CliniCal pharmaCology & TherapeuTiCs | VOLUME 84 NUMBER 1 | JULY 2008 149

translational medicinenature publishing group

Probing the Mind: Anesthesia and NeuroimagingMT Alkire1,2

In 1947, a second power of anesthesia was described: With anesthetic agents we seem to have a tool for producing and holding at will, and at little risk, different levels of consciousnessa tool that promises to be of great help in studies of mental phenomena.1 In 1995, anesthetic manipulation was coupled with neuroimaging,2 paving the way for detailed assessments of the relationship between the structure and the functioning of the brain.3 Anesthesia combined with neuroimaging thus provides a unique tool for investigating the neural correlates of human cognition.

The anesthesianeuroimaging approach has already been used to help identify neural correlates of consciousness,4 and it provides a method for investigating other components of consciousness, such as memory, attention, pain processing, and emotion. As neuroimaging continues to provide insights into human cogni-tion, the therapeutic implications of the anesthetic manipula-tion approach deserve some consideration and discussion. One popular misconception about anesthesia is that unconsciousness occurs immediately after it is administered. In fact, this happens only when a large enough dose is administered rapidly enough. If a constant low dose of an anesthetic is given, then one can be held indefinitely in a mild drunken-like state. This is what allows the investigation of the effects of any particular anesthetic on cognition.

The effects of anesthetics on the brain are dose-dependent. The inhalation of certain gas anesthetics at the lowest doses will cause changes in pain processing and emotional responsiveness.3,5 At slightly higher doses, anesthetics begin to affect long-term memory processing and begin to slow reaction times.6 Sedative effects become noticeable with a further increase in the dose, and short-term memory also starts to get impaired.7 At these doses, anesthesia also induces an intense desire to fall asleep. Then, at even higher levels, anesthetics will induce a sleep-like state causing a loss of voluntary motor responses to nonpain-ful external sensory stimuli. This is the definition of anesthetic-induced unconsciousness. At doses that are approximately three times greater, anesthetics will produce immobility even in the presence of the most intensely painful stimuli, as in surgery.

General anesthesia: are you unconscious?How is unconsciousness determined during anesthesia? Classically, brain functioning is monitored by observing respon-siveness and clinical signs (changes in blood pressure, heart rate, breathing, etc.) as described in stages of ether anesthesia by Snow in 1847 and as refined for surgical planes of ether anes-thesia by Guedel in 1937 (refs. 8,9). Today the primary method for determining anesthetic depth remains, as it was in 1847, the assessment of clinical signs. However, these do not always cor-relate with a persons depth of anesthesia, and unresponsiveness is not necessarily synonymous with unconsciousness.

In order to help avoid potential problems with anesthetic delivery, technology is now available to monitor how anesthesia is affecting the brain. Surprisingly, brain function monitors have been introduced to the practice of anesthesiology only within the past few decades. Their use remains outside the current standard-of-care.10 Nonetheless, monitoring of the electro-encephalogram (EEG) is one popular method for assessing anes-thetic effects on the brain.11 A long history establishes that the pattern of EEG activity is changed by increasing doses of anes-thetics.12 Alert states of wakefulness are associated with high-frequency low-voltage EEG activity (also called desynchronized or fast activity), whereas states of lowered arousal such as sleep, coma, or anesthesia are associated with low-frequency high-voltage EEG activity (also called synchronized or slow activity). One commercially successful EEG brain function monitor is the bispectral index monitor (Aspect Medical Systems, Natick, MA). The bispectral index reduces the complex EEG signal recorded from the forehead into a single number that ranges from 100 (for wide awake) to 0 (for an isoelectric EEG under deep anes-thesia). The number corresponds to a patients depth of sedation or anesthesia.13 The device is useful for guiding anesthetic deliv-ery and reducing the occurrence of intraoperative awareness in patients.14 However, such devices should not be considered monitors of consciousness, because they really assess only a cor-relate of anesthetic action in the brain.

Figure 1 demonstrates the graded doseresponse-related effect of anesthesia in the brain.15 The transition point between conscious and unconscious states is well identified and clearly

1Department of Anesthesiology, University of California, Irvine, California, USA; 2Center for the Neurobiology of Learning and Memory, University of California, Irvine, California, USA. Correspondence: MT Alkire (malkire@uci.edu)

Received 3 March 2008; accepted 4 March 2008; advance online publication 16 April 2008. doi:10.1038/clpt.2008.75

150 VOLUME 84 NUMBER 1 | JULY 2008 | www.nature.com/cpt

translational medicine

obvious behaviorally, but it is not as distinct when assessed in terms of either EEG patterns or brain metabolism. Consciousness remains even when anesthesia causes heavy sedation (Figure 1, second image from left), while consciousness is lost at higher doses (Figure 1, third image from left). The neural correlates of consciousness are contained within this narrow dosage win-dow between these two states of suppressed brain functioning. The critical question is: what are the changes in the brain when consciousness is lost? Evidence from neuroimaging reveals that not only is there a suppression of activity throughout the brain associated with the use of most anesthetics (as illustrated in Figure 1), but some specific regional effects also occur, prima-rily involving the thalamus, occipital/parietal areas, and frontal areas.16 Many neurobiological theories of consciousness have suggested that the thalamus plays a pivotal role in mediating consciousness through corticothalamic connections and reen-trant neural activity.17,18

neuroimaGinG correlates of anesthetic action on consciousnessThe thalamus is a centralized brain structure that is involved in relaying incoming sensory information onward to the cerebral cortex, passing it through a thin overlying sheet of neurons called the thalamic reticular nucleus. Yet, despite its role as a sensory relay station, the thalamus receives most of its inputs from the cerebral cortex through a massive network of corticothalamic feedback fibers. A thalamocortical network is a complex circuit in which information can flow in a looping reentrant man-ner that involves thalamus, reticular thalamic nucleus, cortex, and then back to thalamus. This anatomy puts thalamocortical networks in a key position to participate in consciousness by

providing a mechanism for integrated interactions to occur in separated cortical areas.18

Data from several human neuroimaging studies where anesthetics were given at (or near to) a loss of consciousness end-point reveal that thalamic activity is suppressed with anesthesia.19 This finding led to the development of the tha-lamic consciousness switch hypothesis.16 This hypothetical framework proposed that unconsciousness during anesthesia occurs because the thalamus and cortex become functionally disconnected, causing the suppression of reentrant neural activ-ity. This disconnection occurs with different anesthetics because they all cause neuronal hyperpolarization.20 Membrane hyper-polarization makes neurons less likely to fire action potentials. Action potentials are the electrophysiologic mechanism by which neurons in the brain communicate with one another. In essence then, anesthesia stops consciousness by suppress-ing brain activity and causing the failure of communication between and among brain neurons (although some agents may block neuronal communication by mechanisms other than just suppression).21

Neuroimaging focuses attention on the thalamus and its interactions with the cortex as they relate to anesthetic-induced unconsciousness. But which is affected first by an increasing dose of anesthesia? Neuroimaging does not have the time reso-lution needed to address this question. However, one recent human electrophysiology study suggests an answer. Velly and colleagues reported on a series of patients with Parkinsons dis-ease who underwent a two-stage procedure for implantation of a deep-brain stimulator system.22 After a multichannel elec-trode was placed into the subthalamic region during one opera-tion, the patients returned for a second operation in which the electronic stimulator box was to be implanted under the skin. In the second operation, EEG activity could then be obtained simultaneously from both the surface EEG, representing the cortex, and from the subthalamic electrode, using those chan-nel points that passed through the thalamus. The cortical EEG activity was found to be suppressed at the moment when the patients lost consciousness. This cortical change occurred well before similar changes in thalamic EEG-like activity occurred. This strongly suggests that it is the cortex that is the primary target of anesthetic actions on consciousness. This is consist-ent with the hypothesis that consciousness is dependent on the reentrant neural activity occurring between the cortex and the thalamus.

anesthetic effects on memoryAll general anesthetics cause a temporary and reversible state of anterograde amnesia.23 This occurs only during the time that one is exposed to the anesthetic. Anterograde amnesia means that one forgets experiences that occur after a specific event, such as following a severe brain injury or the administration of an amnesia-inducing drug. In contrast, retrograde amnesia implies that one forgets experiences that occur before a specific event. Retrograde amnesia can occur following severe brain injury or electroconvulsive therapy. Some animal studies suggest retrograde amnesia can be seen with the use of anesthetics;24

None

BaselineAwake

ConsciousStage of

anesthesia

Dose

Clinicalsigns

Reactiontime

Memory

Cerebralmetabolism

EEGbispectral

index(BIS)

UnconsciousStages 1 and 2 Stage 3 Stage 4

Low Moderate Deep

Baseline Progressivelyprolonged Infinite Infinite

Baseline Progressivelyimpaired Plausible Improbable

No effectresponsive

Sedationresponsive

Lightanesthesia

unresponsive

Surgicalanesthesia

unresponsive

100

6040

0 Time (30 min) Time (30 min) Time (30 min) Time (30 min)

figure 1 Clinical behavioral stages of anesthesia and the effect of increasing anesthetic doses on brain glucose metabolism and on the concomitantly measured electroencephalogram (EEG)-derived bispectral index (BIS) value, recorded as a trend plot over the 30-minute tracer uptake period of each positron emission tomography scan. The figure illustrates how various stable levels of brain suppression can be obtained with the use of anesthetics. The figure also shows that an EEG-based determination of consciousness is difficult near the responsive/nonresponsive movement transition point. Additionally, the figure also reveals that a dose of anesthesia large enough to stop all electrical activity and cause a flat-line EEG is easily detectable.

CliniCal pharmaCology & TherapeuTiCs | VOLUME 84 NUMBER 1 | JULY 2008 151

translational medicine

however, human studies fail to show retrograde amnesic effects of anesthesia.25 This indicates that potentially traumatic memo-ries formed during surgery (i.e., intraoperative awareness) can-not be erased after the fact by using an additional dose of an anesthetic.

The effects of anesthetics on memory are dose-dependent and dissociable from their effects on sedation; thus, forget-fulness is not just due to a lack of paying attention caused by the sleepiness component of anesthesia.26,27 Interestingly, the dose- dependency follows an approximate time gradient, such that long-term memory is affected at the lowest doses, fol-lowed by short-term memory, and then working or immediate memory.3,7

The few neuroimaging studies that have investigated the amnesic effect of anesthetics have revealed that these drugs affect the brain in a complex manner. The memory effects are dose-dependent7,28 and agent-specific; and they reflect the regional effects of the agent being used to cause the amne-sia.3,29 Low doses of the inhalational anesthetic sevoflurane have been found to block long-term human memory.3 This occurs at a very low dose of sevoflurane that suppresses tha-lamic activity and changes network interactions between the amygdala and hippocampus.3 These two brain regions are thought to be involved in mediating normal human memory and the effect of emotional arousal on memory consolidation.30 At the other extreme, higher amnesic doses of the intravenous anesthetic agent propofol were recently found to affect frontal lobe working memory systems primarily.7 These studies illus-trate how different doses of anesthesia can be used to study different components of human memory processing. It is antici-pated that future studies will continue to take advantage of this dose- related effect of anesthesia in order to provide additional insights into human memory processing.

anesthesia as a DiaGnostic toolAlong similar lines, the possibility is raised that anesthesia could be used not only as a tool for the scientific study of memory, but also as a potential diagnostic tool for detecting early mem-ory dysfunction. Neurophysiologist Chris J Pomfrett has long championed the idea that anesthesiologists should start utilizing anesthesia for its diagnostic potential. For example, one could use anesthesia as a memory-screening tool. Patients with greater-than-expected memory deficits after a standardized amnesic test dose of an anesthetic might be referred for further evaluation. It is anticipated that Alzheimers disease would be detectable years before symptoms appear if this approach were to be used, because pre-Alzheimers patients will likely be a group that will perform below an expected normal level on account of a lim-ited cognitive reserve. Many additional diagnostic applications for anesthetics can be envisioned. These range from helping to establish a diagnosis of attention-deficient/hyperactivity disor-der, for example (low doses of anesthetics might be found to improve disproportionately or impair attention performance in such patients), to the confirmation of narcolepsy (such patients might reveal abnormally long sleep times following a small test dose of an induction agent).31

anesthetic effects on emotion anD the treatment of DepressionThe therapeutic potential of anesthetics for treating depression was recently discovered in a clinical study. A single dose of the anesthetic ketamine, an N-methyl-d-aspartate (NMDA) antago-nist, has efficacy for treating depression.32,33 The response is rapid, occurring within hours and lasting for days. This find-ing has focused researchers toward investigating the role of the NMDA channel in depression.34 The mechanism for the response is unknown, although effects at the NMDA channel,35 interactions with mu-opioid receptors,36 and changes in pro-tein phosphorylation states are all possibilities.37 There are three other anestheticsnamely, nitrous oxide (laughing gas), xenon (an inert noble gas), and cyclopropanethat are also thought to exert their anesthetic effects through interactions with the NMDA channel.38 In our studies on anesthetic-induced amne-sia, we recently found that some agents can change how s ubjects rate the emotionality of standardized pictures.3 Pictures are rated as inducing less of an emotional reaction when viewed during exposure to low doses of certain anesthetics. This could be inter-preted as an anxiolytic-like effect, but also as a potential marker for a particular agents antidepressant efficacy. Interestingly, we recently observed that 40% nitrous oxide (a presumed NMDA antagonist) has some potential for changing the emotional reac-tions to standardized pictures (M.T.A. and P.S. Hockert, unpub-lished data). Studies are planned to determine whether nitrous oxide might have antidepressant activity akin to ketamine. The novel use of anesthetics in the treatment of depression suggests that the anesthesia tool can be readily applied to the study of the brain mechanisms that underlie emotions.

summaryThe coupling of cognitive neuroscience and neuroimaging with the tool of anesthetic manipulation of brain functioning is a tech-nique with great potential. This methodological approach can change our understanding of how the brain works and may pro-vide additional future therapeutic insights and applications.

conflict of interestThe author declared no conflict of interest.

2008 American Society for Clinical Pharmacology and Therapeutics

1. Beecher, H.K. Anesthesias second power: probing the mind. Science 105, 164166 (1947).

2. Alkire, M.T., Haier, R.J., Barker, S.J., Shah, N.K., Wu, J.C. & Kao, Y.J. Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography. Anesthesiology 82, 393403; discussion 27A (1995).

3. Alkire, M.T., Gruver, R., Miller, J., McReynolds, J.R., Hahn, E.L. & Cahill, L. Neuroimaging analysis of an anesthetic gas that blocks human emotional memory. Proc. Natl. Acad. Sci. USA 105, 17221727 (2008).

4. Alkire, M.T., Haier, R.J. & Fallon, J.H. Toward the neurobiology of consciousness: using brain imaging and anesthesia to investigate the anatomy of consciousness. In Toward a Science of Consciousness II (eds. Hameroff, S.R., Kaszniak, A.W. & Scott, A.C.) 255268 (MIT Press, London, 1998).

5. Zhang, Y., Eger, E.I. 2nd, Dutton, R.C. & Sonner, J.M. Inhaled anesthetics have hyperalgesic effects at 0.1 minimum alveolar anesthetic concentration. Anesth. Analg. 91, 462466 (2000).

6. Alkire, M.T. & Gorski, L.A. Relative amnesic potency of five inhalational anesthetics follows the Meyer-Overton rule. Anesthesiology 101, 417429 (2004).

152 VOLUME 84 NUMBER 1 | JULY 2008 | www.nature.com/cpt

translational medicine

7. Veselis, R.A., Reinsel, R.A., Feshchenko, V.A. & Dnistrian, A.M. A neuroanatomical construct for the amnesic effects of propofol. Anesthesiology 97, 329337 (2002).

8. Guedel, A.E. Inhalation Anesthesia: A Fundamental Guide (Macmillan, New York, 1937).

9. Snow, J. Narcotism by the inhalation of vapors. London Med. Gazette 6, 850854 (1848).

10. American Society of Anesthesiologists Task Force on Intraoperative Awareness. Practice advisory for intraoperative awareness and brain function monitoring: a report by the American Society of Anesthesiologists Task Force on Intraoperative Awareness. Anesthesiology 104, 847864 (2006).

11. Voss, L. & Sleigh, J. Monitoring consciousness: the current status of EEG-based depth of anaesthesia monitors. Best Pract. Res. Clin. Anaesthesiol. 21, 313325 (2007).

12. Levy, W.J. Power spectrum correlates of changes in consciousness during anesthetic induction with enflurane. Anesthesiology 64, 688693 (1986).

13. Drummond, J.C. Monitoring depth of anesthesia: with emphasis on the application of the bispectral index and the middle latency auditory evoked response to the prevention of recall. Anesthesiology 93, 876882 (2000).

14. Myles, P.S., Leslie, K., McNeil, J., Forbes, A. & Chan, M.T. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 363, 17571763 (2004).

15. Alkire, M.T. Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers. Anesthesiology 89, 323333 (1998).

16. Alkire, M.T., Haier, R.J. & Fallon, J.H. Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious. Cogn. 9, 370386 (2000).

17. Crick, F. The Astonishing Hypothesis (Scribner, New York, 1994).18. Tononi, G. An information integration theory of consciousness. BMC Neurosci.

5, 42 (2004).19. Alkire, M.T. & Miller, J. General anesthesia and the neural correlates of

consciousness. Prog. Brain Res. 150, 229244 (2005).20. Nicoll, R.A. & Madison, D.V. General anesthetics hyperpolarize neurons in the

vertebrate central nervous system. Science 217, 10551057 (1982).21. Cariani, P. Anesthesia, neural information processing, and conscious

awareness. Conscious. Cogn. 9, 387395 (2000).22. Velly, L.J. et al. Differential dynamic of action on cortical and subcortical

structures of anesthetic agents during induction of anesthesia. Anesthesiology 107, 202212 (2007).

23. Eger, E.I. 2nd et al. Hypothesis: inhaled anesthetics produce immobility and amnesia by different mechanisms at different sites. Anesth. Analg. 84, 915918 (1997).

24. OGorman, D.A., OConnell, A.W., Murphy, K.J., Moriarty, D.C., Shiotani, T. & Regan, C.M. Nefiracetam prevents propofol-induced anterograde and retrograde amnesia in the rodent without compromising quality of anesthesia. Anesthesiology 89, 699706 (1998).

25. Bulach, R., Myles, P.S. & Russnak, M. Double-blind randomized controlled trial to determine extent of amnesia with midazolam given immediately before general anaesthesia. Br. J. Anaesth. 94, 300305 (2005).

26. Veselis, R.A., Reinsel, R.A. & Feshchenko, V.A. Drug-induced amnesia is a separate phenomenon from sedation: electrophysiologic evidence. Anesthesiology 95, 896907 (2001).

27. Veselis, R.A., Reinsel, R.A., Feshchenko, V.A. & Wroski, M. The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations. Anesthesiology 87, 749764 (1997).

28. Veselis, R.A. et al. Midazolam changes cerebral blood flow in discrete brain regions: an H2(15)O positron emission tomography study. Anesthesiology 87, 11061117 (1997).

29. Alkire, M.T., Haier, R. & Fallon, J. PET imaging of conscious and unconscious verbal memory. J. Conscious. Studies 3, 448462 (1996).

30. McGaugh, J.L. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu. Rev. Neurosci. 27, 128 (2004).

31. Kelz, M.B. et al. An essential role for orexins in emergence from general anesthesia. Proc. Natl. Acad. Sci. USA 105, 13091314 (2008).

32. Berman, R.M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351354 (2000).

33. Zarate, C.A. Jr. et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856864 (2006).

34. Mathew, S.J., Manji, H.K. & Charney, D.S. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology (2008); e-pub ahead of print 2 January 2008.

35. Witkin, J.M., Marek, G.J., Johnson, B.G. & Schoepp, D.D. Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol. Disord. Drug Targets 6, 87100 (2007).

36. Sarton, E. et al. The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception. Anesth. Analg. 93, 14951500 (2001).

37. Snyder, G.L., Galdi, S., Hendrick, J.P. & Hemmings, H.C. Jr. General anesthetics selectively modulate glutamatergic and dopaminergic signaling via site-specific phosphorylation in vivo. Neuropharmacology 53, 619630 (2007).

38. Franks, N.P. Molecular targets underlying general anaesthesia. Br. J. Pharmacol. 147 (suppl.), S72S81 (2006).

Probing the Mind: Anesthesia and NeuroimagingGeneral anesthesia: Are you unconscious?Neuroimaging correlates of anesthetic action on consciousnessAnesthetic effects on memoryAnesthesia as a Diagnostic toolAnesthetic effects on emotion and the treatment of depressionSUMMARYConflict of interestReference