Scientists find ‘hidden brain signatures’ of consciousness in vegetative state patients

There has been a great deal of interest recently in how much patients in a vegetative state following severe brain injury are aware of their surroundings. Although unable to move and respond, some of these patients are able to carry out tasks such as imagining playing a game of tennis. Using a functional magnetic resonance imaging (fMRI) scanner, which measures brain activity, researchers have previously been able to record activity in the pre-motor cortex, the part of the brain which deals with movement, in apparently unconscious patients asked to imagine playing tennis.

Now, a team of researchers led by scientists at the University of Cambridge and the MRC Cognition and Brain Sciences Unit, Cambridge, have used high-density electroencephalographs (EEG) and a branch of mathematics known as ‘graph theory’ to study networks of activity in the brains of 32 patients diagnosed as vegetative and minimally conscious and compare them to healthy adults. The findings of the research are published today in the journal PLOS Computational Biology. The study was funded mainly by the Wellcome Trust, the National Institute of Health Research Cambridge Biomedical Research Centre and the Medical Research Council (MRC).

The researchers showed that the rich and diversely connected networks that support awareness in the healthy brain are typically – but importantly, not always – impaired in patients in a vegetative state. Some vegetative patients had well-preserved brain networks that look similar to those of healthy adults – these patients were those who had shown signs of hidden awareness by following commands such as imagining playing tennis.

Dr Srivas Chennu from the Department of Clinical Neurosciences at the University of Cambridge says: “Understanding how consciousness arises from the interactions between networks of brain regions is an elusive but fascinating scientific question. But for patients diagnosed as vegetative and minimally conscious, and their families, this is far more than just an academic question – it takes on a very real significance. Our research could improve clinical assessment and help identify patients who might be covertly aware despite being uncommunicative.”

The findings could help researchers develop a relatively simple way of identifying which patients might be aware whilst in a vegetative state. Unlike the ‘tennis test’, which can be a difficult task for patients and requires expensive and often unavailable fMRI scanners, this new technique uses EEG and could therefore be administered at a patient’s bedside. However, the tennis test is stronger evidence that the patient is indeed conscious, to the extent that they can follow commands using their thoughts. The researchers believe that a combination of such tests could help improve accuracy in the prognosis for a patient.

Dr Tristan Bekinschtein from the MRC Cognition and Brain Sciences Unit and the Department of Psychology, University of Cambridge, adds: “Although there are limitations to how predictive our test would be used in isolation, combined with other tests it could help in the clinical assessment of patients. If a patient’s ‘awareness’ networks are intact, then we know that they are likely to be aware of what is going on around them. But unfortunately, they also suggest that vegetative patients with severely impaired networks at rest are unlikely to show any signs of consciousness.”

Functional brain imaging reliably predicts which vegetative patients have potential to recover consciousness

A functional brain imaging technique known as positron emission tomography (PET) is a promising tool for determining which severely brain damaged individuals in vegetative states have the potential to recover consciousness, according to new research published in The Lancet.

It is the first time that researchers have tested the diagnostic accuracy of functional brain imaging techniques in clinical practice.

“Our findings suggest that PET imaging can reveal cognitive processes that aren’t visible through traditional bedside tests, and could substantially complement standard behavioural assessments to identify unresponsive or “vegetative” patients who have the potential for long-term recovery”, says study leader Professor Steven Laureys from the University of Liége in Belgium.

In severely brain-damaged individuals, judging the level of consciousness has proved challenging. Traditionally, bedside clinical examinations have been used to decide whether patients are in a minimally conscious state (MCS), in which there is some evidence of awareness and response to stimuli, or are in a vegetative state (VS) also known as unresponsive wakefulness syndrome, where there is neither, and the chance of recovery is much lower. But up to 40% of patients are misdiagnosed using these examinations.

“In patients with substantial cerebral oedema [swelling of the brain], prediction of outcome on the basis of standard clinical examination and structural brain imaging is probably little better than flipping a coin,” writes Jamie Sleigh from the University of Auckland, New Zealand, and Catherine Warnaby from the University of Oxford, UK, in a linked Comment.

The study assessed whether two new functional brain imaging techniques—PET with the imaging agent fluorodeoxyglucose (FDG) and functional MRI (fMRI) during mental imagery tasks—could distinguish between vegetative and MCS in 126 patients with severe brain injury (81 in a MCS, 41 in a VS, and four with locked-in syndrome—a behaviourally unresponsive but conscious control group) referred to the University Hospital of Liége, in Belgium, from across Europe. The researchers then compared their results with the well-established standardised Coma Recovery Scale–Revised (CSR-R) behavioural test, considered the most validated and sensitive method for discriminating very low awareness.

Overall, FDG-PET was better than fMRI in distinguishing conscious from unconscious patients. Mental imagery fMRI was less sensitive at diagnosis of a MCS than FDG-PET (45% vs 93%), and had less agreement with behavioural CRS-R scores than FDG-PET (63% vs 85%). FDG-PET was about 74% accurate in predicting the extent of recovery within the next year, compared with 56% for fMRI.

Importantly, a third of the 36 patients diagnosed as behaviourally unresponsive on the CSR-R test who were scanned with FDG-PET showed brain activity consistent with the presence of some consciousness. Nine patients in this group subsequently recovered a reasonable level of consciousness.

According to Professor Laureys, “We confirm that a small but substantial proportion of behaviourally unresponsive patients retain brain activity compatible with awareness. Repeated testing with the CRS–R complemented with a cerebral FDG-PET examination provides a simple and reliable diagnostic tool with high sensitivity towards unresponsive but aware patients. fMRI during mental tasks might complement the assessment with information about preserved cognitive capability, but should not be the main or sole diagnostic imaging method.”

The authors point out that the study was done in a specialist unit focusing on the diagnostic neuroimaging of disorders of consciousness and therefore roll out might be more challenging in less specialist units.

Commenting on the study Jamie Sleigh and Catherine Warnaby add, “From these data, it would be hard to sustain a confident diagnosis of unresponsive wakefulness syndrome solely on behavioural grounds, without PET imaging for confirmation…[This] work serves as a signpost for future studies. Functional brain imaging is expensive and technically challenging, but it will almost certainly become cheaper and easier. In the future, we will probably look back in amazement at how we were ever able to practise without it.”

Researcher Seeks to Help Those Who Can’t Speak for Themselves

When people appear comatose, how can we know their wishes?

A Michigan Technological University researcher says many non-communicative individuals may actually be able to express themselves better than is widely thought.

Syd Johnson, assistant professor of philosophy, has just published a paper in the American Journal of Bioethics: Neuroscience that argues that even patients with severe brain injuries  could have more self-determination and empowerment. “New research with people using just their brains to communicate reveals that more of them might be able to make their own decisions,” she says. 

Those decisions can literally be life and death, and the first question a caregiver should ask is “How do we determine if they are capable—as an ordinary person would be—of making these decisions?” Johnson asks.

She says because of their brain injuries, many have limited attention spans or movement/speech disorders that make it very difficult to communicate. “That’s why it’s important to find ways of assessing their wellbeing other than by asking them,” she says. “Being able to do that would open up the possibility of assessing quality of life even in those who have never been able to communicate, such as infants or people born with severe cognitive disabilities.”

And that leads to the tough questions, Johnson points out.

“Who makes the decision that someone desires, or not, to live in this state? Who makes the life assessment for people: to treat them or to allow them to die.”

The range of potential patients runs the gamut from grandparents to infants, Johnson says. Sometimes you can’t ask them, including those with cognitive disabilities, but sometimes you can.

She acknowledges the complexity of the issue, especially when decisions involve quality of life. “We assume they don’t want to live that way, but sometimes, are they okay?”

She uses the example of locked-in syndrome, where patients can blink “yes” or “no.” A majority says they are doing okay.

“So, then do we make a decision based on what we think it is like to be in that position?” Johnson says.

Many people adjust to this new way of life, she says, and it’s important for caregivers to get into their mind, to recognize what might be a foreign viewpoint for an able-bodied person.

“Then there are the misdiagnosed,” Johnson says. “As many as 40 percent could be conscious at some level, even in a permanent vegetative state. Even in a nursing home, it can be that no one is assessing them, and they might improve. Nobody is diagnosing anymore, and they are treated as if they are not ever going to get better.”

Researchers around the globe have begun to address these issues, and new evidence is coming in, thanks in part to fMRI: functional magnetic resonance imaging—a technique that directly measures the blood flow in the brain that can provide information on brain activity.

“Even EEGs [electroencephalograms, which measure electrical activity in the brain] can be used,” she says. “The patients can be asked questions and given two things to think about for answers: playing tennis for yes, walking around in their house for no. And different parts of their brain will light up. People can be conscious while appearing outwardly unconscious.”

The end-result could mean reassessing the quality of life, Johnson says. Some patients can be asked—the so-called “covertly aware” patients who are conscious but can communicate only with technological assistance.

“Just as importantly, we might be able to use technology to objectively measure aspects of quality of life even in patients who cannot communicate at all,” Johnson says.

The ethical issues loom.

“A person’s quality of life is inherently subjective, and the aim of quality of life assessment has always been to find ways to objectively measure that subjective state of being,” she says. “New technologies like fMRI might be able to provide a different kind of objective assessment of subjective wellbeing—by looking at brain activity—in those individuals who are unable to tell us how they’re doing.”

Patient in ‘vegetative state’ not just aware, but paying attention

Research raises possibility of devices in the future to help some patients in a vegetative state interact with the outside world.

A patient in a seemingly vegetative state, unable to move or speak, showed signs of attentive awareness that had not been detected before, a new study reveals. This patient was able to focus on words signalled by the experimenters as auditory targets as successfully as healthy individuals. If this ability can be developed consistently in certain patients who are vegetative, it could open the door to specialised devices in the future and enable them to interact with the outside world.

The research, by scientists at the Medical Research Council Cognition and Brain Sciences Unit (MRC CBSU) and the University of Cambridge, is published today, 31 October, in the journal Neuroimage: Clinical.

For the study, the researchers used electroencephalography (EEG), which non-invasively measures the electrical activity over the scalp, to test 21 patients diagnosed as vegetative or minimally conscious, and eight healthy volunteers. Participants heard a series of different words  - one word a second over 90 seconds at a time - while asked to alternatingly attend to either the word ‘yes’ or the word ‘no’, each of which appeared 15% of the time. (Some examples of the words used include moss, moth, worm and toad.) This was repeated several times over a period of 30 minutes to detect whether the patients were able to attend to the correct target word.

They found that one of the vegetative patients was able to filter out unimportant information and home in on relevant words they were being asked to pay attention to. Using brain imaging (fMRI), the scientists also discovered that this patient could follow simple commands to imagine playing tennis. They also found that three other minimally conscious patients reacted to novel but irrelevant words, but were unable to selectively pay attention to the target word.

These findings suggest that some patients in a vegetative or minimally conscious state might in fact be able to direct attention to the sounds in the world around them.

Dr Srivas Chennu at the University of Cambridge, said: ”Not only did we find the patient had the ability to pay attention, we also found independent evidence of their ability to follow commands – information which could enable the development of future technology to help patients in a vegetative state communicate with the outside world.

“In order to try and assess the true level of brain function and awareness that survives in the vegetative and minimally conscious states, we are progressively building up a fuller picture of the sensory, perceptual and cognitive abilities in patients. This study has added a key piece to that puzzle, and provided a tremendous amount of insight into the ability of these patients to pay attention.”

Dr Tristan Bekinschtein at the MRC Cognition and Brain Sciences Unit said: “Our attention can be drawn to something by its strangeness or novelty, or we can consciously decide to pay attention to it. A lot of cognitive neuroscience research tells us that we have distinct patterns in the brain for both forms of attention, which we can measure even when the individual is unable to speak. These findings mean that, in certain cases of individuals who are vegetative, we might be able to enhance this ability and improve their level of communication with the outside world.”

This study builds on a joint programme of research at the University of Cambridge and MRC CBSU where a team of researchers have been developing a series of diagnostic and prognostic tools based on brain imaging techniques since 1998. Famously, in 2006 the group was able to use fMRI imaging techniques to establish that a patient in a vegetative state could respond to yes or no questions by indicating different, distinct patterns of brain activity.

Neuroscientists get yes-no answers via brain activity

Western researchers have used neuroimaging to read human thought via brain activity when they are conveying specific ‘yes’ or ‘no’ answers.

Their findings were published today in The Journal of Neuroscience in a study titled, The Brain’s Silent Messenger: Using Selective Attention to Decode Human Thought for Brain-Based Communication.

According to lead researcher Lorina Naci, the interpretation of human thought from brain activity – without depending on speech or action – is one of the most provoking and challenging frontiers of modern neuroscience. Specifically, patients who are fully conscious and awake, yet, due to brain damage, are unable to show any behavioral responsivity, expose the limits of the neuromuscular system and the necessity for alternate forms of communication.

Participants were asked to concentrate on a ‘yes’ or ‘no’ response to questions like “Are you married?” or “Do you have brothers and sisters?” and only think their response, not speak it.

“This novel method allowed healthy individuals to answers questions asked in the scanner, simply by paying attention to the word they wanted to convey. By looking at their brain activity we were able to correctly decode the correct answers for each individual,” said Naci, a postdoctoral fellow at Western’s Brain and Mind Institute. “The majority of volunteers conveyed their answers within three minutes of scanning, a time window that is well-suited for communication with brain-computer interfaces.”

Naci and her Western colleagues Rhodri Cusack, Vivian Z. Jia and Adrian Owen are now utilizing this method to communicate with behaviorally non-responsive patients, who may be misdiagnosed as being in a vegetative state.

“The strengths of this technique, especially its ease of use, robustness, and rapid detection, may maximize the chances that any such patient will be able to achieve brain-based communication,” Naci said.

Awoken from a persistent vegetative state: First successful treatment of paediatric cerebral palsy with autologous cord blood

The parents searched the literature for treatment options

At the end of November 2008, the child suffered from cardiac arrest with severe brain damage and was subsequently in a persistent vegetative state with his body paralysed. Up to now, there has been no treatment for the cause of what is known as infantile cerebral palsy. “In their desperate situation, the parents searched the literature for alternative therapies”, Arne Jensen explains. “They contacted us and asked about the possibilities of using their son’s cord blood, frozen at his birth.”

“Threatening, if not hopeless prognosis”

Nine weeks after the brain damage, on 27 January 2009, the doctors administered the prepared blood intravenously. They studied the progress of recovery at 2, 5, 12, 24, 30, and 40 months after the insult. Usually, the chances of survival after such a severe brain damage and more than 25 minutes duration of resuscitation are six per cent. Months after the severe brain damage, the surviving children usually only exhibit minimal signs of consciousness. “The prognosis for the little patient was threatening if not hopeless”, the Bochum medics say.

Rapid recovery after cord blood therapy

After the cord blood therapy, the patient, however, recovered relatively quickly. Within two months, the spasticity decreased significantly. He was able to see, sit, smile, and to speak simple words again. Forty months after treatment, the child was able to eat independently, walk with assistance, and form four-word sentences. “Of course, on the basis of these results, we cannot clearly say what the cause of the recovery is”, Jensen says. “It is, however, very difficult to explain these remarkable effects by purely symptomatic treatment during active rehabilitation.”

In animal studies, stem cells migrate to damaged brain tissue

In animal studies, scientists have been researching the therapeutic potential of cord blood for some time. In a previous study with rats, RUB researchers revealed that cord blood cells migrate to the damaged area of the brain in large numbers within 24 hours of administration. In March 2013, in a controlled study of one hundred children, Korean doctors reported for the first time that they had successfully treated cerebral palsy with allogeneic cord blood.

People in a vegetative state may feel pain

It is a nightmare situation. A person diagnosed as being in a vegetative state has an operation without anaesthetic because they cannot feel pain. Except, maybe they can.

Alexandra Markl at the Schön clinic in Bad Aibling, Germany, and colleagues studied people with unresponsive wakefulness syndrome (UWS) – also known as vegetative state – and identified activity in brain areas involved in the emotional aspects of pain. People with UWS can make reflex movements but can’t show subjective awareness.

There are two distinct neural networks that work together to create the sensation of pain. The more basic of the two – the sensory-discriminative network – identifies the presence of an unpleasant stimulus. It is the affective network that attaches emotions and subjective feelings to the experience. Crucially, without the activity of the emotional network, your brain detects pain but won’t interpret it as unpleasant.

Using PET scans, previous studies have detected activation in the sensory-discriminative network in people with UWS but their findings were consistent with a lack of subjective awareness, the hallmark of the condition.

Now Markl and her colleagues have found evidence of activation in the affective or emotional network too (Brain and Behavior).

Her team gave moderately painful electric shocks to 30 people with UWS, while scanning their brains using fMRI. Sixteen people had some kind of brain activation – seven only in the sensory network but nine in the affective network as well.

These results question whether some diagnoses should change from UWS to minimally conscious, which is characterised by some level of awareness.

"I don’t think this paper alone will change the clinical approach to people with diagnoses such as UWS," says Donald Weaver at Dalhousie University in Halifax, Nova Scotia, Canada, who was not involved in the work. But it will encourage future study, he says.

Changing a diagnosis depends on whether neurologists are ready to accept alternative ways of diagnosing disorders of consciousness, says Boris Kotchoubey at the Institute of Medical Psychology and Behavioural Neurobiology in Tübingen, Germany, who worked on the study.

Nonetheless, Kotchoubey is confident that the way people with UWS are cared for will change, even if their diagnoses remain the same. “I know that many doctors working with such patients have been instructed to treat their patients as if they can understand them and perceive at least something in the environment, perhaps pain, pleasure, or emotion,” he says.

But not all people are treated this way. Prior to the study, one of the people in Markl’s study was given no anaesthesia before a tracheotomy, which involves an incision in the neck to allow breathing without using the nose or mouth. As people with UWS are clinically considered unable to understand pain, doctors do not have to give an anaesthetic.