General anesthesia and human brain connectivity

Abstract

General anesthesia consists of amnesia, hypnosis, analgesia, and areflexia. Of these, the mechanism of hypnosis, or loss of consciousness, has been the most elusive, yet a fascinating problem. How anesthetic agents suppress human consciousness has been investigated with neuroimaging for two decades. Anesthetics substantially reduce the global cerebral metabolic rate and blood flow with a degree of regional heterogeneity characteristic to the anesthetic agent. The thalamus appears to be a common site of modulation by several anesthetics, but this may be secondary to cortical effects. Stimulus-dependent brain activation is preserved in primary sensory areas, suggesting that unconsciousness cannot be explained by cortical deafferentation or a diminution of cortical sensory reactivity. The effect of general anesthetics in functional and effective connectivity is varied depending on the agent, dose, and network studied. At an anesthetic depth characterized by the subjects' unresponsiveness, a partial, but not complete, reduction in connectivity is generally observed. Functional connectivity of the frontoparietal association cortex is often reduced, but a causal role of this change for the loss of consciousness remains uncertain. Functional connectivity of the nonspecific (intralaminar) thalamic nuclei is preferentially reduced by propofol. Higher-order thalamocortical connectivity is also reduced with certain anesthetics. The changes in functional connectivity during anesthesia induction and emergence do not mirror each other; the recovery from anesthesia may involve increases in functional connectivity above the normal wakeful baseline. Anesthetic loss of consciousness is not a block of corticofugal information transfer, but a disruption of higher-order cortical information integration. The prime candidates for functional networks of the forebrain that play a critical role in maintaining the state of consciousness are those based on the posterior parietal-cingulate-precuneus region and the nonspecific thalamus.

FIG. 1.

Schematic of the hypothesized consciousness network. The network involves major cortical components of the default-mode network as well as other regions. The PCC serves as the central hub of neuronal information flow that generates both directly and via additional cortical centers the various expressions of human consciousness. The circuit is functionally modulated by the ascending arousal system from the BS, BF and HT regions (simplified for clarity) that converge on the nonspecific ILN, whose connectivity with the cortex plays a major role in regulating the state of consciousness. PCC, posterior cingulate cortex; BS, brainstem; BF, basal forebrain; HT, hypothalamic; ILN, intralaminar thalamic nuclei; LPC, lateral parietal cortex; ACC, anterior cingulate cortex; mPFC, medial prefrontal cortex. Based on (Alkire ; Hudetz , ; Liu et al. 2012a).

FIG. 2.

Specific (A) and nonspecific (B) thalamocortical functional connectivity in baseline wakefulness, deep sedation, and recovery. Functional connectivity was obtained from seed-based analysis of the temporal correlation of fMRI blood oxygen-dependent signals. The brain was partitioned into 300 regions, and the regions containing <10 voxels were removed. Nonspecific connectivity is based on intralaminar nuclei as a seed; specific connectivity is based on the reminder of thalamus as seed. Deep sedation was defined as absent responsiveness to verbal commands. Data are from seven volunteers (Liu et al., 2012b). Note the substantial and reversible reduction of nonspecific thalamocortical connectivity during deep sedation (Figure by the courtesy of Dr. Xiaolin Liu).