We read with great interest the recent article by Vlisides et al.  The authors demonstrated that while intraoperative cortical connectivity measured using 16-channel electroencephalography (EEG) was not linked to postoperative cognitive function, global theta activity was associated with postoperative delirium. The potential utility of intraoperative EEG in predicting or ameliorating postoperative delirium is fascinating, and the authors have provided a dedicated EEG analysis of cortical connectivity.  This leads us to believe that further exploration of connectivity analyses could be valuable. We propose several hypotheses.

First, we suggest considering the depth of anesthesia at the time of EEG acquisition. It is known that EEGs conducted with sevoflurane at low concentrations reveal awake-alpha  and that the alpha oscillatory response differs from that observed with propofol. In figure 1, the alpha (10 to 12 Hz) power is not prominent during loss of consciousness or pre-extubation, but it is prominent during surgery, suggesting that the depth of anesthesia should be factored into connectivity analysis. At the very least, a balance between surgical stimulus and isoflurane concentration should be considered. Additionally, we posit that opioid usage, which was assumed to inversely affect the alveolar concentration of isoflurane, could disrupt oscillatory synchrony, reflecting cortical connectivity under conditions of relatively high opiate and low isoflurane anesthesia. Since surgical stress and nociceptive stimuli varied across different epochs, a post hoc analysis examining various depths of anesthesia could yield insightful findings.

Second, we question the clinical relevance of the cognitive toolbox score for participants with well-functioning brains. The temporary decline in the cognitive function scores observed on the first postoperative day could be attributed to a complex poststress reaction and the residual effects of drugs, including opioids. From a patient perspective, cognitive tests are challenging, and focusing on them the day after surgery is typically difficult. While the decline in cognitive scores was associated with delirium, as assessed by the Confusion Assessment Method, these evaluations or diagnoses should be made at an appropriate time. Nevertheless, the cognitive burden becomes more apparent in aged individuals with poor baseline cognitive function. Subgroup analysis focusing on these vulnerable patients could provide additional insights.

Third, we wonder whether the functional connectivity using the weighted phase lag index could serve as a method for monitoring pain. As shown in figure 1B, the weighted phase lag index showed different patterns between the preincision and surgical periods. This prompts us to inquire about the state of pain reduction methods employed, such as epidural anesthesia, which is different from opioid analgesia.

Last, cortical connectivity during surgery with volatile anesthesia only assessed the patients’ vulnerability to volatiles or opioids. Figure 1 displays varying color patterns in frontal–parietal connectivity between the baseline and the postanesthesia unit period, suggesting that the residual drug affected brain connectivity. Moreover, it is important to consider that the raw EEG data were collected in the operating theater or intensive care unit, where various electrical devices could influence EEG waveforms. Although the wireless device used by the authors would have less noise interference. One might argue that a baseline full-scalp EEG, conducted in a laboratory optimized for EEG recordings, could better screen for patient vulnerability before surgery.

With further advances in EEG analysis, we will be able to predict postoperative cognitive decline or postoperative delirium more accurately and develop a preventative method. In addition to the value of the Bispectral Index, precise functional analysis of the loss of connectivity during anesthesia is critical to expand our understanding and interpretation of brain electrophysiology and establish a link to the next phase.