Autonomic-salience stability as a candidate Gate for awake low-dose ketamine: a systems neuroscience framework with a clinical anchor.

Overview

1. Tokyo Anesthesiology Clinic, Tokyo, Japan
2. Nagoya Anesthesiology Clinic, Medical Corporation Shinkakai, Nagoya, Japan

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data availability statement

The datasets presented in this article are not readily available because the underlying individual-level and session-level datasets are not publicly available and are not available as raw datasets by request because they derive from single-center routine clinical care records and may contain potentially re-identifiable clinical information even after de-identification. De-identified aggregate summaries supporting the clinical-anchor description are provided in the article and Supplementary Data Sheet 1. Selected additional de-identified summary materials may be considered upon reasonable request, subject to institutional approval, ethics requirements, and data protection constraints. Requests to access the datasets should be directed to KT, .

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 2 authors, 8 keywords, 36 references.

Cite

This paper

Torii, K., & Jinno, M. (2026). Autonomic-salience stability as a candidate Gate for awake low-dose ketamine: a systems neuroscience framework with a clinical anchor. Frontiers in systems neuroscience, 20, 1880737. https://doi.org/10.3389/fnsys.2026.1880737

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