Return of the Righting Reflex Does Not Portend Recovery of Cognitive Function in Anesthetized Rats

Abstract

As the number of individuals undergoing general anesthesia rises globally, it becomes increasingly important to understand how consciousness and cognition are restored after anesthesia. In rodents, levels of consciousness are traditionally captured by physiological responses such as the return of righting reflex (RORR). However, tracking the recovery of cognitive function is comparatively difficult. Here we use an operant conditioning task, the 5-choice serial reaction time task (5-CSRTT), to measure sustained attention, working memory, and inhibitory control in male and female rats as they recover from the effects of several different clinical anesthetics. In the 5-CSRTT, rats learn to attend to a five-windowed touchscreen for the presentation of a stimulus. Rats are rewarded with food pellets for selecting the correct window within the time limit. During each session we tracked both the proportion of correct (accuracy) and missed (omissions) responses over time. Cognitive recovery trajectories were assessed after isoflurane (2% for 1 h), sevoflurane (3% for 20 min), propofol (10 mg/kg I.V. bolus), ketamine (50 mg/kg I.V. infusion over 10 min), and dexmedetomidine (20 and 35 μg/kg I.V. infusions over 10 min) for up to 3 h following RORR. Rats were classified as having recovered accuracy performance when four of their last five responses were correct, and as having recovered low omission performance when they missed one or fewer of their last five trials. Following isoflurane, sevoflurane, and propofol anesthesia, the majority (63–88%) of rats recovered both accuracy and low omission performance within an hour of RORR. Following ketamine, accuracy performance recovers within 2 h in most (63%) rats, but low omission performance recovers in only a minority (32%) of rats within 3 h. Finally, following either high or low doses of dexmedetomidine, few rats (25–32%) recover accuracy performance, and even fewer (0–13%) recover low omission performance within 3 h. Regardless of the anesthetic, RORR latency is not correlated with 5-CSRTT performance, which suggests that recovery of neurocognitive function cannot be inferred from changes in levels of consciousness. These results demonstrate how operant conditioning tasks can be used to assess real-time recovery of neurocognitive function following different anesthetic regimens.

Hormonal basis of sex differences in anesthetic sensitivity

“…While the righting reflex is a well-established measure of anesthetic effects in rodents ( 50 ), it has some notable limitations ( 51 , 52 ). To eliminate these potential confounds, we confirmed our results using the adhesive sticker removal test ( Fig.…”

Evaluation of Xylazine Ketamine Anesthesia in Rabbits Undergoing Tendon Surgery: A Prospective Randomized Controlled Study

“…Moreover, the study investigated anesthesia-specific parameters, including induction time and duration. Induction time, defined as the time from the administration of anesthesia to the loss of the righting reflex, is a critical measure of anesthetic efficiency [22] . In our study, the XK group demonstrated a shorter induction experienced by the animals.…”

Time to Wake Up! The Ongoing Search for General Anesthetic Reversal Agents

“…For instance, after anesthesia treatment, rats' performance on the 5-choice serial reaction time task (table 1) returned to preanesthesia levels within 1 to 3 h depending on the dose and type of anesthetic used. 37,43 However, performance on this task had no correlation with the return of righting reflex, indicating that recovery of cognitive function cannot be predicted from a righting reflex assay. Additional tests have been developed to assess behavioral changes in mice due to postoperative delirium.…”

“…109 However, as noted previously, by measuring only the righting reflex, these experiments typically only probe the hypnotic component of general anesthesia, and ignore behavioral responsiveness readouts. Additionally, return of the righting reflex does not mean an animal has recovered its cognitive abilities, 43 which places doubt on whether stimulating cholinergic systems can reverse general anesthesia beyond restoring postural control and locomotion. For example, general anesthetics such as propofol disrupt cortical connectivity 110 while increasing the spectral power of slow (1 to 4 Hz) oscillations, 111 so it might be expected that cholinergic stimulation could return these parameters to baseline, but this is not the case.…”

“…EEG dynamics can return to baseline without a return to consciousness in both rats 41 and humans, 42 and a return of righting reflex does not mean an animal has recovered its cognitive abilities. 43 In studies where only one or a few metrics are used, anesthesia is treated as a binary endpoint-either the animal is awake, or it is not. However, a spectrum of sedation exists between being fully awake and being anesthetized.…”