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Autonomic-salience stability as a candidate Gate for awake low-dose ketamine: a systems neuroscience framework with a clinical anchor
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DOI：10.3389/fnsys.2026.1880737.png)
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Abstract
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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.
Keywords:
heart rate variability
chronic pain
ketamine
salience network
frontoparietal network
central autonomic network
autonomic gating
thalamo-cortical gating
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