Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys

Abstract

Previously our laboratory has shown that ketamine exposure (24h of clinically relevant anesthesia) causes significant increases in neuronal cell death in perinatal rhesus monkeys. Sensitivity to this ketamine-induced neurotoxicity was observed on gestational days 120-123 (in utero exposure via maternal anesthesia) and on postnatal days (PNDs) 5-6, but not on PNDs 35-37. In the present study, six monkeys were exposed on PND 5 or 6 to intravenous ketamine anesthesia to maintain a light surgical plane for 24h and six control animals were unexposed. At 7 months of age all animals were weaned and began training to perform a series of cognitive function tasks as part of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB). The OTB tasks used here included those for assessing aspects of learning, motivation, color discrimination, and short-term memory. Subjects responded for banana-flavored food pellets by pressing response levers and press-plates during daily (M-F) test sessions (50 min) and were assigned training scores based upon their individual performance. As reported earlier (Paule et al., 2009) beginning around 10 months of age, control animals significantly outperformed (had higher training scores than) ketamine-exposed animals for approximately the next 10 months. For animals now over 3 and one-half years of age, the cognitive impairments continue to manifest in the ketamine-exposed group as poorer performance in the OTB learning and color and position discrimination tasks, as deficits in accuracy of task performance, but also in response speed. There are also apparent differences in the motivation of these animals which may be impacting OTB performance. These observations demonstrate that a single 24-h episode of ketamine anesthesia, occurring during a sensitive period of brain development, results in very long-lasting deficits in brain function in primates and provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits. Supported by NICHD, CDER/FDA and NCTR/FDA.

Figure 1

Training scores for OTB task performance. Data are raw means +/- SEMs for 5 test sessions (one week’s worth of data). Dotted lines indicate the scores at which animals began performing under the final rules of reinforcement for the indicated tasks: IRA = incremental repeated acquisition (learning) task; PR = progressive ratio (motivation) task; CPR = conditioned position responding (color and position discrimination) task; DMTS = delayed matching-to-sample (short-term memory) task with no recall delays in place; Max Delay = point at which all DMTS delay sets are attained. Note that the separation between the groups began during the time subjects had to learn the concept associated with correct performance of the DMTS task. Bracket indicates sessions over which training scores for control subjects were significantly higher than those for ketamine-exposed subjects.

Figure 2

Learning (IRA) task raw data presented as averages of over 10 sessions (means +/- SEMs of 4 weeks worth of data). (A) Percent task completed; (B) Response rate; (C) Accuracy. * = P <0.05; # = p < 0.01.

Figure 2

Learning (IRA) task raw data presented as averages of over 10 sessions (means +/- SEMs of 4 weeks worth of data). (A) Percent task completed; (B) Response rate; (C) Accuracy. * = P <0.05; # = p < 0.01.

Figure 2

Learning (IRA) task raw data presented as averages of over 10 sessions (means +/- SEMs of 4 weeks worth of data). (A) Percent task completed; (B) Response rate; (C) Accuracy. * = P <0.05; # = p < 0.01.

Figure 3

Motivation (PR) task response rate (RR) data presented as in Figure 2. * = P <0.05; # = p < 0.01.

Figure 4

Color and position discrimination (CPR) task data presented as in Figure 2. (A) Percent task completed; (B) Response rate; (C) Accuracy. * = P <0.05; # = p < 0.01.

Figure 4

Color and position discrimination (CPR) task data presented as in Figure 2. (A) Percent task completed; (B) Response rate; (C) Accuracy. * = P <0.05; # = p < 0.01.

Figure 4

Color and position discrimination (CPR) task data presented as in Figure 2. (A) Percent task completed; (B) Response rate; (C) Accuracy. * = P <0.05; # = p < 0.01.

Figure 5

Attainment of short-term memory (DMTS) task delay intervals after mastery of DMTS task performance with no delays: delay sets versus number of DMTS sessions. Data are raw means for 5 test sessions (2 weeks) +/- SEMs. There were no significant differences between the groups at any week of testing.

Figure 6

Weekly body weights as means +/- SEMs. * = P <0.05