{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:09:47Z","timestamp":1768568987045,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,21]]},"group-title":"Psychiatry and Clinical Psychology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"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":[[2024,10,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition (E\/I) ratio is discussed as a potential pathomechanism but in-vivo evidence of disturbed neurotransmission underlying these functional alterations remains scarce. We compared rs-fMRI local activity (LCOR) between ASD (N=405, N=395) and neurotypical controls (N=473, N=474) in two independent cohorts (ABIDE1 and ABIDE2). We then tested how these LCOR alterations co-localize with specific neurotransmitter systems derived from nuclear imaging and compared them with E\/I changes induced by GABAergic (midazolam) and glutamatergic medication (ketamine). Across both cohorts, ASD subjects consistently exhibited reduced LCOR, particularly in higher-order default mode network nodes, alongside increases in bilateral temporal regions, the cerebellum, and brainstem. These LCOR alterations negatively co-localized with dopaminergic (D1, D2, DAT), glutamatergic (NMDA, mGluR5), GABAergic (GABAa) and cholinergic neurotransmission (VAChT). The NMDA-antagonist ketamine, but not GABAa-potentiator midazolam, induced LCOR changes which co-localize with D1, NMDA and GABAa receptors, thereby resembling alterations observed in ASD. We find consistent local activity alterations in ASD to be spatially associated with several major neurotransmitter systems. NMDA-antagonist ketamine induced neurochemical changes similar to ASD-related alterations, supporting the notion that pharmacological modulation of the E\/I balance in healthy individuals can induce ASD-like functional brain changes. These findings provide novel insights into neurophysiological mechanisms underlying ASD.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary:<\/jats:title>\n                  <jats:p>Local activity alterations in ASD co-localize with glutamatergic and GABAergic neurotransmission and were similar to ketamine-induced brain changes.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.10.20.24315801","type":"posted-content","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T13:05:17Z","timestamp":1729515917000},"source":"Crossref","is-referenced-by-count":1,"title":["Local activity alterations in autism spectrum disorder correlate with neurotransmitter properties and ketamine induced brain changes"],"prefix":"10.64898","author":[{"given":"Pascal","family":"Grumbach","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Kasper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7875-2988","authenticated-orcid":false,"given":"Joerg F.","family":"Hipp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3283-2691","authenticated-orcid":false,"given":"Anna","family":"Forsyth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2998-6849","authenticated-orcid":false,"given":"Sofie L.","family":"Valk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7042-3920","authenticated-orcid":false,"given":"Suresh","family":"Muthukumaraswamy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6363-2759","authenticated-orcid":false,"given":"Simon B.","family":"Eickhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5547-8309","authenticated-orcid":false,"given":"Leonhard","family":"Schilbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0492-5644","authenticated-orcid":false,"given":"Juergen","family":"Dukart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024102318051425000_2024.10.20.24315801v1.1","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00406-020-01189-w","article-title":"Missed diagnoses and misdiagnoses of adults with autism spectrum disorder","volume":"272","year":"2022","journal-title":"Eur. 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