Steven Laureys 'Neural Correlates of Consciousness: Lessons from Coma and Related States' transcript

thank you very much for this invitation and we'll indeed start by um introducing the conscious and the SS of Consciousness where in the absence of a generally accepted definition uh as Physicians of course we need to make decisions so how do we do that um what if we need to quantify Consciousness at the bedside um in uh patients so let us start by the most difficult patient and that's a philosopher we'll take net block again if we want to say meaningful things about Net's Consciousness how we will do this is to reduce this complexity of Consciousness to two Dimensions first we'll check with the different coma scales Glasco coma is the most used to his level of weight arousal which is quite straightforward we'll just check if Professor block has the eyes wide open if not uh we will stimulate him even apply noxious simulation so to make sure he is fully awake because that is necessary but as we'll see not sufficient for him to be aware of himself and of the environment and that is what we experience every night this relationship between wakefulness arousal and awareness of self our environment when we fall asleep when you fall asleep you at one point lose awareness of your environment already we see that there's an exception a notorious one during REM sleep Lucid Greening is even a very extreme example of one uh becoming aware of your anic activity of your dreaming State while from the outside looking asleep um and a patients in coma uh by definition cannot be awakened meaning they will never Open the Eyes even if stimulated the same holds for general anesthesia where anesthesiologist and we'll hear much about that tomorrow have different drugs to reduce the level of wakefulness so that um the patient will lose awareness of the environment and The Surge can do is CH now coma will not last for long periods of time after a couple of days or weeks some patients might awaken meaning Open the Eyes yet only show reflex behavior that was defined in the 70s as persistent vegetative state it's an unresponsive wakefulness um meaning that the patient is awake passes the wakeful test eyes open yet it fails he fails to pass the awareness test and what is that that is uh first of all looking for non-reflex Behavior that's not so easy um you just moved was that a reflex was that voluntary um there's a lot of uh discussion about what is truly a voluntary action so our um most convincing awareness test is looking for response to command so if we take our patient net again we will ask him to ra the left arm you see philosopher is always a problem nobody saw it um but he made a movement with his left arm and that will be taken as proof of Nets being conscious already you see that this can be problematic um maybe uh he's conscious and yet fails to um move because he can be deaf so we'll write it down um or because and that can happen in some patients he has uh lost his voluntary control of uh his muscles after a traumatic brain injury there can be lesions in the nerves spinal cord brain stem and then we really have a problem so it's important to emphasize that our quantification of Consciousness at the bedsite is or can be biased by um the fact that we are actually um making inferences based on motor behavior and this is why I think it's so exciting now to see we have these functional Imaging um and electr electrophysiological tools to go and measure what's happening in the brain there are some other examples in neurology uh where we can have this dissociation of reflex motor activity in the absence of response to command like epilepsy absence seizures complex partial seizures where also patients can have some automatic motor uh activity just as in sleepwalking but if you would ask them to do something they would not respond and I think these cases are very interesting for us to understand the soal neural corus of awareness some patients uh who are after coma evolving to um vegetative unresponsive wakefulness can remain in that condition for years others can show some minimal signs of Consciousness such as following with the eyes when you would go from left to right in the room or smiling to their mother and only if it's the mother con say it's a reflex and this is point minimally conscious State mind minus so there's evidence of nonreflex behavior and minimally conscious State plus is as soon as the patient shows response to a simple command but not in a way where you can use that response to establish a yes no communication you can't say squeeze my hand twice to say yes once for no this will not work so it's a very frustrating situation where you know where sometimes there's evidence of awareness but it's fluctuating in time and you can't communicate and as David already pointed out this is very important when you want to share your conscious experience well that needs um communication verbal or non-verbal communication which is impossible in this condition called minimally conscious state only defined in 2002 so really medicine is struggling how to deal with these um patients and then um finally there's patients who can awaken from their coma fully conscious yet unable to move their legs their arms they can't speak and this is going locked in syndrome classically caused by a lesion in the brain stem so it's an in brain where all the Moto fibers are damaged classically it's a vascular lesion after a stroke um touching all the um M fibers and cral Nerf NE responsible for speech so it's a form of pseudo it's not a disorder of Consciousness but it can be mistaken for one um as you see these um two dimensions of Consciousness wakefulness and awareness are not black or white or or nothing phenomena we should see them as a more graded um gradual um entity and I think uh as said that functional Imaging now offer us a tool to try and uh measure uh what is needed for us to be conscious and um this uh this slide shows us uh results from posi transmission tomography where you can basically quantify the metabolic activity of the brain so you inject radi actively labeled glucose goes into the nerve cells these cells are the ones using the most of energy of any other um cell of your body and 100% fully awake and aware brain and the question we would ask here is would there be some kind of threshold if overall activity in your cortex would go down you would simply lose Consciousness and definitely um this is the case in brain death this is the uh so-called um um empty uh skull sign where you only see activity in the skin surrounding the skull none in many of these billions of neurons irreversible coma brain death tonight when you fall asleep in deep um slow wave sleep you see overall activity of the brain going down to levels around 60% of normal waking values and in Rapid ey movement sleep or paradoxical sleep something paradoxical happens where you have these dreams occurring um overall brain activities very close to normal waking in jalesia again you see this relationship when anesthesiologist and we will hear about that more tomorrow while har shine give basically any drug that makes you unconscious no respons to command your overall activity will massively decrease around half of normal values when anesthesiologist stop Dr Consciousness regen and so does overall brain activity so so far so good seems to be this correlation between overall activity in the brain and absence of presence of Consciousness now that relationship is not so straightforward in pathological loss of consciousness both coma vegetative state you see this massive Global reduction about 40% of normal waking values when patients can um be in vegetative state awake yet unaware and some of those patients will recover and we have the opportunity to rescan them and you see it's not a recovery of a full 100% in other words you don't need your whole brain to be conscious there is a critical network uh it is I think much less than we historically thought um you need only part of the brain to be active for you to be consciously aware and now using statistical tools we can identify this so-called Consciousness Network it's not a small region in the brain it's um this frontal brial network of both left and right hemispheres you see there in yellow and red uh and this midline um um front and back um Network again that is systematically impaired when patients were studied in a vegetative state unresponsive way wakefulness and which is also observed when we look at seizures you see in green um data obtained in complex partial seizures using spec Imaging you see in blue absent seizures where patients would just uh be absent fail to uh interact for a couple of seconds and this is an fmri study uh showing decreases in blue again in this widespread frontal brital Network and finally in sleepwalking um one patient uh studied so far only by clao basetti um in Switzerland injecting again radioactive label Tracer when the patient in slow wave sleep starts to walk and you see in yellow now the decreases in this um widespread Network so I started by emphasizing that you have this uh relationship between the two components uh the level or arousal and the content or uh awareness um and they so this negative correlation classically observed in sleep I would now propose to again reduce the complexity of awareness into its two main components and that is sensory or perceptual awareness of your environment it's everything you see and hear and feel everything coming to your senses and then uh so-called awareness of your internal World which is this little voice talking to yourself This internal dialogue you can have this mental imagery um um or awareness of self if you want but this is um has a lot of other connotations and there you see this um negative correlation and the take home message of this introduct talk is that you have neural coret for both of these Dimensions we already seen that there's this Global frontal bral Network where we've reason to believe that the lateral areas of both hemispheres front and back are critically important for external or sensor awareness whereas this midline core in blue is important for internal or if you wish uh selfawareness and um we'll now see a couple of studies illustrating that what is important is the interaction between these networks one neuron um we uh think cannot be conscious but the interactions of billions of neurons this um functional connectivity between the gray matter and this um deep structure here the thalamus seems to be of critical importance so um number of studies this one uh done here in in in the lab in in volunteers put into an MRI machine no specific task resting conditions except that they heard a beep once in a while and then they needed to say uh by finger button press whether they were more externally aware or internally aware and then you see if you correlate the scores if the scores were more external you see this lateral frontal pital areas and if there was more internal awareness course you see this midline core and at the behavioral level you see that both scores tend to anti-correlate at then a given moment you're more one or the other and we know that from daily life activity sometimes you can be so absorbed in your uh reading a book or something that uh somebody uh doing something outside you will ignore it or otherwise your neighbor will make a lot of noise external awareness will um be high and making it difficult for you to focus on your uh work and it seems to switch um at a frequency of 0.05 Herz on average which is about every 20 seconds which is also know from these resting state fmri studies these spontaneous fluctuations in the Bold signal uh we uh have reason to believe reflect these external or uh internal awareness um uh thoughts so um how does this apply to patients um this is uh a study you can't read it by uho where she used again posit transmission tomography and as said in patients who are vegetate if you see this widespread frontal prital um Network impairment uh decrease of metabolic uptake as compared to controls in minimally conscious State you see that uh it seems to be more lateral awareness Network um that recovers and these patients show uh a recovery of awareness of the environment but the uh internal awareness network still uh seems to be um impaired when they recover communication locked in syndrome patients uh pseudocoma of course they show no imper whatsoever of the awareness Network and then this is a correlation with um the mostly used uh Consciousness scale which is the coma recovery scale and you see again the higher the score on the scale the higher add activity in the so-called frontal prital um Network and there's uh a lot of evidence and you will hear about it um today and tomorrow that for you to be aware of some external stimulus you don't uh it's not happening in your sensory cortexes you don't hear with your hears or auditory cortex you need this frontal prial Network and this is a study by Melanie Bly uh where she used the laser at such a borderline uh intensity that half of the time you wouldn't even feel it uh and then the other half subjects would say yes I felt a laser on my hand uh if you contrast the fmri images what you identify is not primary suto sensory Vortex as said it's a slave system it's necessary but not sufficient for sensory awareness you see this frontal prital Network studying internal awareness is a bit more difficult for us we use a lot the patient's own name or uh own face this is increasing um it's it's it's attentional grabbing um Auto referential stimuli and this is a study done uh by colleagues in China where you see that the patient's reaction to the uh own name will increase this uh default mode uh midline structure uh and even more so when the coma recovery scales are higher in patients after coma um there's different ways how one can modulate these two dimensions of awareness and in Le we've been working um with an anesthesiologist who introduced hypnosis into the operating room um where um one can do some kinds of surgeries like tectomy uh without general anesthesia but with a patient staying uh conscious yet uh being in this specific condition called hypnosedation which we compared with distraction task and you see here that the scores the subjects give uh during this uh different conditions normal waking distraction and nnos of course it's increase of absorption it's a dissociated state and there's a decrease of external thoughts and the fmri also shows that the external lateral frontal pital network still is there in distraction thoughts but kind of breaks down during hypnosis so you're kind of um disconnected from your environment external awareness Network breaks down and there's an increase of connectivity uh in the internal awareness or default mode Network so Consciousness um does not um happen if if you want to say it a bit provocatively in your primary cortexes this is an old study where we used auditory stimuli they activate your auditory cortex of course but also in coma or vegetative state patients it's necessary it's not sufficient for you to be conscious you need a interaction a communication between the auditory sensory uh slave systems with this frontal parial uh external awareness Network and that is only seen in subjects who are conscious or as here shown minimally cons ious or minimally responsive um there's now many many uh complicated uh ways we can analyze these signals both with NE Imaging and EEG this is high density EG with auditory uh stimuli being presented and one can use Dynamic causal modeling which is a way to look again at connectivity but also at the directionality of the connections and it seems to be that for you to be conscious of an auditory stimulus you need this topd down or feedback connection um Illustrated here by this red arrow between the primary auditory cortex uh and the uh secondary auditory areas here number two and then three is this frontal uh associative area where you need this top down kind of recurrent Loop uh only seen in Consciousness and not in patients in coma or vegetative state and of course if that is true um it is very helpful to make uh or to reduce the uncertainty we face when dealing with patients and that is important because as said our clinical Consciousness test can be biased by uh the assessment of motto responsiveness we try to capture Consciousness but actually all we do is um depending on motal responsiveness and in some patients that can be tricky this is why um there's this uh strange tennis test which is basically uh in FM asking a patient to imagine playing tennis it's the same as what we do clinically it's move your hand or imagine to move your hand but we don't look at the hand anymore we look at the activation in a moto cortex and you see here in uh healthy controls in yellow um that we can capture this increase in Bolt activity this is another question imagine to walk from the front uh of your front door to your um sleeping room it will activate a different set of areas here parah hyoc cample areas and then you see these patients um with severe brain damage uh studied both in uh Belgium in y and in um the UK in Cambridge where you see there's traumatic brain injury very important a lot of atrophy this black is uh C spinal fluid so there's hydris uh at some places there's virtually no uh gray mat left then from the outside some of these patients would fail um the awareness test no respons to commment no functional communication and yet in the fmri you see that they can um respond to the task activate the specific areas and in one uh patient this even permitted a functional communication we could uh explain to the patient well patient was sent to us with the label vegetative it turned out to be U wrong and in the MRI we see activation of the motor cortex we can then say well um if you want to say yes do this motor task and then you can read in the brain more R the patient to the first question is answering yes next question blue no no yes no and six question no answer anymore these were simple questions we knew the answer is your name um Fred is your name um um Mark is your mother's name Maria and so on and so forth to validate the technique of course it's um not practically useful because as soon as the patient comes out of the MRI you have no way anymore to communicate so one needs and we'll hear about that later um to develop cheaper and portable uh Alternatives which are called brain computer inter interfaces where you measure the electrical activity of the brain uh and do the same thing ask the patient to um respon to command and then read the response this is still an other technique where we try to um communicate through movements of the pupil turns out to be that if you're a bit stressed or you do some mental calculation your pupil will dilate and we can again use that signal we can just put a camera on the patient's eye and um ask a question and then say well if you want to say me no do a mental calculation here we see no pupil dilation then we ask uh again if you want to say yes to this question um do 24 * 57 uh and then if the camera detects a dilation uh and this is automatic signal detection we can read that there's um communication of yes this works very fine in lamp conditions in health development it's already more challenging in locked in syndrome patients uh but some of them can do it quite well it even worked in um minimally conscious State patients but it's more a proof of concept because at the beds side again this is terribly challenging um and the signal to noise ratio uh is is not very good um so we've said some of these patients after a severe brain injury traumatic anoxic will evolve to coma it will not um last for more than a couple of weeks this condition of coma some of them will awaken showing reflex movements eye opening but nothing else this resistent vegetative state or unresponsive wakefulness where then again some will show uh visual Pursuit localization to pain or appropriate smiling or crying to familiar faces minimally conscious State minus and then the next step would be response to command minimally conscious State plus these two uh entities and plus and minus differ in terms of their um brain function you see much more left lateralized damage in patients who fail to show the awareness test respons to command which really emphasizes um another clinical problem where all these fancy um tennis tests and brain computer interface will still give us a problem which is when the patient doesn't understand the question when he's a phasic it's not because you don't understand language that you're fully conscious you can still experience pain you can appreciate music some chocolate on your lips and so on so forth so this again is a big problem for us at the bedside uh and I think that these minimally conscious State minus patients with often left lateralized damaged encompassing the language Network illustrates that very well when even these fancy uh fmri tests or brain computer interfaces will fail this is why we've been um investing a lot in tests that do not require any collaboration for the patient and the easiest one can do is to just put her or him in an MRI scan and record resting brain activity because if you would be in MRI um you're you would be thinking what am I doing here what am I going to do tomorrow and we can measure your spontaneous bold fluctuations and the easiest for us to capture is this so-called default mode Network overlapping with the internal awareness Network you see it here in the front in the back um and of course in some patients this can be very helpful this is a classical example in a locked in syndrome patient in the acute setting you see the brain stem Legion here with the white Arrow from the outside it's very hard to make sure that there is some Consciousness and the fmri resting state data clearly show you these yellow blops and you can be all excited to see uh Consciousness and yet of course we need to be very careful sometimes the data are lying to us we're seeing things we think uh represent Consciousness and it's noise coming from the scanner or some other effect or some um mathematical um trick where uh we can get it wrong and get false positives and so of course this is um The Challenge in this field where there's no gold standard there's no way like in a patient with a a brain tumor for example you can do an autopsy you can look under your microscope there is a concer cell or not for Consciousness you have no way even when the patient dies you can't look at Consciousness um under some microscope or whatever so we will validate our paradigms in anesthesia because there we can uh control um the loss of awareness and um again look at the breakdown of connectivity uh in this internal awareness default mode Network when you compare wakefulness to mild sedation to loss of uh reement to command unconsciousness and then the recovery um you see that the connectivity changes depending on Consciousness it's not uh the case for these so-called slave uh sensory systems you see the visual Network still shows activity even in aesthesia and also the auditory Network um as said you need this widespread frontal parital uh connectivity and in disorders of Consciousness after coma you see again here this breakdown when you compare normal or locked in patients with minimally conscious with unconscious vegetative or comos this uh internal awareness Network breaks down its connectivity and the area that separates best um unconscious vegetative from minimally conscious is this um region here in the back of the brain poster singlet cortex and adjacent prunus this seems to be a critical Hub in this uh widespread frontal prital um awareness Network another interesting technique after resting state FM where you don't have to ask anything from the patient is this technique where marello mimini will talk more about it's perturbing the brain with t m s and then measuring the electrical Echo with EEG it's very difficult technically um but it's an elegant way to quantify the complexity of the system we think um and and this is also going with ton integration information Theory um that is needed for uh experience of Consciousness and then if you do this in sleep in different s states of anesthesia and in patients with disorders of Consciousness you can draw some border it turns out to be on this scale that captur this complexity we call the um PC perturbational complexity index um that between 0 and8 uh if you are above 03 um all the uh measurements so far turned out to be in conditions of preserved Consciousness and of course if this is true this can be helpful clinically again to reduce the uncertainty regarding the patient's diagnosis and that is needed because a number of Studies have shown that we can get it wrong we can get it wrong in about three four times of out of 10 where from the outside you think the patient is unconscious um and when you do um appropriate uh assessments even uh with clinical scales the coma recovery scale um if you compare the clinical diagnoses without a standardized validated Tool uh you can miss in this series uh 35% of clinical misdiagnosis uh and then if you have these Hightech tests functional NE Imaging in this case um the tennis FM test or the pet glucose update test you see that again there's about a third of patients uh still showing uh surprise findings meaning that even with the best beds side assessment com recovery scale assessment showing there's nothing yet you have a surprise finding on the new Imaging um and of course this is important because uh Studies have shown that when you have these minimal signs of Consciousness it means the patient can have some perception and your um uh clinical management should be different and also um in this series we uh showed that there is a prognostic information all the uh exceptional uh cases of dissociation between clinical and uh high-tech testing subsequently uh or most of them uh the vast majority also show clinical signs of recovery which are of course important and the study also showed that despite its uh well I would say theoretical uh appeal and and it seems to be uh attractive to do this tennis test in each and every patient it is terribly difficult to do in about four out of 10 patients you will simply not be able to even start the test because the patient moves too much uh and in the remaining 60% it's still going to be very challenging and you will fa face a high number of false negative meaning patient be consci just fails to do the Imagine playing tennis or imagine walking around your house test uh for many many reasons um we will have a low sensitivity whereas the uh posit transmission tomography um is uh in our experience um doable in the vast majority over 90% of of the patients um another technique and I think the the the the the future is really to combine information from the different examinations um as with it in the last lanet paper uh another interesting technique I think is the fusion tensor Imaging this is quantifying U not the gray matter Integrity but the white matter and uh as said when you're in coni conscious we think you need an interaction of functional connectivity uh and that needs structural connectivity you can capture by MRI uh DTI measures you see these blue tracts going down to the spinal cord motor c ises um you see the red uh trans caloso uh tracks um that uh connect both hemispheres and then green front to back uh fibers and we now know that uh if we quantify the damage in the white met track this kind of the highways in your brain um this is helping us again to reduce the uncertainty regarding the prognosis um and I'm convinced that we will see more of this in the future helping us to um um disentangle patients with bad and good prognosis already uh at the Intensive Care setting um after the challenge of getting the diagnosis right the challenge of predicting the outcome the prognosis I think there is this challenge of U treating these patients and um one question I think is important is whether we think these patients can perceive pain it's a difficult question we asked over a thousand medical doctors quite straightforward question do you think that patients in vegetative state can feel pain you see results can be more ambiguous 56% said yes even more so of the nurses and well a kind of uh it's it's uh interesting to see that the the the variable that correlated with their response was whether they were religious or not and of course we want to do better than that in our hospitals uh and uh get it more objective we've developed this um Pain Scale notion Coma Scale uh again the challenge is to um give sense to these um responses do they really represent subjective experience of of pain and if so should we give painkillers function or Imaging can give us uh a more accurate reflection of what's happening in their brain and you see that minimally conscious State patients by definition they can't tell us they feel any pain but their brain scans do you see activation of the whole pain Network as seen in healthy controls uh study done by melan boli here Anor singlet cortex activating to noxious stimulation in these patients we think reflecting um the fact that they experience um some um pain and should systematically receive analgesia uh finally the therapeutic interventions of course better understanding can lead to um better treatments an older study where you see that there's a disconnection between the gray matter uh and the thalamus and uh more specifically the interlaminar Central thalamic nucle and uh um Niko shi's team who stimulated these deep structures both talami which in some patients this case post-traumatic minimally conscious State could improve their level of awareness and now also I think with um noninvasive methods called trans cranial direct C stimulation or others we can try to increase the activity of the brain by putting electrodes not deep into the brain with all the ethical um considerations we will hear more about later uh by Joe fince and others but by simply putting electrodes on the skin and aiming to increase the activity here which seems to work you see in minimally conscious State patients they would increase about two points on the com recovery scale um not so in the unresponsive uh wakefulness or vegetative patients um and now of course the challenge is to identify uh why some patients do and others fail to show Improvement and again and their functional Imaging we think can help in identifying responders from non-responders we'll hear later today and tomorrow about all the ethical um challenging challenges when um trying to do this kind of research in patients who are of course vulnerable uh and should be protected but also should not be overprotected uh which gives the risk to keep them uh from having access to these new technologies and um we'll end with some um challenges uh on quantifying again um the meaning of uh well the quality of life of these patients which is challenging to capture it's hard to quantify Consciousness it's hard to quantify pain the same for a meaningful life what is it like to be minimally conscious I think it's a very important question yet in the absence of a functional communication it it's hard to give a meaningful answer to this uh question so what we did is asked that question to patients who are locked in and maybe we can do this together for those who don't know the study um we use this scale going from minus5 which is the worst period in your life if you can try to imagine they it the worst period in your life paper rejected or divorce or and then plus five which is the best period in your life paper accepted or a divorce um and then if you calibrate your own quality of life scale from minus 5 the worst to plus five the best you can give an answer to the simple question how were you the past two weeks on this scale what is your score you don't have to tell me but this is what we got from locked in syndrome patients so remember you can be more motor handicap than this these are chronic patients can communicate through a small blink of the eye and we see Plus three plus 4 majority of these patients telling us yes it is possible to have a meaningful life don't judge a book on its cover also some of these patients of course score minus five we asked a question about tinesia this was done in France there's no La tinesia um and we try to identify which uh variables could explain why they were so unhappy it seems that time is very important um and also the access to communication devices um and social life so in uh conclusion I hope I've given you some evidence um that for you to be conscious we need activity in a frontal prital Network Nik is going to uh explain the uh miso circuit uh model and the different ways we can try and modulate the activity uh I briefly mentioned the de brain simulation of the talami the transanal dam simulation uh and I'm sure that Nico will tell you about some miracle case basis um showing recovery to zulum which is very interesting Dr and um I would just like to end by how challenging it is to do this kind of research we're talking about Consciousness um it's not neutral um it's trying to capture the Mind Spirits it depends on our aset religious beliefs um at uh one time we ask at meetings like this scientists medical doctors do you think that mind and brain are two separate things uh well many of us are still having this struggle to um deal with dualism or monism it is important I think for many reasons uh some would even claim that near-death experiences I didn't mention it but are taken for some as proof of life after death I don't think that is true I think we have scientific evidence of life after death it is called organ donation um however I think also that science and medicine has not taken this phys physiological reality of near-death experience is serious enough so we're trying now to um record many um testimonies we have over 200 now it is good to know that most of them are positive it's a very pleasant peacefulness experience for those patients who uh have this memory of a card for example um some would explain it simply by a lack of oxygen um it doesn't seem to be that simple we compared the cause of the coma you see 45 had a cardic arrest 30 had trauma 65 had bleedings and other uh uh reasons for their coma and it turns out that uh what they tell us afterwards is very comparable most of them feel peaceful some many uh over 80% have these outof body experiences and we now know that there's in the brain this right and propri region if you stimulate it you can produce these out of body experiences uh so you see here a ranking of the most frequent uh dimension of these phenomena um and trying to link them with um ethology and of course uh the challenge is to explain how a very dysfunctional brain after uh coma can still have these very Vivid uh experiences I thank you for your attention um and I think we can take a couple of questions