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鈥淚 HAVE pictures of five patients on my wall,鈥� says Nicholas Schiff. 鈥淭hey all seem to be in a vegetative state, but we know they are conscious. It鈥檚 to remind me they are out there and we are not helping them.鈥�

Schiff, based at , is one of the world鈥檚 leading experts in disorders of consciousness. Many of his patients are in a vegetative state. Their injuries have left them with no awareness of themselves or of the world around them. Or so we thought.

In 2006, it was discovered for the first time that a woman believed to be in a vegetative state was actually conscious, after brain scans revealed she could imagine different things on request. That breakthrough was quickly followed by a devastating revelation: our ability to determine whether someone is conscious based on their behaviour alone isn鈥檛 accurate enough.

It is now known that some people have what is called 鈥渃overt consciousness鈥�, in which they have awareness that comes and goes, but can鈥檛 move any of their body. At first, it was believed to be a tragic but rare misdiagnosis. Now, results from a 10-year investigation suggest that many people could be trapped in this way. Their bodies lie still, but their minds are active. This creates an urgent need to find techniques that could awaken them. It also raises ethical questions about what we need to ask these people, and ourselves, when they do manage to make themselves heard.

As recently as the late 1990s, it was assumed that people in a vegetative state, by definition, had no conscious awareness. They would show signs of sleep and wake cycles, and occasionally open their eyes or make involuntary movements, but weren鈥檛 aware of themselves or the people around them. However, , then at the MRC Cognition and Brain Sciences Unit in Cambridge, UK, had a worrying thought: what if we were wrong?

Neurologists have long been aware of locked-in syndrome, in which people are awake and aware but unable to move almost all of their body. It was first defined in medical textbooks in 1966, but must have been known about much earlier; it was described in Alexandre Dumas鈥檚 1844 tale, The Count of Monte Cristo. People who are locked in need help breathing and many can communicate only using eye movements. But they aren鈥檛 classed as having a disorder of consciousness, because, unlike people in a coma, vegetative or minimally conscious state, they are fully conscious (See 鈥�Consciousness confusion?鈥�). Still, a diagnosis can take months, or even years if eye movement is limited.

Owen wondered whether people in a vegetative state could also have a hidden awareness. At the time, this was dismissed as a 鈥渂onkers idea鈥�, he says, not least because it made people feel uncomfortable that someone might be trapped inside their body without anyone knowing.

Nevertheless, Owen鈥檚 team began to test his theory. Their first patient was Kate, a woman left in a vegetative state by a virus. In 1997, they scanned Kate鈥檚 brain using positron emission tomography (PET), which can measure brain activity, while showing her pictures of her family or playing familiar speech. To their surprise, her brain responded just as you might expect a healthy person鈥檚 brain to respond. But Owen鈥檚 team faced a problem: a lot of neural activity happens automatically, so the result didn鈥檛 necessarily prove she was conscious. It took another decade to work out a solution.

鈥淢any people in a vegetative state may be trapped. Their bodies lie still, but their minds are active鈥�

In 2006, Owen and his colleagues showed that a 23-year-old woman in a vegetative state , by asking her to imagine walking around her house or playing tennis. These two mental tasks require different brain activity, which can be identified from brain scans. It confirmed, beyond any doubt, that she was consciously aware of herself and the researchers, and that she had the ability to respond to their requests.

Disorders of consciousness are notoriously difficult to diagnose. Most doctors use variations of the Scale to assess someone鈥檚 ability to open their eyes in reaction to various stimuli, and their verbal responses and motor movements. And they can use brain scans to identify physical damage.

However, to identify covert consciousness, you need to use functional MRI (fMRI) or several EEG tests over time to verify brain activity that reflects comprehension and the capacity to follow commands. 鈥淏ut we鈥檙e just not screening patients for this level of higher function,鈥� says Schiff. 鈥淎nd it鈥檚 not that hard to find them when we do.鈥�

The real canary in the coal mine, says Schiff, was a study carried out in 2017 by at Massachusetts General Hospital. Edlow knew that covert consciousness had been discovered in people who鈥檇 had months or years to recover from their injuries, but he wondered whether it might exist in people with more recent brain injuries.

He and his colleagues scanned the brains of 16 seemingly unconscious people with severe head injuries. During the scans, he asked them to do mental tasks, such as 鈥渋magine squeezing your right hand鈥�. Of eight people who had no behavioural evidence of awareness, . It was a small study, but it had massive ramifications.

鈥淭hese people were in intensive care,鈥� says Schiff. 鈥淲hat if you鈥檇 withdrawn their care?鈥� Even for those who are provided with life-sustaining treatment, a misdiagnosis might result in limited rehabilitation that thwarts an opportunity for recovery.

鈥淲e鈥檙e not screening patients for this level of higher function 鈥� and it鈥檚 not hard to find them when we do鈥�

In Schiff鈥檚 own studies, he has identified 16 people with covert consciousness. For some, this diagnosis was life-changing. For instance, one man, thought to be in a vegetative state, made sporadic head movements that had been dismissed as random. Once the team became aware of his covert consciousness, however, these movements were given more attention. A researcher at the hospital developed a head-mounted computer mouse for him, which he used to control a keyboard. Eventually, he was able to write Schiff an email to give his own consent to join his next study.

How many more people might be in this situation? There is no data on the exact number of people with disorders of consciousness across the world, but for the past 10 years, Schiff has been involved in an . The latest conservative estimate is that one in 10 people who appear to be in a coma, vegetative or minimally conscious state actually has covert consciousness. 鈥淚t鈥檚 a big problem,鈥� says Schiff. 鈥淎nd now we know it鈥檚 not a rare problem.鈥�

Coming around

Twenty years ago, there wasn鈥檛 a lot you could do for people in a vegetative state other than hope that they would slowly recover, or have a rare, spontaneous awakening. That changed with Louis Viljoen. In 1996, when he was 24, a truck crashed into him on his bike. The trauma left him in a vegetative state for three years.

One day, when visiting him at his care home, his mother noticed that he seemed restless. She called his doctor who prescribed him a sleeping pill called zolpidem to calm him. His carers crushed it up into some water and got him to swallow it. Fifteen minutes after taking the drug, Louis opened his eyes, turned his head, and said: 鈥淗ello Mummy.鈥� From that day on, Louis could be woken once a day, for 3 hours. He would interact with his family before drifting back into unconsciousness. After six years, he awoke permanently.

His story proved something important: that some people in a vegetative state have the capacity to be awoken with the right intervention. Zolpidem appears to 鈥渟witch on鈥� areas towards the front of the brain involved in higher-level thinking and initiation of movement. This outweighs the sedative effect of the drug on other brain regions. Unfortunately, excitement over zolpidem鈥檚 potential was short-lived. A small, trial found that it benefited just four of 84 patients with disorders of consciousness. , director at the Moss Rehabilitation Research Unit in Pennsylvania, says that despite a few families who use it every day to wake their loved ones, most find the effects diminish with repeat dosing.

Not to be deterred, , a doctor at the University of Li猫ge in Belgium, and his colleagues have begun testing another drug, called apomorphine. The drug mimics dopamine and is regularly prescribed to help people with Parkinson鈥檚 initiate movements. Results from the three people treated so far in a pilot trial look promising: one participant was unable to communicate at all at the start. By the end, she could move her hands in response to commands. 鈥淭here鈥檚 this moment, when they squeeze your hand for the first time, and you know they鈥檙e there, really there, with you,鈥� says Sanz. 鈥淚t鈥檚 like this presence has stepped into the room.鈥�

A second participant has started to turn his head when you call his name, and a third, who was attempting, unsuccessfully, to use his thumbs at the beginning of the trial, can now say 鈥測es鈥� and 鈥渘o鈥� and dress and shave with help. Sanz is now recruiting for a .

Drugs aren鈥檛 the only option. In 2007, Schiff and his colleagues wondered whether they could kick-start the damaged brain using electricity. There was growing support for his 鈥渕esocircuit hypothesis鈥�, which attempted to explain how consciousness is recovered after a brain injury, and how cognition can outpace recovery of motor abilities.

The hypothesis involves several networks associated with the thalamus (see 鈥�diagram鈥�). The thalamus sits just above the brain stem, which connects the brain to the spinal cord and acts like a central station. It relays information towards the basal ganglia, which is involved in movement and reward, and the forebrain, made up of the two hemispheres of the brain, the thalamus and the hypothalamus. Together, these areas are responsible for learning, memory, personality, our senses and regulating breathing and other autonomic functions. It is thought that brain trauma disrupts this network, decreasing activity in the forebrain. A drop in activity also happens in the forebrain as we drift off to sleep or go under with anaesthetic. It is also the last part of the brain to come back 鈥渙nline鈥� when a person emerges from a disorder of consciousness.

To see if they could kick-start this network after injury, Schiff鈥檚 team implanted electrodes in the thalamus of a man who had been in a minimally conscious state for six years following an assault. Improvements were seen straight away. By the end of the , the man could eat, speak and watch a movie.

Despite every major news outlet in the world reporting the result, Schiff鈥檚 research in this area halted. No funding agency was prepared to pay the huge amounts of money required for the participants鈥� rehabilitation and care during such a long study. 鈥淭alk about an uphill battle,鈥� says Schiff. 鈥淣o one wants to pay for it, and researchers can鈥檛 do this alone.鈥�

It wasn鈥檛 until 2016 that Martin Monti at the University of California, Los Angeles, and his colleagues attempted something similar, this time using low-intensity ultrasound, a non-invasive technology that modulates the thalamus without the need for surgery. Once again, the results were impressive: his patient was a 25-year-old man who had received a severe brain injury after being hit by a car and was in a minimally conscious state for three weeks. The morning after the treatment, the man tried to communicate with vocalisations and gestures. Three days later, he started answering questions by nodding or shaking his head. A week later, he got out of bed and attempted to walk. Monti鈥檚 team has since used the technique with other patients and is now moving ahead with a clinical trial.

Meanwhile, Angela Sirigu of the French National Centre for Scientific Research in Bron and her colleagues were trialling another technique. It focuses on , which runs between the brain, the thalamus and several areas of the body.

They implanted electrodes to stimulate the vagus nerve along the neck of a man who had been in a vegetative state for 15 years. By the end of the trial, he was able to smile and to answer questions using his eyes. 鈥淭here was a reactivation of networks important for consciousness,鈥� says Sirigu, adding that it might be possible to combine this treatment with drugs like apomorphine.

In other work, at the University of Li猫ge has been using non-invasive transcranial direct current stimulation (tDCS) to deliver low-level electrical stimulation to switch brain cells on and off. In initial experiments involving 55 people, just one day of brain stimulation over areas of the forebrain allowed some minimally conscious patients to answer questions by moving their eyes or head. Two patients emerged from a minimally conscious state altogether. When they extended the trials, patients were able to communicate for at least a week at a time before losing consciousness again. They gave some families tDCS machines to use at home.

Going home

Now Thibaut intends to use EEG to scan the brain, alongside software that is trained to spot when a patient is most vigilant. At this point, the stimulation will kick in, in the hope that it is more effective. 鈥淚t鈥檚 challenging from an engineering point of view, but in a few years, the idea is that this is something that would be relatively inexpensive, that these patients could wear permanently at home,鈥� she says.

These advances raise new ethical questions. Some people may see surviving a brain injury with some degree of consciousness as worse than being in a vegetative state, because you can experience pain and have some awareness of your predicament. Do we need to question whether to awaken people in the knowledge that it is only temporary? And what about those families who discover that their loved one has covert consciousness, but can鈥檛 offer any means of continuing the conversation?

Whyte says that one of his patients had been in a vegetative state for two years, but he started interacting with his parents after a single dose of zolpidem. After several hours, he lapsed back into unconsciousness. Unlike with Viljoen, the effect couldn鈥檛 be repeated. 鈥淚t was enormously emotional, as you can imagine,鈥� says Whyte. 鈥淭he family went from having given up hope, to learning that their loved one had the ability to be conscious, to discovering that they just couldn鈥檛 realise that ability.鈥�

He believes we should be trialling as many therapies as possible 鈥� as long as we are confident that we won鈥檛 cause a patient any harm. 鈥淯nfortunately, there鈥檚 going to be a lag period where the people you study today aren鈥檛 going to be helped by the results,鈥� he says.

For those that can be awakened, we also need to consider what questions we ask. 鈥淵our first question is always 鈥榓re you in any pain?鈥�,鈥� says Sanz. 鈥淣ormally, other questions that the families ask are quite simple, 鈥楧o you want the TV on? Are you cold?'鈥�

Is it possible for people with disorders of consciousness to have a more meaningful conversation about their welfare? 鈥淥nce a person shows signs of awareness, can they decide whether to live or die?鈥� asks Joseph Fins, a medical ethicist at Weill Cornell Medical College. Historically, we have thought about patients making decisions as all or nothing 鈥� they are either capable of consenting to treatment or not, he says. But now, he says, we have this third scenario, a person who may be aware enough to answer difficult questions some of the time. 鈥淣ow that people with brain injuries are emerging and communicating, we have to listen to what they say,鈥� says Fins.

Most people with covert consciousness still wouldn鈥檛 satisfy requirements to provide legal consent, though, says Fins. 鈥淪o we should be trying to engage them in the decision-making process, but not ask them to participate in a way that is beyond their capabilities.鈥�

The answer, perhaps, is to plan for the worst. , head of the Coma Science Group at the University of Li猫ge, says that until we have a brain-computer interface that can help people with disorders of consciousness communicate better, the best thing that anyone can do is to express their wishes ahead of time. 鈥淭ell your family and friends exactly what you want in a will, or at least talk to them about the subject 鈥� it would all help if something like this happens to you.鈥�

鈥淥nce a person shows signs of awareness, can they decide whether to live or die?鈥�

And when you are considering your options, it may surprise you to hear that a locked-in life isn鈥檛 necessarily a miserable life. A small survey of people who could only communicate using eye movements found that the majority were happy, and the longer they had been locked in, the happier they were. But that stems from their ability to engage those around them regularly. Without that, Schiff fears people with disorders of consciousness face extreme isolation. What is life like for the people in his pictures?

鈥淭here hasn鈥檛 been a formal study of well-being in people with disorders of consciousness,鈥� says , UK, who was one of Viljoen鈥檚 doctors. 鈥淏ut anecdotally from what people have told me during periods of awareness, they are happy.鈥�