Using a technique called transcranial direct current stimulation, researchers at the Coma Science Group in Liège, have managed to improve the consciousness of some patients emerging from a coma caused by cranial trauma or a heart attack.

 

At the the Coma Science Group, in Liège, scientist are testing the level of awareness of brain injury patients

with various exercises, such as this one which consist to follow their own reflection in a mirror.
Photo © Coma Science Group/Giga-Consiousness, Université de Liège

 

Since the invention of artificial ventilation in the 1950s, patients who have suffered a prolonged heart attack or a serious road traffic accident have a chance of survival. This incredible medical advance has revolutionised intensive-care medicine. However new challenges rapidly arose, as the survivors of a serious brain injury do not always recover all of their motor and cognitive functions. Following a period of coma, a patient may evolve towards a state of altered consciousness: unresponsive wakefulness syndrome (unfortunately also called a “vegetative state”) or a minimally conscious state. In the first case, the patient’s eyes are open but they are unaware of their surroundings. In the second, the patient shows non-reflex behaviours, such as following someone with their gaze or answering simple commands such as “move your foot” or “shake my hand”. Both states may be transitory or permanent.

 

In both cases, the patients require heavy care. Which treatments can be offered? The pharmacological option is usually preferred despite mixed clinical results. Indeed, there is no miracle drug that can “wake” these patients up.

 

Neither are these treatments without any risk; there are many side effects, including an increased risk of epilepsy or serious fatigue. Amantadine, for example, a dopaminergic antiviral drug that excites neurons, is frequently used. Effective in around half of patients, it sometimes causes epileptic seizures. Zolpidem, a drug usually used as a sedative, can in some rare cases, have a spectacularly paradoxical effect on the cognitive abilities of brain-injured patients, with recovery of speech, the ability to read or to eat alone. Unfortunately, only 5 to 10% of patients demonstrate this type of progress. Brain stimulation is an interesting alternative to these treatments. It may be invasive (as is deep brain stimulation used mainly to treat epilepsy or Parkinson’s disease), or non-invasive. We, in the Coma Science Group, are exploring the latter method at Liège University. In particular, we are working on tDCS or Transcranial Direct Current Stimulation, which consists in stimulating the brain by applying a direct, weak electrical current (of the order of the milliampere) on the scalp using electrodes.

 

In 2006, Friedhelm Hummel and Leonardo Cohen, neuroscientists at the American Health Institute, demonstrated that transcranial stimulation of a few minutes can cause effects in the brain that last for several hours. These effects seem to share characteristics with neuronal plasticity – the ability of the brain to form connections, for example when learning new mental or motor skills.

 

A large number of studies have already confirmed the many positive effects of this technique, namely an improvement in motricity, following a stroke, or in memory in patients suffering from Alzheimer’s disease. It has also been used to successfully treat chronic pain and depression. Another approach is the stimulation of the vagus nerve. In May 2018, the publication of a first case describes recovery of signs of consciousness in a patient in a state of unresponsive wakefulness syndrome for fifteen years. However, this technique needs to be tested in controlled studies.

 

PREFRONTAL REGION

 

For eight years now, these results have led us to study the advantages of transcranial stimulation in altered states of consciousness. Our target? The prefrontal region. It underlies cognitive functions such as attention and memory; it is also important in regaining consciousness.

 

Our first clinical trial included 55 patients in a state of unresponsive wakefulness syndrome or minimally conscious state. Each patient received twenty minutes of stimulation to the prefrontal cortex, with a direct current of 2 milliamperes. Following one session, we observed positive effects in nearly half of patients in a minimally conscious state. Using validated international scales, we measured a recovery of response to a command (squeeze a hand, look down), the ability to follow a moving target with the gaze or to recognise an object. Five of them, who had nevertheless been in a minimally conscious state for more than a year, showed improvement, suggesting that tDCS remains effective even after long periods. Furthermore, we noted no harmful side effects, be they signs of pain, epileptic seizures or skin irritation under the electrodes.

 

Following these encouraging results, we tried to understand why some patients respond to tDCS and others don’t. We used neuro-imaging to compare the atrophy in the gray matter (the neurons) and the brain metabolism of patients responding to stimulation with those of patients who showed no signs of improvement. Result: it seems that the improvement in consciousness requires relative preservation of cortical volume and metabolic activity in the area being stimulated, here the prefrontal cortex, but also other distant cortical or deep subcortical areas (the thalamus and the precuneus) involved in attention and working memory.

 

How can we enhance the benefits of tDCS and ensure it is more effective for patients? To answer these questions, we decided to stimulate another crucial region in the consciousness recovery process: the precuneus. This subcortical structure is involved in what is known as “internal consciousness”, i.e. self-awareness. We know that this region is very active in healthy subjects and inactive in unconscious patients and in unresponsive wakefulness syndrome. We therefore placed the stimulating electrode on the parietal cortex, a region behind the head, in 33 patients who had been in a minimally conscious state for over three months. Only very small improvements were noted, and the effects did not last when we reassessed them one week later.

 

There may be several explanations for this. Firstly, the precuneus is located several centimetres below the skull. It is probable that some of the electrical current did not reach the targeted area. Furthermore, the distance separating the two electrodes in this experiment was greater than in the previous one involving the prefrontal cortex. Stimulating the precuneus requires separating the electrodes by a distance of 10 to 15 cm, compared to 6 to 7 cm in prefrontal cortex stimulation. As a result, the density of the current is lower and the stimulation may be all the less efficient. In 2017, we conducted a clinical trial to evaluate the potential long-term effects of transcranial stimulation. We specifically stimulated the left prefrontal region of the brains of 16 patients in an altered state of consciousness, three months to thirty years following their brain injury. Each patient received twenty minutes of stimulation daily for five days. The medium-term effects, (one week after the end of the stimulations) were evaluated according to the “Coma Recovery Scale-Revised”, performed at the start of the study, immediately after the five days of stimulation, and one week later.

 

This protocol enabled us to show an improvement in signs of consciousness after five days of stimulation, and maintenance of these behavioural effects one week later in half of patients. Concretely, they recovered a variety of behaviours, such as reproducible responses to commands, the ability to locate and manipulate objects, or to visually follow their reflection in a mirror. Two patients who, prior to stimulation were able to communicate non-functionally (they could reply “yes or no” to some questions, not necessarily coherently), recovered functional communication, i.e. they were able to correctly answer 6 out of the 6 questions asked.

 

These results are extremely promising for future clinical applications, in rehabilitation centres or nursing homes, in addition to physiotherapy or occupational therapy. In that respect, we just published the results of a study assessing whether tDCS could be used directly by health care professionals or the patients’ relatives in their homes and not in a research centre, as it has been the case up to now. The patients included in this study, in a minimally conscious state for over three months, received 20 sessions of stimulation over four weeks. The effects were evaluated up to eight weeks after the end of stimulations in 27 patients. We noted a significant improvement in the level of consciousness only in those who had received a minimum of 16 sessions of stimulation out of the 20 scheduled.

 

PERSONALISED APPLICATION

 

We now have enough experience about the effectiveness of stimulation (50% of patients are responding to it), but also about its safety in the medium-term. The effects in the very long term, when stimulation is applied over several weeks, still have to be assessed. Further clinical trials are therefore needed to ensure that prolonged use is safe, and to evaluate the potential long-lasting beneficial effects.

 

Another essential step in its development is the personalised application of stimulation, as patients have very different types of brain injuries that must be taken into account. Therefore, it is possible that the application of stimulation to the left prefrontal cortex is not the most effective strategy for everyone. Studies combining stimulation with neuro-imaging to locate the injuries, need to be conducted to better target the region to be stimulated on a case by case basis.

 

 

HOW STIMULATION ACTS ON THE BRAIN

 A direct current circulating between two electrodes (*) modifies cortical excitability, i.e. the probability of triggering action potentials (the production of nerve pulses by the neurons) to activate or inhibit activity in a region of the brain. Neuro-imaging studies conducted in healthy subjects seem to show that this technique increases excitability and brain connectivity in the whole related network. The brain area is stimulated, as are the regions of the brain connected to it and involved in the same cognitive functions. The neurophysiological mechanism at work is not really understood. It is known however, that stimulation facilitates the triggering of an action potential and modifies the excitability of NMDA synaptic receptors, located at the ends of nerve cells, essential in memory and neuronal plasticity.

(*) A weak electric current (yellow) circulates between the two electrodes placed on the skull, modifying cortical excitability.

 

 

> AUTHOR

 

Géraldine Martens, Aurore Thibaut and Steven Laureys

Physiotherapists and neurologists

All three are working on ways of diagnosing altered states of consciousness more accurately in patients with brain injuries, and on the possible treatments that can be used to improve their condition and care.

 

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