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

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.