Representation of pain affect in the central nervous system under nitrous oxide-induced anesthesia
Bibliographic record
Abstract
Approximately 0.2% of patients undergoing surgery with general anesthesia report experiencing intraoperative awareness, wherein they are aware of their surroundings and the procedure despite not showing signs of consciousness. These experiences are traumatic, can hinder recovery, and are underreported as general anesthetics cause amnesia. Improving both our understanding of mechanisms by which general anesthesia induces analgesia, separately from unresponsiveness or unconsciousness, and methods of accurately monitoring levels of consciousness in patients are necessary to ensure that patients receive adequate analgesia.Nitrous oxide is a fast-acting general anesthetic that produces analgesia but does not induce loss of consciousness or impair sensory thresholds. As such, nitrous oxide anesthesia presents a unique opportunity to concurrently study the sensory-discriminative and the affective-motivational components of the pain experience. Interestingly, descriptions of nitrous oxide-induced analgesia match those of anterior cingulate cortex (ACC) lesions, which selectively inhibit pain aversion but not sensory-discrimination. Past studies agree that neuronal activity in the ACC correlates strongly with perceived pain intensity. We therefore predicted that nitrous oxide anesthesia, a known analgesic, would decrease neuronal activity in the ACC. Surprisingly, nitrous oxide exposure results in rapid, robust activation of ACC neurons. The ACC is highly interconnected to anesthesia- and pain-processing regions in the brain, including the midbrain periaqueductal gray (PAG), which has been hypothesized to mediate nitrous oxide analgesia by engaging descending inhibition of nociceptive input from the spinal cord. However, whether nitrous oxide directly acts on PAG neurons, or indirectly via upstream structures like the ACC, is currently unknown.\nOur objective is to investigate the circuit mechanisms by which nitrous oxide activates ACC neurons, which we hypothesize is critical for maintaining nitrous oxide-induced analgesia. To this end, we perform in vivo calcium imaging in the ACC of mice exposed to air or nitrous oxide before and after painful stimuli to characterize real-time changes in neuronal activity. We also use immunohistochemistry, in situ hybridization, and viral tracing techniques to characterize the pattern of nitrous oxide-induced neuronal activation throughout the central nervous system, using probes against the Fos protein (or c-Fos messenger ribonucleic acid) as a proxy for neuronal activation. We find that nitrous oxide-induced analgesia likely arises from activation of the ACC itself and not through PAG-mediated descending inhibition of the spinal cord. We propose that monitoring ACC activity can therefore be an effective way to determine that a patient is receiving sufficient analgesia even under intraoperative awareness where other metrics fail to do so.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".