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REVIEW ARTICLEpain and suffer. Furthermore, only a smallportion of the diagnostic errors concerned thepatients who were in full possession of HOC.Therefore, a method capable of assessing thefull-blown, ‘normal’ awareness would onlymoderately decrease the error rate.Thus, the aim of the present project was thedevelopment of a set of stimulation paradigmsdesigned to investigate different levels ofconscious experience without the patient’sability to demonstrate overt behavior. LikeOwen et al., we use fMRI as the recording techniquewhose relative slowness (as comparedto the EEG) is more than compensated for byits ability to reveal the activity of various brainstructures including those related to “primary”emotional processes.The battery needed to fulfil several criteria.Firstly, it should address the different levels ofcognitive functions that could possiblyremain. Secondly, these functions should berelated to consciousness, which is not trivialgiven that even very complex cognitiveprocesses (e.g., learning) can run unconsciously.Thirdly, the patients’ ability to appropriatelyrespond to the stimuli should be manifestedin their fMRI responses. Last but notleast, the overall examination time should belimited because DoC patients quickly becometired, and the probability of severe movementartefacts increases with time of testing.For this reason, our project included thefollowing hierarchical procedure.1. The mental imagery paradigm was anexact replication of 20 and addressed HOCincluding its important components, selectiveattention and working memory. 222. Patients who cannot follow verbal instructionscan nevertheless understandlanguage. In the language paradigm shortcorrect (e.g., May is the month that followsApril) and incorrect sentences (e.g., Marchis the month that follows April) werepresented. The paradigm was based on theidea that whereas semantic associations(e.g., cat-dog) can be processedadequately at an automatic level, theunderstanding of the factual correctness ofsentence requires its conscious apprehension.On the basis of the literature, weexpected a larger activation in the classicallanguage areas to false than correctsentences as a neurophysiological sign ofsentence understanding.3. Patients who do not understand languagecan nevertheless retain the ability toconsciously learn. The simplest form ofconscious learning is trace conditioning. 23We used a trace conditioning procedurein which two tones were randomlypresented 30 times each. One of them (aconditional stimulus, CS) was followed 15times by a weak electric shock (unconditionalstimulus), whose intensity twiceexceeded the average pain threshold in acomparable control group. The intervalbetween the CS and the shock was 3 s. TheBOLD-contrast was that between the CSnot followed by the shock and the othertone, which was never accompanied by ashock.4. Patients who lost the ability to build newexplicit associations can neverthelessretain emotional responses to affectivestimuli. Whereas the processes depictedabove are learning-related and probablybelong to HOC, at least some kinds ofemotional experience might be speculatedto be inborn and to belong to LOC (ofcourse, we do not know exactly which kindof consciousness is simpler than anotherkind, because the criteria of simplicity/complexity are highly controversial in thisrespect). Brain responses to exclamations(screams) expressing pain and sufferingwere compared with the responses to othersounds of human voice, both positive (e.g.,laughing) and negative (e.g., snoring). Inhealthy individuals, such pain-relatedsounds elicit activation of the whole painmatrix of the brain even though they arenot nociceptive. 245. Finally, the fifth paradigm was simply thepresentation of nociceptive stimuli, i.e.,electrical shocks to the index finger. Here,again, the activation of the pain matrix (ascompared with rest) was expected. It isalso worth noticing that while severalcomponents of this matrix (e.g., thesomatosensory cortex) are mainly relatedto sensory aspects of pain, other components(e.g., the insula and the cingulategyrus) are closely related to its subjective,emotional aspects.To avoid the unnecessary patient transportation,two different Siemens MRT devices (1.5 Tand 3 T) were used for examinations. In theformer, in which fourteen patients were examined,T2* weighted MR signal was measuredusing a gradient echo-planar imagingsequence (TR = 3.41 s, TE = 50 ms, FoV = 192mm, flip angle = 90°, 64 x 64, 36 slices coveringthe whole brain, slice thickness 3mm, no gap,voxel size 3x3x3mm). In the latter (sevenpatients), the corresponding parameters wereTR = 2.38 s, TE = 25 ms, FoV = 210mm, 40 slices,voxel size 3.3x3.3x3mm. Individual T1weighted anatomical images served as anunderlay for the activation pictures. The datawere processed using SPM8.Figure 1. Top row: group average brain activation patterns in healthy participants. Bottom row:examples of brain activations in selected VS patients. For a better comparison, the same sliceis shown for patients and controls. Leftmost column: the contrast between pain stimulationand rest. Note the activation in the structures (i.e., ACC and insula) related to the emotionalrather than sensory aspects of pain. Middle left column: empathy paradigm, the contrastbetween pain-related and pain-unrelated sounds of human voice. Middle right column: traceconditioning paradigm, the contrast between CS+ and CS-. Rightmost column: language paradigm,the contrast between correct and wrong sentences. According to [26], the activationthreshold for individual patients (p <strong>ACNR</strong> > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011
REVIEW ARTICLEA total of twenty-one patients (aged 16-75;11 females) carefully diagnosed as VS tookpart in the study after the approval of theEthics Commission of the University ofTübingen and the informed consent of eachpatient’s legal representative. The characteristicsof the patients are described in the Tableabove.In the imagery paradigm, three of the 21patients showed responses similar to those ofcontrol individuals. In the language paradigm,activations in some of the expected brainstructures were found in three of 17 patients(the language paradigm was not performed infour patients with a different mother tongue).In trace conditioning, similar positive findingswere obtained in eight patients. However, noneof the patients displayed a pattern of activitythat would entirely correspond to that ofhealthy individuals in any of these paradigm.Different results were obtained in the othertwo paradigms. In response to emotionalsounds, four patients demonstrated significantactivations of the entire pain matrix of thebrain including both sensory and affectivecomponents, nine patients showed activity inseveral (but not all) regions of this network,and eight patients showed no response orresponses inconsistent with the expectedones. During pain stimulation, eight patientsdemonstrated activations in the entire painmatrix, practically identical to the responses ofhealthy controls, and three further patientsshowed a widespread activity in the componentsof this matrix related to sensory aspectsof pain (thalamus, putamen, cerebellum,somatosensory cortex).Clearly, these data do not strongly prove thepatients’ real experience of negative emotionsrelated to pain and emotional cries. However,the opposite thesis that an unresponsivepatient has no subjective experience at all isdifficult to defend when significant activity isobserved in the entire brain network, or even aconsiderable part of it, which is known tostrongly correlate with such subjective experience.Also, the exact quantitative data reportedabove should be treated with caution. Thereare numerous reasons as to why a particularfMRI test may yield a negative result even if thecorresponding function in the given patient ispreserved. However, the general qualitativetrend in the data is unequivocal. Whereasneural correlates of cognitive (presumablyconscious) processes are rare findings in VS,correlates of emotional processes are wellexpressed in many patients. This is in line withthe hypothesis 11 that emotional consciousnesscan remain even despite the nearly completeloss of cognitive awareness. It is furthermoreworth noting, that our previous experiment 25has indicated that patients in acute non-traumaticcoma can consistently respond toemotional screams like those used in the paradigm4 of the present study.From a theoretical viewpoint, the data indicatethat the essential cognitive functionsconstituting our everyday awareness, such asexplicit learning ability, biographical memoryand language comprehension, do not makethe whole of human subjectivity. There may beeven more basic and probably simpler functions,which include not only feeling pain andpleasure, but also feeling pain (and perhapspleasure) of others. However simple, thesefunctions importantly contribute to beinghuman. From a practical viewpoint, the datasuggest that emotional contact with caregivers(e.g., using affective prosodic cues, music asaffective stimulus, or touch) can be establishedeven in patients with a complete loss ofall major cognitive functions. People havingpets, and parents of young children, know thatthe lack of HOC does not completely precludecommunication. For many patients fulfillingthe diagnostic criteria of VS the same mayhold true as well. lEmotional contact with caregivers (e.g., using affective prosodic cues,music, or touch) can probably be established even in patients with acomplete loss of all major cognitive functionsREFERENCES1. Baars BJ. In the Theater of Consciousness. New York - Oxford: Oxford University Press1997.2. Damasio AR. The Feeling of What Happens: Body and Emotion in the Making ofConsciousness. San Diego: Harcourt 1999.3. Block N. Consciousness, accesibility, and the mesh between psychology and neuroscience.Behav Brain Sci 2007;30:481-499.4. Edelman DB, Baars BJ, Seth AK. Identifying hallmarks of consciousness in non-mammalianspecies. Cons Cogn 2005;14:99-118.5. Edelman G. Consciousness: The remembered present. Ann NY Acad Sci 2001;929:111-122.6. Rosenthal DM. State consciousness and transitive consciousness. Cons Cogn 1993;2:355-363.7. Searle JR. Consciousness. Ann Rev Neurosci 2000;23:557-578.8. Bennett MR, Hacker PMS. Philosophical Foundations of Neuroscience. Oxford: Blackwell,2003.9. Humphrey NA. History of the Mind. Evolution and the Birth of Consciousness. New York -London - Toronto - Sydney: Simon & Schuster 1992.10. Panksepp J. Affective consciousness: Core emotional feelings in animals and humans. ConsCogn 2005;14:30-80.11. Panksepp J, Fuchs T, Garcia VA, Lesiak A. Does any aspect of mind survive brain damagethat typically leads to a persistent vegetative state? Ethical considerations. Philos EthicsHumanities Med 2007;2(32): doi:10.1186/1747-5341-2-32.12. Kotchoubey B. Vegetative state. In: Squire L, ed. Encyclopedia of Neuroscience. Vol. 10.Amsterdam: Elsevier, 2009:61-66.13. Childs NL, Mercer WN, Childs HW. Accuracy of diagnosis of persistent vegetative state.Neurology 1993;43:1465-1467.14. Andrews K, Murphy L, Munday R, Littlewood C Misdiagnosis of the vegetative state:Retrospective study in a rehabilitation unit. BMJ 1996;313:13-16.15. Schnakers C, Vanhaudenhuyse A, Giacino J, Ventura M, Boly M, Majerus S, et al.Diagnostic accuracy of the vegetative and minimally conscious state: Clinical consensusversus standardized neurobehavioral assessment. BMC Neurology 2009;9:Article 35.16. Kotchoubey B, Lang S, Bostanov V, Birbaumer N. Is there a mind? Psychophysiology ofunconscious patients. News Physiol Sci 2002;17:38-42.17. Kotchoubey B, Lang S, Mezger G, Schmalohr D, Schneck M, Semmler A, et al. Informationprocessing in severe disorders of consciousness: Vegetative state and minimally consciousstate. Clin Neurophysiol 2005;116:2441-2453.18. Laureys S, Antoine S, Boly M, Elincx S, Faymonville ME, Berre J, et al. Brain function in thevegetative state. Acta Neurol Belg 2002;102:177-185.19. Owen AM, Menon DK, Johnsrude IS, Bor D, Scott SK, Manly T, et al. Detecting residualcognitive function in persistent vegetative state. Neurocase 2002;8:394-403.20. Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness inthe vegetative state. Science 2006; 313: 1402.21. Bardin JC, Fins JJ, Katz DI, Hersh J, Heier LA, et al. Dissociations between behavioral andfunctional magnetic resonance imaging-based evaluations of cognitive function after braininjury. Brain 2011;134:769-782.22. Tulving E. How many memory systems are there? Amer Psychol 1985;40:385-398.23. Bekinschtein T, Shalom F, Herrera M. Classical conditioning in the vegetative and minimallyconscious state. Nature Neurosci 2009;12:1343-1349.24. Lang S, Yu T, Markl A, Müller F, Kotchoubey B. Hearing others' pain: Neural activity relatedto empathy. (in press). Cogn Affect Behav Neurosci 2011: doi 10.3758/s13415-011-0035-0.25. Daltrozzo J, Wioland N, Mutschler V, Lutun P, Calon B, Meyer A, et al. Emotional electrodermalresponse in coma and other low-responsive patients. Neurosci Lett 2010;425:44-47.26. Lieberman MD, Cunnigham W Type I and Type II error concerns in fMRI research: Rebalancingthe scale. SCAN 2009;4:423-428.<strong>ACNR</strong> > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 13
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