Eyes open, mind off

Brain imaging methods give researchers a better understanding of patients in a vegetative state

By Stephen Lowris

Advances in medicine have greatly increased the number of people who survive brain damage. Doctors can save the lives of many patients suffering from brain trauma (often due to a car accident) or lack of oxygen (eg after a heart attack or drowning), but if the damage is too severe, the victim will sink into a coma. People in a coma do not open their eyes, and at most, move their limbs in reflexive movements. Usually, a coma does not last more than two to five weeks. Those who regain consciousness usually do so within a few days. Others will die, while the rest will wake up from the coma but remain unconscious, in a state known as a vegetative state ("plant").

Even the experts are very disturbed by the vegetative state. Because this situation demonstrates how the two main components of consciousness can undergo a complete separation: wakefulness is not impaired, but awareness, which embraces the multitude of thoughts and feelings, disappears. The word 'awake' describes a situation in which patients in a vegetative state sleep and wake up periodically. When they act as if they are awake, their eyes are open and even wandering. Other times, their eyes are closed and they appear to be asleep, although they may open their eyes and move when touched or spoken to. These patients usually breathe without mechanical assistance and can perform a variety of spontaneous movements, such as grinding teeth, swallowing, crying, smiling, holding someone else's hand, moaning or sighing. But these movements are always reflexive and are not the result of intentional behavior. Usually their eyes will not focus on a particular detail for long, although in rare cases they are able to briefly follow a moving object or turn slightly towards a loud sound.

Many people in a vegetative state regain consciousness in the first month after the injury. But if this does not happen, their condition is defined after a month as persistent vegetative state (PVS) and the chance that they will recover decreases as time passes. Each year, approximately 14,000 American victims of acute brain injury remain in a vegetative state one month after the injury. In 1994, the Multidisciplinary Society for PVS (a group of 11 researchers from different institutions) concluded that the chances of recovery tend to be zero if the patient does not show any signs of consciousness one year after brain injury or six months after brain damage due to lack of oxygen or other causes. The association called these long-term cases "permanent vegetative state".

PVS research was thrust into the spotlight in 2005 when politicians discussed the case of Terri Schiavo, a Florida woman who had been in a vegetative state since 1990. (Her parents and her husband disagreed about her chances of recovery. The court ultimately authorized doctors to remove Schiavo's feeding tube, and she died of dehydration after 13 days.) The dispute underscored the need to develop more effective ways to determine whether a particular patient is in the condition. Permanent or hopeful vegetative. Scientists have recently explored the use of brain imaging methods to detect signs of consciousness that may be hidden in the recesses of the patient's mind. With effective methods for detecting states of consciousness and awareness, doctors may be able to distinguish between patients who have a chance of recovery and those with a bleaker future. At the same time, this study may illuminate cognition itself in a new light.

A difficult diagnosis

In patients recovering from a vegetative state, the first signs of consciousness are often faint and appear gradually. The patient may begin to make deliberate, non-reflexive movements, but not express thoughts and feelings. To classify these cases, doctors defined a clinical condition known as minimally conscious state. Like the vegetative state, the state of minimal consciousness may be a temporary state on the way to full recovery, or chronic and sometimes even permanent. But the crucial difference is that patients who have been in a minimally conscious state for years may still recover. A well-publicized case is that of Terry Wallis, a man from Arkansas, who was in a minimally conscious state due to a car accident in 1984, and who started talking in 2003. And Ellis can also move his limbs, although he is unable to walk and needs round-the-clock care.

The distinction between the vegetative state and the state of minimal consciousness is difficult and involves repeated tests carried out by doctors who have experience with such patients. Doctors diagnosing a vegetative state will rely on the absence of signs of consciousness. In simple terms, if the patient appears as if he is awake (ie his eyes are open), he is unable to follow commands (such as "pinch my hand" or "look down") and all his movements are reflexive, the doctor will conclude that the patient is in a vegetative state.

However, in the early 90s, studies led by Nancy Childs of the Center for Rehabilitation Health Services in Austin, Texas, and Keith Andrews of the Royal Hospital for Neurological Disabilities in London showed that more than a third of patients initially diagnosed in a vegetative state actually showed any signs of recognition on close examination. To reach a more reliable diagnosis, doctors should use standard clinical tests that assess the patient's response to a wide range of sound, sight and touch stimuli. Examples of such tests are the Coma Recovery Index developed by Joseph Giacchino of the JFK Johnson Rehabilitation Institute in Edison, New Jersey, and the Sensory Stimulation Assessment and Rehabilitation Method developed by Helen Gill-Thwaites, also of the hospital Royal for Nervous Disability. There is no doubt that these measures of consciousness have a higher diagnostic capacity, but they require more time than a routine neurological examination or more than simpler tests such as the Glasgow Coma Scale.

But recognition and awareness are subjective experiences that are difficult, by their very nature, to measure in another person. Is it possible for even the most careful assessment to miss signs of recognition in patients with acute brain damage who are unable to communicate? Over the past ten years, researchers have tried to find an objective test that would confirm or refute a clinical diagnosis of a vegetative state. Imaging the structure of the brain, with the help of magnetic resonance imaging (MRI) or with the help of computed tomography (CT), may indeed help doctors see the extent of brain damage, but not detect signs of consciousness. Nevertheless, recent studies show that MRI images of traumatic brain injuries may help doctors predict whether the patient will recover from the vegetative state. For example, it seems that the chances of recovery are low for patients who have been damaged in certain areas of their brains, such as the brain stem or the corpus callosum, the nerve tissue that connects the two halves of the brain. Furthermore, studies that used a new imaging method known as MRI diffusion tensor, which estimates the integrity of the white matter in the brain, i.e. the nerve fibers that transmit the nerve signals, deepened the understanding of the mechanisms responsible for recovery from a vegetative state. For example, a research group led by Nicholas Schiff of Cornell University recently used this method to show that in the brain of Wallis, the patient who came out of a state of minimal consciousness after 19 years of silence, there is a regrowth of nerve fibers.

Another widely used test is electroencephalography (EEG), which measures the electrical activity in the brain. EEG results can indicate the patient's state of wakefulness because the electrical activity of the brain is slower during sleep that is not dream sleep. The EEG device can indeed confirm a clinical diagnosis of brain death in comatose patients (a straight line on the EEG), but the method is not so reliable for measuring changes in the level of consciousness. In patients who are in a vegetative state, the device cannot confirm the diagnosis nor can it predict the chance of recovery. My colleagues and I at the University of Liege in Belgium have shown that when minimally conscious patients hear their name, an electrical response known as the P300 potential is evoked in their brains, in contrast to hearing other names. But since some patients in a chronic vegetative state also have similar P300 responses, this method does not seem to have diagnostic value.

The recognition zone?

Perhaps the most promising method for studying the vegetative state is functional imaging. Studies using positron emission tomography (PET) have shown that the level of brain metabolism, which can be measured by the level of glucose consumption, decreases in the vegetative state to values ​​less than half of the normal value. These experiments were first conducted in the late 80s by a research group led by Fred Plum from Cornell University, and then by several European groups, including our group. But our group reported in the late 90s that some patients recover from the vegetative state without significant changes in the general level of brain metabolism. Furthermore, we discovered that the level of metabolism in the brains of some of the healthy volunteers, who were fully conscious, was similar to that of some of the patients in a vegetative state. Schiff also reported that the level of metabolism in the cerebral cortex of some patients in a vegetative state was close to normal values. That is, measuring the general level of energy consumption in the brain cannot indicate awareness.

However, our group was able to identify areas of the brain that may be particularly important for the emergence of awareness. When we compared patients in a vegetative state with a large group of healthy volunteers, we found that there was no metabolism in the extensive neural network of associative cortices (located in the frontal and parietal lobes of the brain) involved in the cognitive processing of sensory information. We also showed that awareness is related to the ability to communicate between this network and deeper centers in the brain, especially the thalamus. It seems that in the brains of patients in a vegetative state there is a disturbance in the long-term connections between different cerebral cortices, as well as between the cerebral cortices and the thalamus. Moreover, at the same time as recovery from the vegetative state, it is possible to see a restoration of activity in the parietal-frontal network and the areas related to it.

Unfortunately, minimally conscious patients have similar impairments in brain activity. As a result, PET measurements of the level of metabolism in the brain cannot differentiate between a vegetative state and a minimally conscious state when the patient is at rest. However, the method showed differences when examining changes in brain activity due to external stimuli such as pain or speech. We investigated the sensation of pain by electrically stimulating the palm of the hand (experienced as a painful stimulus by the healthy volunteers) and using PET to measure cerebral blood flow, which serves as another measure of neural activity. In both the vegetative patients and the healthy volunteers, the results showed activity in the brainstem, thalamus and primary sensory cortex, which receives sensory information from the peripheral nerves. But in the vegetative patients, the rest of the brain did not respond. The small area of ​​the cerebral cortex that responded (the primary sensory cortex) was isolated and would not communicate with the rest of the brain, and especially would not communicate with neural networks considered vital for the conscious sensation of pain. (These results can reassure family members and caregivers because patients in a vegetative state do not feel pain like healthy people.)

The PET studies showed a similar phenomenon when we talked to the vegetative patients. Just as with the pain stimulus, activity was restricted to simpler areas of the cerebral cortex (in this case the primary auditory cortex), while more advanced areas did not respond and remained inactive. This level of brain processing is not considered sufficient for auditory awareness. On the other hand, in minimally conscious patients, sound stimuli can trigger extensive activity in the more advanced areas of the cerebral cortex, an activity that does not normally occur in the vegetative state. Schiff was the first to use functional MRI (fMRI) and showed that the language areas of the brains of minimally conscious patients were activated when a familiar voice read them a personally meaningful story. When the story was played from end to beginning, it did not provoke such a reaction, unlike what happens in the minds of healthy people.

Similarly, in 2004, our research group reported that emotionally meaningful sound stimuli (such as a baby crying or the patient's name) elicit a much more extensive response in the brains of minimally conscious patients compared to meaningless noise. These results indicate that content is important when talking to patients who are in a minimally conscious state. But for this method to become a diagnostic tool, we knew we had to show that complex sound stimuli never activate extensive neural networks in the brains of vegetative patients.

Tennis in the brain

This theory was put to its toughest test in 2006, when a research group led by Adrian Owen from the University of Cambridge in collaboration with Melanie Boley from our research group examined a 23-year-old woman who had suffered a brain injury due to a car accident. She went into a coma for over a week and then went into a vegetative state. The woman opened her eyes spontaneously but did not respond to verbal or other commands.

Five months after the accident, Owen and his colleagues examined the woman with fMRI. During the scan, the researchers played recordings of sentences, such as "His coffee has milk and sugar," as well as noise sequences that resembled these sentences acoustically. The sentences evoked activity in areas of the brain associated with language comprehension and word meaning, similar to healthy subjects. These results may indicate conscious language processing in the vegetative woman, but not necessarily. Studies on healthy subjects have shown that such processing also occurs during sleep and even under general anesthesia.

To clarify whether the patient consciously responded to the language, the researchers conducted another experiment in which they asked her to perform mental tasks. When a patient was asked to imagine herself playing tennis, the fMRI scan showed activity in motor subregions of the brain, just like in healthy subjects. When asked to imagine herself moving between the rooms of her home, the scan showed activity in a neural network involved in spatial navigation. Here too, the response was exactly the same as that of healthy subjects. That is, despite the clinical diagnosis stating that the patient was in a vegetative state, she understood the tasks and performed them repeatedly, and therefore was actually conscious.

The first question that arises due to these amazing results is whether the patient was misdiagnosed. Although experts confirmed several times that she was in a vegetative state, tests revealed that her eyes focused on objects for short periods of time. Such findings are occasionally obtained in a vegetative state, but they are unusual and should prompt doctors to look for additional signs of recognition. During another examination, about six months after the study, the patient was able to focus her eyes on an object for a considerable period of time (more than five seconds) and follow her reflection in the mirror. These two signals indicate a transition to a state of minimal consciousness. Today the patient is still in this condition. Occasionally she is able to follow orders, but she does not communicate.

Considering her young age, the cause of the vegetative state and the length of time it lasted, we knew from the beginning that her chances of recovery were not zero, but about one in five. That is, the results of the study should not be interpreted as if they indicate that any patient in a vegetative state may actually be conscious. In fact, we did not detect similar recognition signals in the fMRI scans of more than 60 other vegetative patients examined at the University of Liege. The most likely explanation for these findings is that the 23-year-old patient had already begun to go into a state of minimal consciousness at the time of the experiment. Indeed, other studies have also shown that activation of more advanced centers in the brain during fMRI scans can predict transition to a minimally conscious state.

These findings emphasize that diagnosing cognition is a complicated business. We have learned a lot from the new imaging methods that measure neural activity in brain-damaged patients, but more research is needed before scientists can use functional imaging to confirm a diagnosis of vegetative state and to help determine the chances of recovery and treatment of this difficult medical condition. For now, doctors continue to rely on comprehensive clinical tests when they are required to make their difficult treatment decisions.

Overview/ The vegetative state
Every year, thousands of Americans who have suffered brain injuries go from a coma to a vegetative state. If the patients remain in this condition for more than a year, their chance of recovery tends to zero.
Researchers are trying to develop brain imaging methods to diagnose the vegetative state. This diagnosis will help doctors determine which of the patients with brain damage have a chance of recovery.
Functional imaging of vegetative patients has provided new clues about the mechanisms of cognition, but more research is needed before researchers can use this tool for diagnostic purposes.

Awake but unconscious
After a brain injury that causes a coma, the patient can continue on several routes. If the patient is not dead, he will likely go into a vegetative state. (In rare cases, a person can remain in a coma or develop "lockdown syndrome", meaning complete paralysis of the body's voluntary muscles.) From there, the patient can go into a state of minimal consciousness and further recovery, or remain in a permanent vegetative state. Compared to other mental states, vegetative patients have a high level of alertness and, unlike comatose people, they sleep and wake periodically, but lack the consciousness and awareness that characterizes conscious and normal wakefulness.

About the author
Stephen Laureys
Heads the research group that deals with coma at the Belgian National Foundation for Scientific Research and manages the clinics in the Department of Neurology at the University Hospital Sarte Tilman Blaise in Belgium. In 2000 he was awarded a doctorate at the Cyclotron Research Center at the University of Liège for the study of brain activity in patients in a vegetative state. He supports increasing research on the vegetative state and the state of minimal consciousness, and recently published the book "Limits of Consciousness: Neurobiology and Neuropathology" (Elsevier, 2006).

A look at the damage

In the brains of vegetative patients, it is possible to see a decrease in the level of metabolism, measured by the consumption of glucose in the tissues. The activity in different areas in the prefrontal and parietal cortices was considerably less in vegetative patients. The reason for this could be damage to the cerebral cortex or connections between the cerebral cortex and the thalamus.

And more on the subject

The Vegetative State: Medical Facts, Ethical and Legal Dilemmas. B. Jennett. Cambridge University Press, 2002.

Science and Society: Death, Unconsciousness and the Brain. Steven Laureys in Nature Reviews Neuroscience, Vol. 6, no. 11, pages 899–909; November 2005.

Detecting Awareness in the Vegetative State. AM Owen, MR Coleman, M. Boly, MH Davis, S. Laureys and JD Pickard in Science, Vol. 313, page 1402; September 8, 2006.