In 2016, in a Lyon hospital, a man shed a single tear. It took place under the scrutiny of an infrared camera set up to track any movement or action the 34-year-old made. Near-strangers would afterwards watch that footage, curiously, and with concealed excitement. The tear slid down his cheek 15 years after the young man first fell into a coma following a car accident that left him unable to talk, move or exhibit any sign of awareness. Two weeks earlier, he had a device implanted into his chest designed to stimulate the vagus nerve, a body of fibres that extends from behind the ears, through the chest to the stomach, feeding information back to the brain. Almost immediately, his mother began to see signs of something she had not seen for close to two decades: consciousness.
A fortnight later, they played his favourite music to him, and a tear fell from his eye. After 15 years of being in a vegetative state, with no meaningful communication or sign of emotion, he could now be clinically classed as minimally conscious.
“When we saw a tear going down his cheek it was… emotional. It was just…”, says Angela Sirigu, director of the Institute of Cognitive Sciences – Marc Jeannerod, Lyon, who at the time had been working towards this moment for more than five years. Her research focuses on understanding the functions of different brain regions, particularly the role of the parietal cortex, thought to be vital for consciousness.
The case of the young man, now 35, is a single, remarkable study to prove Sirigu’s original hypothesis. Among the many things the vagus nerve does – it’s associated with heart, kidney and lung function, the digestive tract, speech, eye contact and much more – it enhances the firing of neurons in the locus coeruleus, which leads to a massive release of the chemical norepinephrine through a brain pathway linked to alertness and the fight or flight response. “I said to myself and my collaborators, ‘If we stimulate these pathways through the vagus nerve, can we increase alertness in patients in a vegetative state?’.” Now, the appears to be a categorical yes.
T 34-year-old male patient was chosen because of the severity of his case. “If I show you the brain of this patient, you can see the left hemisphere is completely damaged. He could not talk or move because this major centre of the brain important for movement is lesioned,” Sirigu says. “He was the most serious patient that we could have included. We knew if we observed anything, it could not be down to chance. We chose for ourselves a very odd situation. But that was liberating, in our case. Because before stimulation he did not answer to any external stimulation; afterwards, he responded.” The findings of this study, overseen by professor Jacques Luauté, are published in the journal Current Biology.
The operation to implant the device took place in the morning, with the surgeon stimulating the nerve with the electrodes to test it. “I went to visit him with his clinician and we noticed already some kind of alertness we hadn’t noticed before,” Sirigu explains. “Of course it could have been chance. But we had this feeling from the first day.”
She and her team had to wait one month to record real results – enough time to measure any change at a neurological level. On the surface, those changes were already visible day to day. The man would respond to simple orders, following objects with his eyes and turning his head. His mother, who was integral to the study, noted that he would stay awake for longer when listening to his therapist read a book. His threat response also appeared to have been regained – his eyes would widen when Sirigu approached his face.
“We were so happy,” she says. “We had a patient who was improving. We saw him all the time, examining him even outside the different experimental sessions. On one occasion, I was lying on his left side and talking to him. He looked at me but he cannot answer because he cannot talk. But when I moved to the other side of the bed, his eyes tried to turn around as if listening in another direction. You could see in his eyes moving towards a new direction.”
On another occasion, at his home in a small town 40 kilometres south of Lyon, Sirigu and his mother were talking to the man and asked him to turn his head towards them. “It took one minute for him to rotate his head very slowly towards us. It was really amazing from somebody that never answered you and was always in the same position.” His mother describes it as now being able to feel that her son is present; they can understand each other. Communication might be limited, but after 15 years of no response, it enabled them to once again form some kind of interaction between mother and child. “It’s not part of the science, but I think the feelings are also important, and everything his mother reported. The mother was fantastic; always there,” Sirigu says.
But the science is where the fruits of this intensive process lie, and what Sirigu plans to build on. An EEG reading showed a significant increase in electrical activity in regions of the brain used in movement, sensation and awareness. A PET scan, which uses an injectable dye to monitor organ function and blood flow, showed an increase in metabolic activity in the cortical and subcortical brain regions. The scans showed that activity was coming from the parietal cortex, a region linked to consciousness. The results bore this out.
“When you reactivate the parietal cortex we showed that there is a spread of connectivity between the parietal cortex and other regions, including those responsible for motor functions, which are very important for consciousness. This increase leads to more interaction between the brain and the external environment as the patient starts to communicate with the external world. The brain starts to be reactivated in a way it wasn’t before,” Sirigu says. More brain regions could potentially be reactivated as a result, as they react to the increase in activity and connectivity spreads.
Sirigu emphasises that while the patient still cannot walk or talk, it is the neural improvement that represents the greatest result for the study, demonstrating a significant increase in metabolic activity. “Vagus nerve stimulation (VNS) might have great potential for this patient.” Beyond the individual case, Sirigu is recruiting for a further study focusing on minimally conscious patients, where she believes the greatest benefit could be achieved. “It could push them to consciousness, and I think actually they are the best patients that can take advantage of this technique.”
In the future, she hopes to be in a position to apply VNS early on after an injury occurs, to potentially help the patient avoid major damage. This could work because of the protectionist nature of the neural system in question – VNS is known to increase the supply of Brain-Derived Neurotrophic Factor, which protects against neuron cell death.
You’d be forgiven for not knowing what the vagus nerve is. But everyone from neuroscientists to immunologists are working on harnessing its reach to treat different disorders. It has been used to treat epilepsy since the 1990s; depression; and, more recently, rheumatoid arthritis, a debilitating autoimmune disorder. Vagus means wandering in Latin, and with its 100,000 nerve fibres sprawling from the brain stem to a myriad of organs, it has become a target of study looking at the links between the nervous and immune systems. Around 80 per cent of those fibres take information from the body to the brain, with the remaining 20 per cent sending instructions back across the body.
The rise of electroceuticals – devices that stimulate nerves to release chemicals, in place of traditional drug treatments – has also coincided with piqued interest in the vagus nerve, which seems like an obvious place to focus on if you want to reach many different areas of the body and their corresponding conditions.
But there is still not enough known about all the nerve circuits of the body and their role, and many of the discoveries about the vagus nerve’s potential role in treating disorders have been inadvertent. For example, in the ’90s neuroscientist Kevin Tracey was conducting experiments with a drug designed to prevent inflammation by reducing levels of a known immune protein, tumour-necrosis factor-α (TNF-α). One day, he injected the drug into a rat’s brain rather than the bloodstream to test its use for strokes. He found this process 100,000 times more effective in reducing TNF-α. He concluded this was down to neural signals rather than the drug, and found his way to the vagus nerve. Other autoimmune disorders, including Crohn’s disease and Lupus, have also been targets of VNS. There has been interest in VNS for brain trauma for a number of years now. But Sirigu’s study has shown the physical difference it can have to brain activity.
In Minneapolis, neurosurgeon Uzma Samadani has been working towards the same goal, using VNS to help brain trauma patients, for more than a decade. She is currently recruiting for a VNS trial of people with moderate injuries that have a “certain amount of critical substrate”, and says she’s “encouraged” by the results of Sirigu’s trial, though points out how limited it is in scope. “I used to work at Penn and was writing about VNS for epilepsy,” Samadani says, explaining the beginnings of her decade-long pursuit of a VNS trial. “I was reading about circuits and pathways and it occurred to me that the very logical disruption of circuits was somewhat similar in impaired consciousness. One never knows why a patient is unconscious – whether it’s a lack of a pathway or the overactivity of a pathway. Consciousness itself is a little bit of a mystery for us. The vagus nerve has multiple projections, and we don’t know which is causing the difference yet.”
Her study will use non-invasive stimulation, an option that wasn’t open to Sirigu when she began the trial in France. “We don’t know whether an external stimulator would have the same effects. With another group in France we are planning to externally implant the stimulator in a group of patients to investigate whether the same effects are observable.”
It has taken Samadani more than a decade to get her trial in motion, largely due to a lack of funding for brain injury trials. Yet in the US alone, an estimated 1.7 million suffer a traumatic brain injury each year, which could lead to lifelong disability, depression and other issues. Families of the worst affected spend years searching for answers, cures and miracles. The mother of Sirigu’s patient had already “tried everything”, including the drug zolpidem, which has borne incredible results for some people. The ordinary sedative was administered to a coma patient in the 90s to help reduce spasms and help him rest. Thirty minutes later, he was talking for the first time in five years. Doctors worldwide have witnessed these kinds of results, which wear off once the drug passes through the system, returning the patient to their previous state.
There have been no major clinical trials investigating or proving its effect, so it’s hard to know what type of injury it would reliably work on. For Siguru’s patient, it had no effect. “Patients that have had success have mostly been minimally conscious,” she says. “The patient I saw that improved with zolpidem was not in a vegetative state; they had a motor disorder.” The chemical dopamine has also been successful in temporarily reigniting consciousness in some cases – the neurons that need dopamine link to the prefrontal cortex, so if those pathways are broken it could be one strand of the consciousness puzzle.
The past few decades have been littered with success stories, of the extraordinary moments when people that have been in comas or a vegetative state for years suddenly wake up. In some cases, the brain’s plasticity has allowed it to repair damage to pathways over time, but there is still so little understood about those pathways and how to purposefully instigate repair.
Sirigu’s study brings a concrete example of a hypothesis leading to clinical evidence that consciousness can be sparked in dormant areas of the brain, even decades after injury. It sets a path for research that is looking increasingly promising, at least for those with lesser brain injuries that could make the greatest strides in recovery.
But the work does raise an important question about care of the most severely brain-damaged patients. In the UK, the NHS states that after a minimum of 12 months it may be recommended to withdraw nutritional support from such patients in a vegetative state. This is around the time a continuing vegetative state becomes classed as a permanent one. The NHS argues that at this point there is little chance of recovery and prolonging life would have no benefit to the individual or their loved ones. In England, a court order needs to be made to withdraw care, however, if the family want to go ahead with a medical recommendation of this nature.
Research such as Sirigu’s will doubtless have an impact on those decisions as more evidence begins to develop. In 2006, when zolpidem was making headlines, UK courts refused a family’s plea to let a woman in a vegetative state die. Doctors, and the courts, agreed that zolpidem should be administered to see if her condition could be altered. The family argued that the woman would not want to live while being aware of her severe disabilities, an awareness that zolpidem could potentially bring. It shows the impossible complexities of such decisions – while our knowledge of consciousness remains greatly obscured, rare cases of successful treatment continue to bring hope and confusion.
“It’s an important clinical and moral question: are we authorised to remove the life from a patient that may still have some possibilities with the advancement of science?” Sirigu says. “I think that each clinical case should be considered on its own, the only thing we can generalise is if VNS works in this patient who has very severe brain trauma, it will probably work in other patients and those that are less severe will have more to gain from this technique.”