\u003e","description":"","filename":"Figure1CONSORTTMStargeting.png","url":"https://assets-eu.researchsquare.com/files/rs-8321466/v2/cb9c8d9cdbb5f8c1f66acf67.png"},{"id":101148850,"identity":"342278ca-2fb9-4aa5-a37a-53f95ecd4fdc","added_by":"auto","created_at":"2026-01-26 15:27:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2178500,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePipeline for personalized fMRI-guided rDLPFC TMS target definition.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResting state functional MRI was collected prior to transcranial magnetic stimulation (TMS). A correlation map between the extracted timecourse of the right amygdala region of interest (CIT168) and the right dorsolateral prefrontal cortex (rDLPFC) region of interest (BA8, BA9,BA10,BA46; WFU_PickAtlas) was generated and unwarped into native space. Brainsight neuronavigation was used to identify the TMS target. The TMS target in the right dorsolateral prefrontal cortex (rDLPFC) was defined as the positive correlation in functional connectivity to the right amygdala for pre-TMS scan 1. Three criteria were used: 1. Largest positive resting state functional connectivity (rs-FC) peak, 2. Peak within 1.0 cm of the cortex, 3. Location tolerable for 3600 1Hz TMS pulses per day.\u003c/p\u003e","description":"","filename":"Figure2DLPFCpipeline.png","url":"https://assets-eu.researchsquare.com/files/rs-8321466/v2/aaa57ab35f29f9ad5997b40c.png"},{"id":101148851,"identity":"ad2740ed-9220-4adc-8064-fabc5bf8f7f7","added_by":"auto","created_at":"2026-01-26 15:27:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1050475,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePersonalized fMRI-guided rDLPFC TMS target variability between subjects and methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e (Top) Targets in the right dorsolateral prefrontal cortex (rDLPFC) with positive correlation in functional connectivity to the right amygdala for pre-TMS scan 1(positively defined targets; n=46) mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of positively defined targets. \u003cstrong\u003eb\u003c/strong\u003e. (Top) Targets in rDLPFC with negative correlation (anti-correlation) in functional connectivity to the right amygdala for the pre-TMS scan 1 (negatively defined targets; n=46) mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of negatively defined targets. \u003cstrong\u003ec.\u003c/strong\u003e \u0026nbsp;Example pre-TMS positively defined targets from subjects A, B, and C and their corresponding electric field, or e-field, models simulated using SimNIBS based on each participant’s motor threshold (MT) and maximum stimulator output (MSO), overlayed on their head mesh constructed from T1w structural scans (\u003cem\u003e\u003cstrong\u003eSupplemental Materials S2 \u003c/strong\u003e\u003c/em\u003efor details).\u003c/p\u003e","description":"","filename":"Figure3variability.png","url":"https://assets-eu.researchsquare.com/files/rs-8321466/v2/5c9e6475ee45daaae473f506.png"},{"id":101148855,"identity":"f8bc49da-f037-4601-b65f-a78308ec610f","added_by":"auto","created_at":"2026-01-26 15:27:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":313667,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTMS target stability after engaging threat neurocircuit behaviorally\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e. (Top) Targets in the right dorsolateral prefrontal cortex (rDLPFC) with positive correlation in functional connectivity to the right amygdala for pre-TMS scan 1(positively defined targets; n = 44) mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of pre-TMS positively defined targets using scan 1. \u003cstrong\u003eb\u003c/strong\u003e. (Top) Positively defined targets within the rDLPFC using pre-TMS scan 2 (n=44) collected after engaging the threat circuit behaviorally with threat processing, contextual inhibition, and fear conditioning tasks. Targets are mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of pre-TMS positively defined targets using scan 2 collected following fMRI task.\u003c/p\u003e","description":"","filename":"Figure4stability.png","url":"https://assets-eu.researchsquare.com/files/rs-8321466/v2/d59eebbf9e2eade736e88262.png"},{"id":101148854,"identity":"98e6c1c8-1026-4d4a-add9-790b97347a97","added_by":"auto","created_at":"2026-01-26 15:27:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":665302,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of active \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eversus\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e sham TMS on personalized fMRI-guided rDLPFC target\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea. \u003c/strong\u003e(Top) Targets in the right dorsolateral prefrontal cortex (rDLPFC) with positive correlation in functional connectivity to the right amygdala for pre-TMS scan 1(positively defined targets) in the active TMS group (n=22) mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of pre-TMS positively defined targets. \u003cstrong\u003eb\u003c/strong\u003e.\u003cstrong\u003e \u003c/strong\u003e(Top) Positively defined targets within the rDLPFC using post-TMS scan in the active group (n=22) mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of post-TMS positively defined targets. There is a significant change in TMS target topography in the active group from pre- to post-TMS. \u003cstrong\u003ec\u003c/strong\u003e. (Top) Positively defined targets within the rDLPFC using pre-TMS scan in the sham group (n = 19) mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of pre-TMS positively defined targets. \u003cstrong\u003ed\u003c/strong\u003e.\u003cstrong\u003e \u003c/strong\u003e(Top) Positively defined targets within the rDLPFC using post-TMS scan in the sham group (n=19) mapped to a common MNI template. (Bottom) Density plot showing the distribution of the x, y, and z MNI coordinates of post-TMS positively defined targets. There is no significant change in TMS target topography in the sham group from pre- to post-TMS. \u003cstrong\u003ee.\u003c/strong\u003e Box plots show the change from pre-TMS to post-TMS for x (active, mean 2.2cm; sham, mean 2.4cm), y (active, mean 2.7cm; sham, mean 2.0cm) and z (active, mean 1.8cm; sham, mean 1.9cm).\u003c/p\u003e","description":"","filename":"Figure5effectTMS.png","url":"https://assets-eu.researchsquare.com/files/rs-8321466/v2/7caa80003fee06f19df9aa78.png"},{"id":101751229,"identity":"ffc3f1fa-eb12-4df2-bed3-7acd00e29daa","added_by":"auto","created_at":"2026-02-03 10:18:29","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2977870,"visible":true,"origin":"","legend":"","description":"","filename":"BPSvanRooijetalTMStargeting.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8321466/v2_covered_3813d759-19b0-4789-85aa-3f1ca80046c1.pdf"},{"id":101148852,"identity":"39ac5a92-f123-4e74-a136-06adf47141c6","added_by":"auto","created_at":"2026-01-26 15:27:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":51337,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Materials\u003c/p\u003e","description":"","filename":"BPSvanRooijSupplementalMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-8321466/v2/e345f4c83a259c50d9c57e0f.docx"}],"financialInterests":"The authors declare potential competing interests as follows: Dr. van Rooij is a consultant for Skyland Trail, Motif Neuro, and is compensated as the chair of the DSMB for a NIMH sponsored study. Dr. Riva-Posse has received consulting fees from LivaNova, Abbott, Johnson and Johnson, and Motif Neuro. Dr. Rauch receives royalties from Oxford University Press and American Psychological Association Press and served on an advisory board for Otsuka Pharmaceuticals and the Anxiety and Depression Association of America. Dr. Holtzheimer receives royalties from Oxford University Press and UpToDate. All other authors declare no conflicts of interest, financial or otherwise. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. William M. McDonald, M.D. was a member of the American Psychiatric Association (APA) Council on Research representing ECT and Neuromodulation Therapies until 2024. He has received funding from NIMH and NIA. Dr. McDonald is compensated as the chair of the DSMB for an NIA and NIMH sponsored multicenter study. He is on the boards of Skyland Trail and 3Keys. He is on the editorial boards of the American Journal of Geriatric Psychiatry, Brain Stimulation and Personalized Medicine in Psychiatry. He is compensated for his role as a Deputy Editor of the American Journal of Psychiatry. He received honorarium from the Lurie Endowed Psychiatric Lecture Series, University of Cincinnati College of Medicine (2023) and expenses for grand rounds at the University of Texas, Austin (2023). He has endowed chair funded by the JB Fuqua Foundation and is an employee of Emory School of Medicine. All other authors declare no conflicts of interest, financial or otherwise.Dr. Camprodon is on the scientific advisory board for Flow Neuroscience, and Grey Matter Neuroscience, and is a consultant for Neuroelectrics and Fisher Wallace. All other authors declare no conflicts of interest, financial or otherwise.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eTarget variability and stability of neuroimaging-guided transcranial magnetic stimulation of the amygdala circuitry for posttraumatic stress disorder\u003c/strong\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"transcranial magnetic stimulation (TMS), neuronavigation, resting state functional connectivity (rs-FC), functional magnetic resonance imaging (fMRI), precision psychiatry, threat neurocircuitry ","lastPublishedDoi":"10.21203/rs.3.rs-8321466/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8321466/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/em\u003e Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation therapy that is applied across psychiatric conditions to modulate specific neural circuits and improve clinical symptoms. While functional magnetic resonance imaging (fMRI)-guided personalized TMS targets are increasingly used, there are critical unresolved methodological, neurobiological, and clinical questions. Addressing topographic variability, stability, and associations with clinical outcomes is essential for advancing clinical development and scalable precision neuromodulation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/em\u003e A precision neurocircuitry-based fMRI-guided TMS approach was developed to treat disorders of the amygdala. In a randomized clinical trial for posttraumatic stress disorder (PTSD; n=50), topographic variability and stability of patient-specific right dorsolateral prefrontal cortex (rDLPFC) targets with the strongest functional connectivity to the right amygdala were analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/em\u003e There was significant target variability between participants and between targeting methods, but target stability was observed after engaging the amygdala circuitry with behavioral threat-related tasks. Target topography did not change after 20 sessions of sham TMS. However, after active TMS (1Hz, 36,000 pulses) target topography was significantly different. A larger change in the medial-anterior direction correlated with greater PTSD symptom improvement.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/em\u003e Target variability and stability for fMRI-guided TMS of the amygdala circuitry is demonstrated, supporting the use of patient-specific targeting strategies for TMS. A clinical change in PTSD symptoms was associated with greater change in target topography, which suggests neuroplastic adaptations in the targeted networks and a possible treatment-dependent shift towards more medial prefrontal control over amygdala regulation. These findings are important for fMRI-guided precision neuromodulation therapy development, particularly for the amygdala circuitry.\u003c/p\u003e","manuscriptTitle":"Target variability and stability of neuroimaging-guided transcranial magnetic stimulation of the amygdala circuitry for posttraumatic stress disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-01-26 15:26:55","doi":"10.21203/rs.3.rs-8321466/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-12-12 13:12:53","doi":"10.21203/rs.3.rs-8321466/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d2628788-8398-4333-ae0d-7fe88636832d","owner":[],"postedDate":"January 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61453680,"name":"Biological sciences/Neuroscience/Neural circuits"},{"id":61453681,"name":"Health sciences/Diseases/Psychiatric disorders/Post-traumatic stress disorder"}],"tags":[],"updatedAt":"2025-12-18T15:48:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-26 15:26:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-8321466","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8321466","identity":"rs-8321466","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}