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Anesthetics on Human Brain Connectivity 

The most widely known explanation for how general anesthesia suppresses human consciousness is the wet-blanket theory, which proposes anesthetics suspend all brain functions in a ubiquitous, indiscriminate manner [1]. However, we now understand many subconscious neural operations are still functional; it is conscious perception and volition which are suppressed. At very small doses, anesthetics stifle thinking, working memory, and focused attention. Increasing the dosage causes consciousness and voluntary behavior to fade. A further increase suppresses nociceptive sensations, i.e. pain, and autonomic reflexes, which are thought to mediated by anesthetic agents penetrating the brainstem. Lastly, neural electrical activity becomes intermittent [1,2]. Anesthetics affect both neural activity in brain regions and functional connectivity between brain regions. 

The thalamus is a common site of anesthetic modulation; anesthetic agents including benzodiazepines, ketamine, propofol, isoflurane and halothane have significant effects on thalamic activation [3]. The thalamocortical theory of anesthesia-induced unconsciousness was first proposed due to several neuroimaging cases and suggests anesthesia induces a hyperpolarization block of thalamocortical neurons, which then enhances inhibitory circuitry functioning through GABAergic synaptic neurotransmission [4]. In other words, a large proportion of these neurons experience hypertonic rather than isotonic conditions; the subsequent bursting activity blocks synaptic transmission throughout and from the thalamus, diminishing the high-frequency rhythms of awake and dreaming states [3].  

The central position of the thalamus and its direct access to sensory information and cortical feedback sets the thalamus as a primary region of interest for consciousness, perception, and attention [3,5]. Additionally, clinical and preclinical studies show lesions of the thalamus, especially the intralaminar nuclei, result in impairments of consciousness [6]. The intralaminar nuclei is often considered an extension of the brainstem’s reticular activating system, a network of neurons that has long been implicated for activation of awake or sleep states [5,6].  

Another major brain region whose functional connectivity is dampened by anesthetics is the frontoparietal association cortex. A clinical study tracked regional cerebral blood flow (rCBF) in the brains of patients anesthetized with either propofol or thiopental. Propofol induced strong reductions in rCBF to the right-sided anterior brain, while thiopental reduced rCBF to the left-sided cerebellum. The authors speculate that, because numerous regions are involved in the functionality of memory or sedation, inhibition of a subset of these regions does inhibit the process, but a graded response is produced when more regions are affected. Thus, while both propofol and thiopental may produce sedation, propofol patients commonly experience amnesia as well [7].  

Unlike activity in cortical regions, sensory cortical responsiveness is relatively unaffected by anesthesia. In 2005, Dueck et al. found concentration-dependent reduction of neural activity, as measured by fMRI, to auditory stimulation after propofol administration; however, even at the deepest sedation level, primary cortical responses to acoustic stimulation were preserved, indicating auditory information was still being processed [8]. Another study with healthy volunteers observed no identifiable relationship between level of consciousness and cross-modal interactions between visual and auditory cortices [9]. Finally, Liu et al. found preservation of task-related responses to auditory stimulation in the primary auditory cortex, but not in higher areas of cognition such as the inferior frontal gyrus [10]. Altogether, these neuroimaging studies suggest general anesthetics may preferentially reduce connectivity in higher-order cortical regions, but not in primary sensory areas.  

In the future, multimodal assessments of connectivity in humans as well as animals are needed to increase our understanding of the impact of general anesthetics on brain connectivity.  

References 

  1. Sukhotinsky, I., Zalkind, V., Lu, J., Hopkins, D. A., Saper, C. B., & Devor, M. (2007). Neural pathways associated with loss of consciousness caused by intracerebral microinjection of GABAA-active anesthetics: Ascending pathways of the mesopontine tegmental anesthesia area (MPTA). European Journal of Neuroscience, 25(5), 1417–1436. https://doi.org/10.1111/j.1460-9568.2007.05399.x 
  1. Hudetz, A. G. (2012). General anesthesia and human brain connectivity. Brain Connectivity, 2(6), 291–302. https://doi.org/10.1089/brain.2012.0107  
  1. Alkire, M. T., & Miller, J. (2005). General anesthesia and the neural correlates of consciousness. Progress in Brain Research (Vol. 150, pp. 229–597). Elsevier. https://doi.org/10.1016/S0079-6123(05)50017-7  
  1. Alkire, M. T., Haier, R. J., & Fallon, J. H. (2000). Toward a unified theory of narcosis: Brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Consciousness and Cognition, 9(3), 370–386. https://doi.org/10.1006/ccog.1999.0423  
  1. Afrasiabi, M., Redinbaugh, M. J., Phillips, J. M., Kambi, N. A., Mohanta, S., Raz, A., Haun, A. M., & Saalmann, Y. B. (2021). Consciousness depends on integration between parietal cortex, striatum, and thalamus. Cell Systems, 12(4), 363-373.e11. https://doi.org/10.1016/j.cels.2021.02.003 
  1. Bogen, J. E. (1997). Some neurophysiologic aspects of consciousness. Seminars in Neurology, 17(2), 95–103. https://doi.org/10.1055/s-2008-1040918  
  1. Pedersen, J. L., Lillesø, J., Hammer, N. A., Werner, M. U., Holte, K., Lacouture, P. G., & Kehlet, H. (2004). Thiopental and propofol affect different regions of the brain at similar pharmacologic effects. Anesthesia and Analgesia, 99(2), 912–918. https://doi.org/10.1213/01.ane.0000131971.92180.df  
  1. Dueck, M. H., Petzke, F., Gerbershagen, H. J., Paul, M., Hesselmann, V., Girnus, R., Krug, B., Sorger, B., Goebel, R., Lehrke, R., Sturm, V., & Boerner, U. (2005). Propofol attenuates responses of the auditory cortex to acoustic stimulation in a dose-dependent manner: A fMRI study. Acta Anaesthesiologica Scandinavica, 49(6), 784–791. https://doi.org/10.1111/j.1399-6576.2005.00703.x  
  1. Boveroux, P., Vanhaudenhuyse, A., Bruno, M.-A., Noirhomme, Q., Lauwick, S., Luxen, A., Degueldre, C., Plenevaux, A., Schnakers, C., Phillips, C., Brichant, J.-F., Bonhomme, V., Maquet, P., Greicius, M. D., Laureys, S., & Boly, M. (2010). Breakdown of within- and between-network resting state functional magnetic resonance imaging (fMRI) connectivity during propofol-induced loss of consciousness. Anesthesiology, 113(5), 1038–1053. https://doi.org/10.1097/aln.0b013e3181f697f5  
  1. Liu, X., Lauer, K. K., Ward, B. D., Rao, S. M., Li, S.-J., & Hudetz, A. G. (2012). Propofol disrupts functional interactions between sensory and high-order processing of auditory verbal memory. Human Brain Mapping, 33(10), 2487–2498. https://doi.org/10.1002/hbm.21385