Thanks a lot for those kind words and the nice introduction. Let me see what I can yes So I was asked to speak. Thanks a lot for coming up here and out out here I was asked to speak on who is and who is not in coma from the perspective of cognitive motor dissociation locked-in syndrome and minimally responsive state So I will try to sort of set the ground and talk a little bit about these these Specific states and syndromes to sort of put the these disorders of consciousness into perspective Heard about that. These are my disclosures. They my funding and I'm an I'm a minority shareholder in ice neural systems So the learning objectives today is we're going to talk a bit about what is coma How is it does it is it different to other disorders of consciousness? What can cause coma? What is the problem with our current assessments, how do we assess patients in coma Currently and possibly in the future and then what is cognitive motor dissociation or covert consciousness? So to start out with coma Thank you to start out with the question What is coma so coma typically is defined as a patient that has the eyes closed They do not arouse to vigorous stimulation they may show some grimacing so facial expressions and Some stereotypes motor response if you put them patients that have normal consciousness and a comatose patient on two axes of Arousal so being awake for example and awareness That means you're able to process content that is exposed that you're exposed to Normal consciousness has both at the maximum and a comatose patient has both as an at a minimum if If what so what can cause this state that we define there there's a number of different etiologies First of all, you can think about the path of physiological location that can cause coma You can see here an example for example of this could be a patient in black You can see you see what's injured This could be a patient that for example has a cardiac arrest and has diffuse injury to the cortex like in hypoxic ischemic injury But you can also have more strategically placed lesions here in the brainstem upper brainstem a little bit lower down That might be much much smaller But they cause the same behavioral phenotype of a patient that does not arouse and does not follow commands If you look at imaging for example, you can see here This is a nice example down here of patients that had all traumatic brain injury But they have all very different causes for the coma So one patient here in the left upper region has an epidural hematoma Here a patient has contusions and a hematoma Diffuse axonal injury doesn't actually have any blood but it's sort of twisting and tearing off the of the neurons Down here you can see a patient with a subdural hematoma subarachnoid hemorrhage or IVH and diffuse brain swelling But it is not only what you see on the imaging it is much much more and just to give you an example Here are three patients that have different kinds of did a very very similar brain injury They have actually a hemorrhage in the cerebellum in the back part of the brain, but they have very different Trajectories and this is because one of them was intervened on early So the time to treatment may matter as well And the other one one of them actually was the course was complicated in the emergency room by a cardiac arrest so there's a number of things that factor in but When a patient is in coma that may actually matter and being partially or fully responsible for this behavioral state So, how do we determine if someone is a coma in a coma the classic is is all based on a behavioral assessment So here you can see the physician and here's a patient and the patient is examined by behavioral assessment But this is actually so what does this lead to very often in the past? We just communicated by saying the patient is in a coma but what does that mean to me versus another physician or a nurse or a Physician assistant so this communication is very challenging So a number of scales have been developed to support our communication about behavioral states The most widely used scale is the Glasgow coma scale that actually looks at eye opening best verbal response and best motor response But it doesn't truly assess whether somebody's in a coma There's a number of ways where you can get end up with a scale that actually is associated with coma But that doesn't directly assess whether a patient is in coma the best behavioral scale that looks at different features of Consciousness is the coma recovery scale revised This was developed by Joji Asino who is at MGH and is one of the leaders in the field has developed this but has Influenced many many many of us and inspired many of us this scale looks at different parts of command following There's a visual function scale an auditory function scale a motor function scale And it tries to then comes up with this number that reflects the behavioral impairment There's a number of problems with this using this in the critical care setting because it may actually take in some patient quite a long Time, but he's working on. I don't know whether it's published yet Brian may know but there is a scale that is developed being developed by him Just for the ICU setting that may be much much quicker, and I think that will be revolutionary So we've talked about coma a bit So you can see here down here if you put motor function and cognitive function here Coma has very poor motor function and very poor cognitive function, but there are many other behavioral states that are Clearly defined and different to fully recovered or fully conscious patients where they have very good Motor and very good cognitive function first to mention is the vegetative or the unresponsive wakefulness syndrome These patients have no evidence of awareness of self or the environment, but they may open their eyes That's an important distinction to a comatose patient the minimally conscious state More recently to sort of described has reproducible, but inconsistent awareness There's MCS minus and MCS plus this basically means whether they are verbal evidence of command following in The locked-in state patients have a much better level of consciousness than their motor expression would suggest Typically the patients have parallel paralysis of all four limbs and the lower cranial nerves They may have some vertical eye movements, and this is very very important Maybe one of the most important things to take home from today's talk here is to carefully examine the patient And when you go into the room to ask them to move their eyes up and down it is still to this day often missed In in in the critical care and even in the subacute care setting these patients may fully hear what you're saying What's happening with them when they're operated on or all sorts of things and they have to be care taking care very very very carefully and with compassion The epidemiology of disorders of consciousness is not fully known there was a very interesting paper done recent Recently where they by survey they estimated a point prevalence in the u.s. and in England of seven to thirty one per hundred thousand and an incidence of 135 to 258 per hundred thousand in the UK in the u.s. One important thing is what's the trajectory? What's the outcome of these patients many of these patients die in the context of withdrawal of care? And what is this based on it's based on predictions that the care team? Provides to the families and together then they come up with the goals of the care. This is typically determined by age Comorbidities injury mechanisms time to treatment at the best neurological exam There's a number of scales that have to be developed been developed for different brain injuries for ICH for example There's a primary ICH score There's a number of these scores But whether or not they accurately predict recovery is not known because very often these sample sets where they were developed on They were also patients that underwent withdrawal of care and so then it's a self-fulfilling prophecy We know that in TBI 70% of patients die due to withdrawal of life-sustaining therapy and it ranges between 45 and 87 percent In ICH early withdrawal is very common in acute ischemic stroke mortality is associated with disorders of consciousness and in cardiac arrest Jonathan Elmer at Pittsburgh estimated that 64% of the patients the 2,300 Americans each year that under that die in the context of withdrawal of life-sustaining therapy Could actually have had good functional outcomes So I think those numbers whether or not they're exactly correct does not really matter But it highlights the importance of looking into this more carefully. What is the natural history of patients with? disorders of consciousness and acute brain injury that's very difficult to study because Withdrawal of care is a fact in most countries in Japan. However, withdrawal of care is not widely practiced So we identified 40 patients there with a number of different brain injuries where the physicians Within four days of admission to the ICU said there's no chance for meaningful recovery That may or may not have been based on different different criteria But the physician the attending physician determined that there was no chance of meaningful recovery While in the majority of cases the physicians were right the patients didn't have meaningful recovery It is important to notice that rarely Patients actually may have good recovery and two of those patients in the court of 40 patients had actually very very high functional outcome So it's important for us to be very modest when we give our predictions So can we go beyond the behavioral exam right now? Everything I told you was just by examining the patients, but can we go beyond that? There's a number of different approaches so we can look at measures that we acquire at rest with the patient So structural imaging for example EG at rest We can passively perturb the patient and we can also engage the patient that's lying in front of you in an active task I won't be able to go over all of this, but let me just highlight a couple of things So the EEG recorded while the patient is just lying in front of you at rest Can be analyzed and the EEG basically detects the neuronal activity in the brain You can look at the complexity of the EG signal down here and can see that conscious patients Strikingly look different to unconscious patients. You can also see that this is looking at the spectral Composition so slow waves and fast waves in the brain how they sort of are distributed across this EEG Actually go through different stages when patients recover and can we beyond that not just correlate this EEG? Analyzed at rest with the behavioral exam that we is in front of us But can we also potentially predict the future this was actually indicated by a study from Paris by Jacobo sit and colleagues and Leon and an Akash where they I where they took a data set of EEG recorded in patients that did not seem like they were following any commands had the system the The machine learning algorithm learn what the signature of patients that were conscious and patients that were not conscious looked like and had said that learn that and then Predicted purely based on EEG of patients that were not part of this training set what actually the level of consciousness was and in 33 percent of patients that clinically looked like they were in a Vegetative state the the algorithm predicted that the patients were actually conscious So what were they? Incorrect actually on the contrary because those patients had a much higher chance to recover in the next couple of months So what that tells you is that potentially this EEG signature picks up something that the behavioral exam can't even detect yet You can not only analyze functional connectivity using EEG. This is a These are studies here using Functional connectivity analyzed by resting state MRI. There's for example, the default mode network that has been described Brian Adler will talk probably quite a bit about that because a lot of his work is focused on that and Here you can see the resting state network identified that correlates with the intactness of this correlates with different behavioral states and in a recent paper By Daniel Conciela from Denmark he added these resting state metrics to EEG metrics and found that that added to the accuracy of the predictions of outcome We can then very quickly. Also, I just mentioned this passively stimulate the brain. This is a technique which is Calculates the perturbational complexity index. It is a predefined area of the brain that's identified by MRI So by imaging and then a magnetic stimulus is administered to that part of the brain and then the EEG is recorded and Analyzed and based on the response that you get in this network analysis of the EEG You can actually correlate this with behavioral states. So that's probably the most accurate behavioral correlation with with any of these biomarkers that is available if you actively Stimulate the patient. This is allows you to diagnose covert consciousness the first case of that was described by Adrian own now quite a while ago where he had a woman in After traumatic brain injury that was in a vegetative state Behaviorally, and he put her in an MRI scanner and asked her to imagine certain things so asked her imagine playing tennis and he asked her imagine walking through your apartment and In Impressively this woman activated similar brain areas Compared to healthy controls. This is a function MRI study. This looks at blood Blood basically bold signal in the brain and you can see that there's a similarity of these brain Activations that you can see in controls compared to the the patient that he had there have been a number of papers very important papers Subsequently by a number of investigators including Nico Schiff and others But more recently we published a paper where we used EEG to detect covert consciousness or this cognitive motor dissociation So this fact that the patient is not behaviorally following commands But on EEG you analyze the EEG and you present them with different commands and systematically the patient responds differently But that was their brain activity to a move your right hand Compared to a stop moving your right hand command and this is then called covert consciousness what we found This was replicating other people's work But what we found we were able to identify that this covert consciousness put you in a much better chance to have long-term Recovery, so patients had a much higher chance to be functionally recovered 12 months later. I Just want to share a case that Brian and I published last year where we saw Away and we had a patient that we traded at Columbia a 30-year-old woman with a frontal ICH And she was in a prolonged coma and just to sort of put this into a sort of the patient care team Perspective the parents asked over and over again, and I'm sure many of you have had similar questions Can we talk to our daughter? Does she hear us? Can we communicate with her? What's she feeling? And Obviously we had to say we don't know but they asked is she still in there? And so we Put her to this covert consciousness assessment and diagnosed a week after the injury that she was in covert consciousness so she could understand to a certain degree these commands that we were presenting her with and She we also have a brain-computer interface that we built at Columbia We're basically the patient even if they're in covert in in an unresponsive behaviorally unresponsive state Theoretically they can activate a brain-computer interface and hopefully one day This will allow them to communicate with us even in this state She was not able to activate that but what was striking was that 12 months later? She was fully recovered and working as a pharmacist Now that doesn't mean that all of these patients recover here can see patient trajectories over the time following the injury Hospital discharge three six twelve months and you can see CMD patients how they recover based on the Glasgow outcome scale extended And you can see that also some of the covert consciousness patients die And this is you know There may be other reasons why they die if you have a patient with cardiac arrest They may have another cardiac arrest or they may actually have brain swelling even though they had covert consciousness early on but overall with this Replicatory sort of this validation court of 93 patients We were able to show that covert consciousness or CMD was an independent predictor of time to recovery Together with younger age with admission etiology of the brain injury So structural TBI had the best prognosis, which has been shown many times before non-structural the worst outcome and with the admission Glasgow coma score So this is not only predicts long-term recovery, but it's an independent predictor. So to end the talk I know I'm probably I don't know whether I ran over but So the future so why is it important to talk about all of these very specific states? And why can't we just keep it simple because these patients actually have very different pheno and endotypes So doing assessments like that will allow us to To right now these patients have all different outcomes and different red trajectories and we don't really know why pay one patient is on one trajectory versus another trajectory and the hope is that with better characterizing this endotype of underlying connectivity underlying injuries ideally also what what Neurotransmitters are abnormal in these patients even on a molecular level if we can get better down to these details We can very likely predict have very much much more accurate predictions in addition to hopefully Identifying patients that will response better respond best to treatment interventions and the treatment interventions Brian Adler will talk about I think as the third talk. Thank you

consciousness

coma

cognitive motor dissociation

CMD

Covert consciousness