Consciousness regained

After years of deep therapeutic pessimism, emerging therapies offer hope for patients trapped between coma and wakefulness

by Aurore Thibaut + BIO

The first time I saw Valerie (not her real name) she was lying on a hospital bed completely still, staring at the ceiling. She didn’t react as we entered her room. I looked at her parents standing next to her, their eyes full of hope and despair. She was so young; her life was supposed to be ahead of her, but a dramatic car accident had put all their lives on pause.

My colleagues and I evaluated her by her bedside every day for a week. We were trying desperately to detect any signs, any tiny responses, that would mean she was still there – that she could hear what we were saying; that she could feel the immense love her parents had for her. But each day, nothing.

Although the evaluations were inconclusive, there was still some hope. Using cutting-edge neuroimaging scanners and software, we had the ability to detect if Valerie, though otherwise completely incapacitated, could nonetheless listen to our instructions and so activate a specific area of her brain upon request.

Valerie’s parents waited several agonising days as we conducted these complex analyses. Finally it happened – Valerie showed some residual brain activity that suggested she could (partially) hear and understand some of our instructions. It felt like a breakthrough, but what did it mean for her? Would she continue to improve? What did she really feel? Could she understand everything we said? Would she ever be able to walk or speak again? Answering the first question about her brain activity just led to so many more questions. That day, I decided that, even if it was an enormous challenge, I wanted to work on the development of new treatments to help patients such as Valerie recover, even a little bit.

I started working at the Coma Science Group at the University of Liège in Belgium. Our aim is to understand the neural correlates of (un)consciousness by studying patients with severe brain damage who have emerged from coma. Thanks to the development of advanced resuscitation techniques and related advances in intensive-care treatment, in rare cases patients with severe acquired brain injury can survive even after being in a coma, yet they remain in a condition called ‘unresponsive wakefulness syndrome’ (previously known as persistent vegetative state) – that is, apparently awake but without any awareness. Or, if it’s believed they have some residual awareness, they’re said to be in a ‘minimally conscious state’. These conditions are known collectively as ‘disorders of consciousness’ (DoC).

While medical progress has undoubtedly helped to save lives, it has also created mysterious states of limbo. For example, in cases of unresponsive wakefulness syndrome, patients open their eyes but don’t express any purposeful behaviours. In a minimally conscious state, patients are almost entirely incapacitated, and yet they’re able, for instance, to track moving objects with their gaze, answer simple commands to move their feet, or squeeze someone’s hand.

In the past 20 years, advances in neuroimaging techniques have allowed us to explore brain functions in these altered states of consciousness. One breakthrough study conducted at our lab, in collaboration with the University of Cambridge in the United Kingdom, involved 54 DoC patients. The researchers asked the patients to perform two mental-imagery tasks while they lay in a brain scanner. In the first, they were asked to imagine playing tennis; in the second, to imagine walking from room to room in their home – mental tasks that are associated with contrasting patterns of neural activity. Remarkably, five patients were able to wilfully modulate their brain activity, suggesting that, though unable to express any outward signs of consciousness at the bedside, they could understand and follow the researchers’ instructions.

Inspired by these findings, the researchers conducted further repeated behavioural assessments on these five patients and managed to observe outward signs of awareness in three of them. Yet still, no voluntary behaviour could be detected in the remaining two patients. This was the first large, multi-patient study to demonstrate that a small proportion of patients who are entirely unresponsive when assessed at the bedside do, in fact, have some residual awareness and cognition.

This was a dramatic result, making us realise that some unresponsive patients are more conscious than we thought. What if, in coming years, we can develop more tools to detect awareness in more patients? What if it turns out that the majority of unresponsive patients have residual brain function that could sustain some cognition? What if the majority of them still feel pain?

Even with the incredible progress scientists and clinicians have made in the past decade, DoC patients can remain in these states for months or even years, unable to communicate how they feel or what they want. Their predicament presents multiple ethical challenges. What should we, as researchers and health carers, do to meet these challenges? One priority is improving our tests so that we can better determine who will recover and who won’t. We’re still far from having a perfect biomarker to tell us this. But this also leaves the question of what we can and should do for patients who remain in a prolonged DoC. We cannot abandon them. That’s why my colleagues and I are working hard to develop effective therapeutic strategies.

Disorders of consciousness are thankfully rare, affecting up to six people per every 100,000. However, DoC patients are at the receiving end of what’s called therapeutic nihilism due to the chronic nature and perceived incurability of their condition. This is reflected in the current scientific literature where only a limited number of published studies have investigated how to treat these patients in order to improve their quality of life and their functional recovery.

Imagine how difficult it was for his wife to accept that her husband would be awake only a few hours per day or week

Therapeutic nihilism is a historical mistake that should be corrected. As a medical community, we must be careful not to give false hope to families, yet we should also avoid the despair of the past. There are promising signs that this is beginning to change, with researchers challenging the old dogma that patients with prolonged DoC cannot improve.

Recent studies have demonstrated the potential therapeutic benefits of both pharmacological and nonpharmacological interventions. For instance, amantadine – a neurostimulant drug, used to manage the symptoms of Parkinson’s disease – seems to slightly speed up DoC patients’ recovery. And deep brain stimulation – implanting electrodes in the brain to reconnect neuronal axons and boost brain activity – led to behavioural improvements, including the ability to name objects and chew food, in a man who was previously in a minimally conscious state. Nevertheless, these treatments involve risks and potentially severe side-effects, especially in the case of deep brain stimulation, given the invasiveness of the procedure.

Another potential drug treatment with intriguing effects is zolpidem. Usually used to help you fall asleep, in rare cases (5 to 7 per cent) it can literally wake patients from an unconscious state. For example, one patient whose capabilities were limited to using his gaze to track a person in his room and sometimes answering simple commands such as ‘squeeze my hand’ was able, 30 minutes after taking zolpidem, to reliably respond to commands, speak, and read a journal. Unfortunately, the effects lasted only a few hours, after which the patient returned to a minimally conscious state. Imagine how difficult it was for his wife to understand what was happening, and to accept that her husband would be awake only a few hours per day or week.

In other cases, when zolpidem has had a waking effect this has produced other downsides: as patients become more conscious, they also develop greater awareness of their still highly impaired condition, leading them to become seriously depressed. Ethically, it’s extremely complicated to decide whether or not to try zolpidem. There’s no correct answer; however, when such treatments do induce some improvement, they clearly need to be given under medical supervision and frequently reassessed.

In clinical practice, because it’s relatively easy to give a patient a pill, pharmacological options are often preferred to other approaches (such as physical therapy or more invasive procedures), despite mixed results and the lack of robust clinical trials. Yet, without a miracle drug that can wake and work for all patients, we must pursue and improve alternative treatment options for DoC patients.

One such alternative is transcranial direct current stimulation (tDCS), a noninvasive technique that involves stimulating the brain with weak levels of electricity. It’s been used successfully to improve cognitive functions in healthy people and in brain-injured patients, including those with DoC.

I remember the intriguing case of a patient with whom we tried tDCS a few years ago. The 67-year-old woman had been diagnosed with unresponsive wakefulness syndrome almost four years earlier. When we tested her thoroughly at her bedside, she was completely unresponsive and showed no signs of consciousness, except for one evaluation (out of seven) in which she was able to localise a painful stimulus. However, after we applied tDCS, she was able to answer a simple command (ie, she could open and close her eyes upon request in three out of four tests). Everyone in the team was surprised because she’d never answered any commands before. In the following days, we also analysed her brain activity and found that she, in fact, had relatively well-preserved brain function. We call this ‘covert consciousness’ – when a patient is (relatively) conscious, but this is undetectable through behavioural tests.

Just a few minutes of stimulation can induce beneficial aftereffects that last several hours

In the case of this particular woman, we hypothesised that tDCS applied over the prefrontal region of her brain had helped her to demonstrate signs of consciousness by ‘unlocking’ neural pathways involved in initiating voluntary movements. However, from a neurophysiological point of view, how tDCS works remains poorly understood. Our best guess is that it increases the excitability of neurons, boosting their activity levels and their ability to communicate (in other words, jumpstarting the kind of ‘neuroplastic’ processes that underlie learning and memory).

Promisingly, just a few minutes of stimulation can induce beneficial aftereffects that last several hours. Unfortunately, without repetition of the brain stimulation, the benefits usually disappear after that time. On a positive note, recent studies suggest tDCS can strengthen synaptic connections between neurons related to the specific task being performed during stimulation, which could have benefits for the rehabilitation of specific activities.

Compared with other brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS, which involves modifying brain activity via weak magnetic fields) or deep brain stimulation, tDCS also has the advantage that it’s inexpensive and probably safer and easier to implement in clinical practice. Like other forms of noninvasive brain stimulation, tDCS is also particularly promising because it doesn’t require patients’ active participation, and is safe and painless. After experimenting with different numbers of tDCS stimulations, our results – collected over the past 10 years – show that about 30 to 50 per cent of patients in a minimally conscious state improved clinically afterwards.

However, a significant hindrance to the clinical use of tDCS is that it requires patients, and their relatives, to commute to hospitals or research centres to receive treatment. To overcome this problem we recently collaborated with a Belgian company (Cefaly Technology) to develop a tDCS machine that can be used at home. The patients’ relatives followed instructions we gave them and, when they applied the stimulations correctly, we observed clinical improvements, even if moderate. For instance, some patients regained some automatic motor responses, and another could answer a simple command. These improvements might seem negligible, but for patients and their relatives even small steps forward are important, especially when patients have been in a minimally conscious state for months or even years.

Research on therapeutic approaches to DoC is not only vital for clinical reasons; it’s also shedding valuable new light on the brain processes that underlie consciousness in healthy people. For instance, the American neurologist Nicholas Schiff has proposed a model to explain how pharmacological and brain-stimulation treatments help patients with DoC. His frontoparietal mesocircuit model is based on the idea that, in normal cognitive processing, the central thalamus (a deep-brain structure that acts like a relay station for sensory and movement-related information) is regulated by regions at the front of the brain and via the modulation of other central-brain structures, such as the internal globus pallidus, which is involved in controlling voluntary movements.

Usually, when the thalamus is activated, this in turn activates the frontoparietal cortex (the interconnected front and more posterior regions of the brain that are involved, among other things, in decision-making and control of movement). However, after a severe brain injury of the kind that is often responsible for the onset of DoC, neurons are lost that would normally modulate the connectivity between the thalamus and the cortex, and control the activity levels of the thalamus itself. The consequence is a fall in the activity of the thalamus and reduced activation across the vital frontoparietal networks.

What the most promising brain stimulation techniques have in common is that they stimulate regions that are involved in these critical circuits. For instance, most trials of tDCS have specifically targeted the prefrontal region because it’s responsible for various cognitive functions, such as memory, attention or movement execution. So far, stimulating this brain region seems the most efficient option. Studies targeting other brain regions, such as the motor cortex and the precuneus (an area involved in self-awareness, among other functions), which are located toward the posterior of the brain, have mostly had less success.

For now, the debate over the precise neural basis of consciousness remains open

These results might suggest that the frontal cortex plays a key role in supporting consciousness, but this remains a matter of debate. Some researchers take this position, whereas others think that consciousness is supported by cortical hotspots mainly located in the back of the brain. Some recent studies support this view. For instance, when rTMS was applied to the angular gyrus (located at the junction of the parietal and temporal lobes and involved in monitoring self-initiated movements, among other functions) this improved signs of consciousness in 19 out of 22 patients after 10 sessions, which is a very good rate of response compared with previous studies (however, these results should be taken with caution, given that there was no control group).

For now, the debate over the precise neural basis of consciousness remains open. Ongoing therapeutic work using tDCS or rTMS to target different specific neural regions will surely help to further unveil the mystery of which brain regions and networks actually support consciousness.

Another contrasting approach to treating DoC also holds some promise. Whereas the different transcranial techniques stimulate the brain via a ‘top-down’ process – meaning from the cortex to central areas of the brain, such as the thalamus – other approaches go in the opposite direction, with a ‘bottom-up’ approach – from central structures to the cortex. This is the case with a highly experimental technique known as ‘vagus nerve stimulation’.

The vagus nerve is the principal nerve of the parasympathetic system, which regulates automatic physiological functions, such as heart rate. Stimulating this nerve, via a branch located in the ear, is thought to activate various structures in the brainstem before reaching the thalamus and then widely activating the cortex. However, so far this intervention has been trialled only with a few patients with DoC and needs further validation before it can be rolled out more widely.

For now, consciousness, and its underlying neural mechanisms, remains an unsolved mystery. This makes it a huge challenge to work with patients who suffer from DoC, both from a medical and scientific point of view. Despite the promising findings that I’ve outlined, we doubt that we’ll ever be able to find a treatment that could restore all brain functions and help patients with chronic DoC to return to their previous life. The extreme brain lesions often incurred by these patients are simply too profound. It’s a constant challenge to communicate this reality to families because their expectations are high, and false hope beckons daily. However, it’s our duty to be as transparent as possible and explain that, even if an improvement is seen, it will be small and won’t last long after the treatment has ended.

At the same time, we shouldn’t give up. It’s important to improve therapeutic options for DoC patients, who are often forgotten by the scientific and medical communities. For years, people thought there was no chance of recovery. However, recent evidence shows that, in very rare cases, some patients can show positive changes even years after the injury. We need to increase our efforts to help these patients regain the maximum of their capacities. Helping Valerie and others like her to regain a ‘yes/no’ communication code (for instance, by moving her thumb to say ‘yes’ and closing her eyes to say ‘no’) might sound like a modest goal, but this would dramatically improve her quality of life – she could tell her carers whether she’s in pain, whether she’s comfortable in her bed, or indicate if she wants to watch a movie.

This field is a balancing act between avoiding false hope and false despair. Complicating matters further, funding clinical trials for DoC patients is a problem. Pharmaceutical companies and the wider medical industry are not interested in this very small and unprofitable market. Laboratories and research teams such as ours must rely on governmental funding, which is extremely competitive to obtain and rarely funds clinical trials. To help people regain their lost consciousness, we must find increasingly creative ways to fund our research.

This Essay was made possible through the support of a grant to Aeon from the John Templeton Foundation. The opinions expressed in this publication are those of the author and do not necessarily reflect the views of the Foundation. Funders to Aeon Magazine are not involved in editorial decision-making.