The Role of Cortico-Thalamocortical Interactions in General Anesthesia

General anesthesia is administered to induce a reversible state of unconsciousness, along with amnesia, analgesia, and immobility.1 However, researchers are still seeking to uncover the precise neural mechanisms underlying general anesthesia. While anesthetic-induced unconsciousness resembles natural sleep in certain ways, such as the activation of sleep-promoting neural regions and the suppression of specific arousal nuclei, anesthetics will target both cortical and subcortical structures. Contemporary theories of consciousness assert awareness arises from recurrent communication between separate cortical areas. Emerging evidence suggests the bulk of this communication relies on cortico-thalamocortical circuits, whereby higher-order thalamic nuclei facilitate cortical communication by linking distributed cortical regions. Disruption of these cortico-thalamocortical circuits under general anesthesia may cause cortical disintegration and loss of consciousness.2 Additionally, recovery from this artificially induced state of unconsciousness requires the restoration of bidirectional communication across critical neural areas, including the brainstem, thalamus, and cortex.

The thalamus regulates consciousness by coordinating rhythmic brain activity, which can be observed through EEG during wakefulness and anesthesia-induced unconsciousness. When awake, the brain shows fast, irregular activity, but under anesthesia, it exhibits slow, synchronized oscillations associated with reduced cortical communication. These patterns (e.g., alpha, delta, gamma) contribute to prolonged hyperpolarization. GABAergic inhibition in the thalamus has been shown to induce alpha and delta oscillations between the higher-order thalamus and the prefrontal cortex. Notably, alternating delta (slow) and gamma (fast) waves are the primary EEG features observed in patients under general anesthesia with ketamine.3 This is thought to result from either reduced brainstem input to the thalamus and cortex or through ketamine’s direct inhibition of the thalamus.

There are many thalamic nuclei that contribute to modulating arousal under anesthesia. The thalamic reticular nucleus (TRN) acts as an inhibitory shell around the thalamus, regulating thalamocortical neurons through GABAergic inhibition driven by cortical and subcortical inputs. In this cortico-thalamocortical circuit, the TRN suppresses cortical activity and limits sensory signal propagation by synchronizing thalamic relay nuclei and generating rhythmic oscillations such as spindles and slow waves, thus contributing to the loss of consciousness under general anesthesia.4 Spindle waves are also observed in patients under barbiturate, ketamine-xylazine, or dexmedetomidine anesthesia. A 2016 clinical study suggested that the binding of dexmedetomidine to presynaptic alpha-2 adrenergic receptors causes neuronal hyperpolarization and decreased norepinephrine release.5 The increased inhibition may be the reason why TRN activation deepens the inhibitory effect of anesthesia by modulating existing slow waves. Additionally, it was also found that chemogenetic activation of the noradrenergic nerve terminals in the TRN prolongs emergence from propofol anesthesia.6 

The posteromedial nucleus (PoM) is another higher-order thalamic nucleus that has projections to cortical L5 and L1 pyramidal cells. Researchers used a mouse model and found PoM activity was significantly elevated during wakefulness, compared to anesthetized states. When exposed to isoflurane anesthesia, the PoM was downregulated, suggesting the inactivation of this region impairs cortical coupling and, in turn, consciousness.7 The central medial thalamus (CMT) projects into the cortex and accentuates cortical arousal. An in vitro study on mouse thalamic brain slices demonstrated sevoflurane inhibited firing frequency and delayed the onset of action potentials in CMT neurons, which could be prevented by inhibiting potassium channels in the CMT.8

Evidence indicates that general anesthesia induces unconsciousness by disrupting cortico-thalamocortical communication, primarily through suppression of thalamic nuclei that sustain cortical integration. Inhibitory mechanisms within the thalamic reticular nucleus and higher-order thalamic regions such as the PoM and central medial thalamus contribute to reduced excitability and synchronization of slow oscillations, which is characteristic of anesthetic states. Together, these findings suggest that anesthetics act on multiple thalamic targets to suppress arousal, impair cortical coupling, and prevent the neural integration necessary for consciousness.

References

  1. Ward C.G., Loepke A.W., Anesthetics and Sedatives: Toxic or Protective for the Developing Brain? Pharmacological Research. 2012;65(3):271-274. https://doi.org/10.1016/j.phrs.2011.10.001
  2. Zhou Y., Huang S., Zhang T., Deng D., Huang L., Chen X., Deciphering Consciousness: The Role of Corticothalamocortical Interactions in General Anesthesia. Pharmacological Research. 2025;212:107593-107593. https://doi.org/10.1016/j.phrs.2025.107593 
  3. Akeju O., Brown E.N., Neural Oscillations Demonstrate That General Anesthesia and Sedative States are Neurophysiologically Distinct From Sleep. Current Opinion in Neurobiology. 2017;44:178-185.   https://doi.org/10.1016/j.conb.2017.04.011
  4. Steriade M., McCormick D.A., Sejnowski T.J., Thalamocortical Oscillations in the Sleeping and Aroused Brain. Science. 1993;262(5134):679-685. https://doi.org/10.1126/science.8235588
  5. Akeju O., Kim S.E., Vazquez R., et al. Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations. Pouratian N, ed. PLOS ONE. 2016;11(10):e0163431. https://doi.org/10.1371/journal.pone.0163431
  6. Zhang Y., Fu B., Liu C., et al. Activation of Noradrenergic Terminals in the Reticular Thalamus Delays Arousal From Propofol Anesthesia in Mice. 2019;33(6):7252-7260.  https://doi.org/10.1096/fj.201802164rr
  7. Suzuki M., Larkum M.E., General Anesthesia Decouples Cortical Pyramidal Neurons. Cell. 2020;180(4):666-676.e13. https://doi.org/10.1016/j.cell.2020.01.024
  8. Lioudyno M., Birch A., Tanaka B.S., et al. Shaker-Related Potassium Channels in the Central Medial Nucleus of the Thalamus Are Important Molecular Targets for Arousal Suppression by Volatile General Anesthetics. The Journal of Neuroscience. 2013;33(41):16310-16322. https://doi.org/10.1523/jneurosci.0344-13.2013