{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:54:39Z","timestamp":1782917679306,"version":"3.54.5"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Syst. Neurosci."],"abstract":"<jats:p>Ketamine responses vary across patients and sessions, suggesting that dose alone is an incomplete organizing principle. We propose a state-first Gate-Amplifier-Reintegration framework in which awake low-dose ketamine acts primarily as an Amplifier of transient network flexibility, whereas autonomic-salience stability is treated as a candidate Gate that may shape whether this flexibility remains steerable. In this framework, cardio-autonomic and interoceptive state may constrain or modulate salience-network gain, interoceptive precision, and thalamocortical selectivity, thereby influencing whether ketamine-associated loosening of default-mode constraints is available for frontoparietal-control-compatible reintegration or drifts toward dysphoric dissociation and vigilance instability. We formalize a three-step sequence: Gate, Amplifier, Reintegration. Gate refers to candidate autonomic-salience stability; Amplifier refers to awake low-dose ketamine delivered under operational invariants that preserve vigilance and behavioral interpretability; Reintegration refers to the organization of ketamine-amplified flexibility into language, joint attention, task context, and action-oriented consolidation. Heart-rate variability (HRV) is used only as a bounded peripheral state-verification proxy. We distinguish observed Autonomic Affirmative Window quality assurance (AAW-QA), a post-sequence quality-assurance signal, from AAW-Gate, a proposed prospective pre-dose criterion. The framework is informed by, but not validated by, observations from a single-center outpatient chronic pain care pathway using awake low-dose ketamine and route-defined cervicothoracic sympathetic modulation. These observations document clinical provenance but do not provide comparative efficacy evidence, causal efficacy, dose-sparing evidence, salience-network mediation, or HRV biomarker validity. The clinical provenance was nonrandomized, chart-based, clinician-directed, and lacked concurrent neural measurement. The framework yields falsifiable predictions: prospective Gate manipulation should reproducibly alter pre-dose autonomic state; prospectively defined AAW-Gate-positive sessions should be tested for convergence with low-burden EEG\/fNIRS markers of salience switching and task control; and randomized Gate designs should determine whether autonomic shifts moderate, and in adequately powered designs mediate, session-level tolerability, reintegration, and usable clinical change. Alternative accounts, including analgesia, expectancy, clinician attention, workflow era, documentation bias, respiratory\/postural effects, and photoplethysmography (PPG) artifact, are treated as competing explanations that future designs must separate.<\/jats:p>","DOI":"10.3389\/fnsys.2026.1880737","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:19:44Z","timestamp":1782915584000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Autonomic-salience stability as a candidate Gate for awake low-dose ketamine: a systems neuroscience framework with a clinical anchor"],"prefix":"10.3389","volume":"20","author":[{"given":"Kei","family":"Torii","sequence":"first","affiliation":[{"name":"Tokyo Anesthesiology Clinic","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maho","family":"Jinno","sequence":"additional","affiliation":[{"name":"Nagoya Anesthesiology Clinic, Medical Corporation Shinkakai","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10503","DOI":"10.1523\/JNEUROSCI.1103-13.2013","article-title":"The autonomic brain: An activation likelihood estimation meta-analysis for central processing of autonomic function.","volume":"33","author":"Beissner","year":"2013","journal-title":"J. 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