D. Debatisse, E. Fornari, E. Pralong, P. Maeder, H Foroglou, M.H Tetreault, J.G Villemure. NCH-UNN and Neuroradiology Dpt. CHUV Lausanne Switzerland

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1 Vegetative comatose and auditory oddball paradigm with Cognitive evoked potentials (CEPs) and fmri: Implications for the consciousness model of Damasio and Guerit D. Debatisse, E. Fornari, E. Pralong, P. Maeder, H Foroglou, M.H Tetreault, J.G Villemure NCH-UNN and Neuroradiology Dpt. CHUV Lausanne Switzerland Sept 2006 Edinburgh

2 Plan 1. Theoretical introduction 2. Aim and design of the study 3. Damasio model of consciousness 4. CEPs and FMRI results 5. Conclusions 2

3 Introduction Oddball designs are often used in clinical domain to get information on: 1. the integrity of stimulus analysis in sensory-specific cortex (N1-P2) 2. the patient's ability to orient his/her attention to a target stimulation (N2-P3a) 3. cognitive processing related to memory and/or response (P3a-P3b) 3

4 Oddball design Presentation of a frequent stimuli (1000 Hz, 100ms) : exogenous response Presentation of a rare stimuli (1500 Hz,100 ms) : endogenous response The oddball stimuli is presented to the subjects in a pseudorandom sequence, that allows to control the target to target intervals (TTI) 4

5 Frontal (Fz) CEP recording (P3a) P2 Endogenous P300 Freq-rare 20 µv 15 µv 10 µv 5 µv 0 µv -5 µv F z f requent rare f req - rare -10 µv -15 µv N1 MMN Exogenous P µv ms SD 5

6 Central (Cz) CEP recording P2 Endogenous P300 Freq-rare 20 µv 15 µv 10 µv 5 µv 0 µv -5 µv C z f requent rare f req - rare -10 µv -15 µv MMN N1 Exogenous P µv m s SD 6

7 Parietal (Pz) CEP recording (P3b) P2 Endogenous P300 Freq-rare 20 µv 15 µv 10 µv 5 µv 0 µv -5 µv Pz f requent rare f req - rare zero -10 µv -15 µv MMN N1 Exogenous P µv m s 7 SD

8 Topography of the P3a and P3b P3a is localised in frontal P3b is localised in parietal 8 From D.Debatisse et al.: ( Masson J.M.Guerit 99 )

Normative P300 data 9 Topographical identification of P3 a in frontal leads and P3 b in parietal leads The variability of the latencies in control is small These parameters

9 Normative P300 data 9 Topographical identification of P3 a in frontal leads and P3 b in parietal leads The variability of the latencies in control is small These parameters are therefore sensitive diagnostic tools CEPs latencies remain relatively constant during adult life P3b increases after 25 years From D.Debatisse et al.: ( Masson J.M.Guerit 99 )

10 Language Damasio model of consciousness Memory 2nd-order map Extended consciousness Expands the present toward past and future generates the «autobiographic self» Doesn t need language Not Intelligence = Core consciousness + memory Amydala, hipppocampus, mnesic cortical structures Core consciousness Stream of consciousness of the present time without any reference to the individual s past experience Doesn t need language Recreates the perception of coherence in a stream of parallel processing Second order map Primary cortical areas, posterior cingular cortex, thalamus, mesencephalic tectum and prefrontal areas 10 Stimulus Mapping Comatose status? Wakefulness Minimal attention Map of internal milieu Proto-self Coherent set of neuronal configurations which iteratively map the status of the physical structure of the organism Infraconscious First order map (stimulus, internal) Brainstem, hypothalamus, S1, S2, insula, retrosplenial parietal cortex

11 Correlation between Damasio model and auditory EPs Proto-Self Primary cortical areas evoked potential, Pa, N100-P200 Pa (stimulus physical characteristics) N100-P200 (variation of the auditory environment) Persistence suggest the preservation of the proto-self Frontal mismatch negativity (MMN) Infra-conscious detection of repetitive stimulus variation (n-1) against (n) (comparaison) Frontal P3a ( ms)wave P3a reflects the orientation to rare, uncommon or strange stimuli P3a is associated with autonomic reaction P3a persistence suggests the preservation of the proto-self Core-consciousness and second order map Parietal P3b ( ms) P3b reflect processes that suppose the presence of core-consciousness such as Mnesic encoding (Garcia-Larrea), context updating Closing mechanisme (Desmedt), context closing Supraliminal access (Picton) Extended-consciousness 11 Centro parietal N400 Detection of semantic incongruences Lon latency EPs (N400) could in principle reflect extended consciousness mechanisms

12 Language EP and consciousness (Guerit 2002) Clinical examination EXTENDED CONSCIOUSNESS ERPs to complex Stimuli? Memory 2nd-order map CORE CONSCIOUSNESS P3b P3a, emotion PROTOSELF Stimulus Mapping Cortical EPs 12 Comatose status? Wakefulness Minimal attention Map of internal milieu EEG BAEPs, SEPs Model: J.M. Guerit (2002)

13 EPs can predict coma outcome EP can predict comatose patient outcome It is classically accepted that early evoked potentials (EPs) are a valuable tool for predicting outcome in comatose patients (reviewed in Chatrian et al., 1996) Positive prediction >> Negative prediction their positive predictive value (that is, their ability to predict a poor outcome when the test is positive, i.e. the EPs are markedly abnormal) exceeds by far their negative predictive value (that is, their ability to predict a good outcome when the test is negative, i.e. the EPs are only mildly altered). This holds true especially for early somatosensory EPs (SEPs) and brain-stem auditory EPs (BAEPs) in the absence of a primary brain-stem lesion (Rumpl et al., 1983). Combination of short- and long-latency EP improve the prediction The prognostic value of the technique can be improved by combining the recording of short-latency EPs with that of longer-latency EPs, that is, longlatency AEPs (Greenberg et al., 1977; Rosenberg et al., 1984; Hall et al., 1985; Fischer, 1994) or visual EPs (Greenberg et al., 1977; Guerit et al., 1993). 13

14 Aim of the study 1. Medical, ethical, legal, and economic reasons justify the assessment of possible conscious remnants in comatose and vegetative patients 2. One of the issue as to whether it is possible to bypass communication and examine consciousness thanks to the recording of scalp electrical brain activities with fmri study 3. In this study, 4 patients in a comatose state ( vegetative ) was confronted with a classical auditory oddball P300 design during the recording of event-related potentials (ERPs) and with fmri with the same design 4. ERPs and fmri data were compared in order to assess whether a brain response was generated by deviant rare stimuli, thereby providing some information on the depth of the patient's consciousness 5. Moreover, results are discussed on the basis of the operational model of consciousness developed by Damasio.A and Guerit.J.M for the CEPs in comatose 14

15 Material and methods Patients 4 patients in a vegetative comatose state induced by severe cranial traumatisms were investigated using the auditory oddball paradigm. The design consisted of 80 % frequent and 20 % infrequent (target) sounds in both type of acquisitions. CEPs CEPs were filtered with a band-pass filter (0.1 Hz to 30 Hz) and digitised at 512 Hz. CEPs were recorded using a 1000 ms time-base with a 50 ms prestimulus time using a Micromed EP system. Various components of the P300 were measured. N1-P2-N2 for the exogenous components (frequent stimuli) and N1-P2-N2-P300 (if presents) for the endogenous stimuli. EEG Standard EEG was also performed before the data acquisition in order to access the EEG status. SP and BAP used for coma neuromonitoring were also routinely performed. fmri FMRI oddball paradigm design was identical to CEPs. It should be noted that the patients needed no respiratory assistance and that the vital functions had to be stabilised before fmri. Therefore, fmri acquisitions were performed either the same day that the CEPs or the days following the CEP, depending on the patient state. 15

16 Case 1: MRI case 1: multiple brain lesions and more in the frontal lobes 16

17 Case 1 Case 1 Mean AVG P300 Target (red) Non target (blue) P3a + P3b? P N1 P2 N200? C Target Non Target -20 Latency Pre stim 50 msec 1000 msec 17 Exogenous( blue) and endogenous (red) responses during auditory oddball paradigm. We can observe a N200-P300 component and perhaps 2 components in the P300 ( P3a and P3b?)

18 Case 1 fmri : Posterior cingulate activation during auditory oddball paradigm 18

Case 1 Summary 20 15 P3a + P3b? 10 5 0-5 -10-15 P N1 P2 N200?

19 Case 1 Summary P3a + P3b? P N1 P2 N200? Target Non Target -20 Pre stim 50 msec Latency 1000 msec 19

20 Language Case 1 consciousness level Clinical examination EXTENDED CONSCIOUSNESS ERPs to complex Stimuli? Memory 2nd-order map CORE CONSCIOUSNESS Level for case 1? P3b P3a, emotion PROTOSELF Stimulus Mapping Cortical EPs 20 Comatose status? Wakefulness Minimal attention Map of internal milieu EEG BAEPs, SEPs Model: J.M. Guerit (2002)

21 Case 2 fmri: multiple brain lesion and more in the brainstem Can the patient hear? 21

22 Case 2 22 Exogenous( blue) and endogenous (red) responses during auditory oddball paradigm : no evidence for endogenous responses.

23 Case 2: fmri: no responses? 23

24 24

25 Case 3: fmri: multiple brain lesion and more in the left hemisphere. 25

26 26 Exogenous( blue) and endogenous (red) responses during auditory oddball paradigm: possible N200 (MMN) component but with a very long latency, no evidence for a N2-P3 complex.

27 Case 3 fmri: Anterior cingulate and motor cortex activation 27

28 28

29 Case 4 Post trauma First day Glasgow score: 4 Glasgow score during examination: 6 Spontaneous eye opening 29

30 Case 4 Multiple lesions due to shearing stress in the deep white matter and corpus callosum 30

31 Case 4: P300 acquisition 2 Exogenous EP: N1-P2-N2 Endogenous EP: N2-P3a and confirmation of a P3B N2 P3a P3b? 31

32 Language Case 4 consciousness level Clinical examination EXTENDED CONSCIOUSNESS ERPs to complex Stimuli? Memory 2nd-order map Level for case 4? CORE CONSCIOUSNESS P3b P3a, emotion PROTOSELF Stimulus Mapping Cortical EPs 32 Comatose status? Wakefulness Minimal attention Map of internal milieu EEG BAEPs, SEPs Model: J.M. Guerit (2002)

33 Results summary Results presented here seem to demonstrate the feasibility of the parallel approach (EP and fmri) in order to answer to the essential question: Can the patient detect a change in his/her acoustic environment and what are the structures implicated in this implicit recognition task? 3/4 patients (case 1,2 and 4) presented P300. Suggesting that they ere able to perform complex processing at the level of the core consciousness It should be noted that 2 (case 1 and 3) of our patients were able to activate brain structures such as the cingulate classically observed in the oddball paradigm and implicated in the orientation brain Case 2 presented no CEP, suggesting lesions in the brain stem that should be tested by BAEP. 33

34 Patients Outcome Case 1: good Case 2: bad Case 3: +/- good Case 4: good Good: Awake, aware, contact possible using one or more sensory input Bad: Still in vegetative coma 34

35 Discussion P300 Auditory Oddball paradigm (CEPs ) is a standard tool to investigate cognitive functions in patient with consciousness disruptions such as comatose state These CEPs should naturally be compared with short and medium latencies potentials ( BAEP, SEP and VEP) that test more basal brain structures (functions). As seen in patient 2 fmri is one the most promising technique for the assessment of the higher brain functions present in the cognitive or associative cortices of comatose patients This preliminary study is the first one to our knowledge where CEPs and fmri acquisitions performed using the same stimulation design ( auditory oddball paradigm), have been compared 35

36 Discussion Combination of these investigations, in addition with other clinical approaches should eventually improve the quality of the prognostic in the longitudinal followup of comatose patients. That said we think that the clinical parameters should still prevail in the clinical and decisional algorithm for these type of patients. Despite the use of para-clinical tests in association with EPs and CEPs, we are still unable to give a useful short and medium term prognostic for comatose patients. 36

37 Discussion These preliminary results suggest that the combination of the fmri and the CEPs using the same stimulation design is helpful for the comprehension of the structures still functional in vegetative states. Furthermore, we believe that a major rethinking of the vegetative state should be done. Our observations suggest that perhaps in some cases the comatose patients can still feel and exist using some of their sensory channels, even with very low consciousness level and that they could suffer from their pathology 37

38 Conclusion 1. Cognitive test by P300 auditory oddball paradigm stimuli can be performed by fmri in comatose patient without compromising the vital functions 2. Comparison between CEPs and fmri suggest that both tests are complementary and helpful for the comprehension of the structures implicated in the cognitive processes that don t need patient active cooperation 3. Activation of the cingulate structures confirms their involvement in the genesis of the N1-N2- ( P3 ) in 2 out of 3 of our patients 4. Our observations seem to confirm the Damasio s model of protoself and core consciousness in patients presenting vegetative coma 38

39 Thanks 39

The EEG Analysis of Auditory Emotional Stimuli Perception in TBI Patients with Different SCG Score

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