The contribution of oscillatory synchrony in the primate amygdala-prefrontal pathway to aversive learning remains largely unknown. We found increased power and phase synchrony in the theta range during aversive conditioning. The synchrony was linked to single-unit spiking and exhibited specific directionality between input and output measures in each region. Although it was correlated with the magnitude of conditioned responses, it declined once the association stabilized. The results suggest that amygdala spikes help to synchronize ACC activity and transfer error signal information to support memory formation.

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Background Anesthetics aim to prevent memory of unpleasant experiences. The amygdala and dorsal anterior cingulate cortex participate in forging emotional and valence-driven memory formation. It was hypothesized that this circuitry maintains its role under sedation. Methods Two nonhuman primates underwent aversive tone–odor conditioning under sedative states induced by ketamine or midazolam (1 to 8 and 0.1 to 0.8 mg/kg, respectively). The primary outcome was behavioral and neural evidence suggesting memory formation. This study simultaneously measured conditioned inspiratory changes and changes in firing rate of single neurons in the amygdala and the dorsal anterior cingulate cortex in response to an expected aversive olfactory stimulus appearing during acquisition and tested their retention after recovery. Results Aversive memory formation occurred in 26 of 59 sessions under anesthetics (16 of 29 and 10 of 30, 5 of 30 and 21 of 29 for midazolam and ketamine at low and high doses, respectively). Single-neuron responses in the amygdala and dorsal anterior cingulate cortex were positively correlated between acquisition and retention (amygdala, n = 101, r = 0.51, P < 0.001; dorsal anterior cingulate cortex, n = 121, r = 0.32, P < 0.001). Neural responses during acquisition under anesthetics were stronger in sessions exhibiting memory formation than those that did not (amygdala median response ratio, 0.52 versus 0.33, n = 101, P = 0.021; dorsal anterior cingulate cortex median response ratio, 0.48 versus 0.32, n = 121, P = 0.012). The change in firing rate of amygdala neurons during acquisition was correlated with the size of stimuli-conditioned inspiratory response during retention (n = 101, r = 0.22 P = 0.026). Thus, amygdala and dorsal anterior cingulate cortex responses during acquisition under anesthetics predicted retention. Respiratory unconditioned responses to the aversive odor anesthetics did not differ from saline controls. Conclusions These results suggest that the amygdala–dorsal anterior cingulate cortex circuit maintains its role in acquisition and maintenance of aversive memories in nonhuman primates under sedation with ketamine and midazolam and that the stimulus valence is sufficient to drive memory formation. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Deep brain stimulation (DBS) is commonly and safely performed for selective Parkinson's disease patients. Many centers perform DBS lead positioning exclusively under local anesthesia, to allow for brain microelectrode recordings (MER) and testing of stimulation-related therapeutic and side effects. These measures enable physiological identification of the DBS targets based on electrophysiological properties like firing rates and patterns, optimization of lead placement accuracy, and intra-operative evaluation of therapeutic window. Nevertheless, due to the challenges of awake surgery, some centers use sedation or general anesthesia, despite the distortion of discharge properties, and potential impact on clinical outcomes. Thus, there is a need for a novel anesthesia regimen that enables sedation without compromising intra-operative monitoring. This study investigates the use of low-dose ketamine for conscious sedation during lead positioning in subthalamic nucleus (STN) DBS for Parkinson's disease patients. Three anesthetic regimens were retrospectively compared in 38 surgeries across three DBS centers: 1) Interleaved propofol-ketamine (PK), 2) Interleaved propofol-awake (PA), and 3) Fully awake (AA). All anesthesia regimens achieved satisfactory MER. Automatic detection of STN borders and subdomains using a Hidden Markov Model was similar between the groups. Patients' symptoms and cooperation during stimulation testing in the ketamine group was not altered. No major adverse effects were reported in the different anesthesia protocols. These results support the use of low-dose ketamine as a novel alternative for the existing DBS anesthesia regimens, optimizing patient's experience while preserving lead placement accuracy. A prospective study should be performed to confirm these findings.