Stimulating consciousness

How can we help severely brain-damaged people to regain consciousness? Researchers from the University of Liège’s Coma Science Group showed that in some patients in a minimally conscious state, transcranial direct current stimulation encourages the recovery of cognitive and motor skills. But while 43 % of the patients in a minimally conscious state who were studied showed a temporary improvement, 57 % of them manifested no change at all. Furthermore, patients in a vegetative state/unresponsive wakefulness syndrome don’t benefit in any way from transcranial direct current stimulation. Why? Researchers from the Coma Science Group are currently trying to find an answer to this question. Publication in the journal, Neurology.

In general, a coma lasts several hours, several days or several weeks. As soon as the patient opens their eyes – if they have survived -, they abandon this state either to regain consciousness, albeit sometimes in the form of locked-in syndrome, or to enter into a vegetative/unresponsive or minimally conscious state.

Patients in coma show no voluntary behavioural response to stimulations from their environment and their sleep-wake cycles have disappeared. They never open their eyes, even after intense nociceptive stimulation.

Patients in a vegetative state/unresponsive wakefulness syndrome maintain the ability to open their eyes, as well as other autonomous functions, such as controlling their breathing. Their movements are involuntary and, although their eyes are open when in a state of wakefulness, they have no awareness of their environment. On the contrary, patients in a minimally conscious state have a fluctuating awareness of their environment and they may execute voluntary movements – visually following an object that is moving in space, smiling, respond to a simple command, etc. Nevertheless, they are incapable of communicating their thoughts to those around them.

Electric stimulations

As regards patients in a vegetative state/unresponsive wakefulness syndrome or in a minimally conscious state, specialised centres deploy different strategies to encourage a return to a state of consciousness worthy of this name, where the patient is able to communicate. Sometimes their limbs are mobilised, sometimes music therapy is applied, or sometimes the patient is placed in special light conditions...  "The problem is that none of these approaches have proven their effectiveness", points out Professor Steven Laureys, head of the Coma Science Group at the University of Liège (Cyclotron Research Centre and the Neurology Department at Liège’s university hospital). Of course, some patients recover, but it is incredibly difficult to show that the aftercare given contributed to their recovery.

To untangle this web, there is no other solution than to carry out randomised double-blind placebo-controlled studies. And yet, up until now, there has only been one study of this kind. Published in 2012 by Joseph Giacino’s team from the New Jersey Neuroscience Institute, it showed that by administering amantadine (a nonspecific drug that was initially used for Parkinson’s disease followed by multiple sclerosis) four weeks after coming out of a coma, there was some improvement in the cognitive and motor responses of patients in a vegetative/unresponsive state and a minimally conscious state.

Since the work of Steven Laureys’ team published in 2000 in The Lancet, we know that on a neuroanatomical level, consciousness particularly involves the activation of several nuclei in different areas of the association cortex, as well as thalamocortical loops, which consist of continuously ongoing neural signals between nuclei in the thalamus and neurons in all modular areas of the cortex. Consciousness seems to be indissociable from these feedback loops, which would appear to constitute a mechanism that increases attention allowing a given representation to enter into our conscious work space.

In 2006, an article by Nicholas Schiff from Cornell University (New York) was published in Nature. It informed us that the stimulation of the thalamus by implanted electrodes could be beneficial to patients in a minimally conscious state. “However, this invasive technique risks causing bleeding and infections”, Steven Laureys tells us. “Therefore, in the Coma Science Group, we decided to turn our attention to transcranial direct current stimulation (tDCS), a non-invasive method whose relevance had already been revealed in healthy subjects, where it improved attention, working memory and the language function.”

Healthy subjects were stimulated via two electrodes attached to their head, one positioned over the left prefrontal dorsolateral cortex and the other placed over the right supraorbital region. The Coma Science Group researchers chose the same two spots, since the electric stimulation distributed from these locations seemed to affect the regions previously defined as involved in the phenomenon of consciousness.

Signs of consciousness

Fifty-five patients in a vegetative state/unresponsive wakefulness syndrome or a minimally conscious state were administered tDCS for 20 minutes. Some of them were in a chronic phase, i.e. in a those states for more than three months after coming out of a coma; others were in an acute and subacute phase (less than three months). “Moreover, comas of both traumatic and non-traumatic origin (anoxia) were represented”, explains Steven Laureys.

During the first stage, researchers demonstrated the harmlessness of this type of stimulation. In particular, it didn’t cause epilepsy. The protocol of the actual experiment was double-blind placebo-controlled. The person leading the experiment, Aurore Thibaut, a physiotherapist and a doctoral student from the Coma Science Group, provided the stimulator with a code. Unaware of whether the code was activating the electrodes or not, this code determined whether or not the patients received a continuous current. Fort-eight hours passed between each session, at the end of which the codes were reversed for each patient so that those who had previously been stimulated, weren’t during the next session, and vice versa.

In each case, the patient’s state of consciousness was measured using a standardised tool, the Coma Recovery Scale-Revised (CRS-R), developed in the United Stated by Joseph Giacino’s team and validated in French by Caroline Schnakers, FNRS research associate at ULg, and by Steven Laureys. In total, four assessments were carried out on each patient: before and after the “real” stimulation, and before and after the “false” one (placebo).

A clinical improvement was seen in 43 % of patients in a minimally conscious state after tDCS. “In other words, these patients displayed signs of consciousness that had never previously been observed in them”, Steven Laureys explains. “We were even able to establish functional communication with two of them. We asked them six easy questions such as "Am I touching my nose?", and they replied correctly to each one, either by moving their head or blinking."

A predictive element

For Aurore Thibaut, the first author of the article(1) published on this work in the journal Neurology, "these results were all the more impressive since they occurred in chronic patients, i.e. years after their injury, whose condition is all too often considered as no longer being able to evolve." She adds: “On the contrary, our study shows that the state of consciousness of severely brain-damaged patients can progress following brief cortical stimulation. However, this improvement is only temporary and the patients return to their initial state after several hours."

Patients in a vegetative state/unresponsive wakefulness syndrome don’t benefit in any way from transcranial direct current stimulation. And while 43 % of the patients in a minimally conscious state show a temporary improvement, in 57 % there is no change at all. Why? Researchers from the Coma Science Group are currently trying to find an answer to this question. Aurore Thibaut has already provided some initial answers. By using positron emission tomography (PET scan), she demonstrated that the patients who responded to tDCS were those who have maintained metabolic activity in one of the regions targeted by the propagated current, i.e. the prefrontal left region. It would appear that the presence of this protected metabolic activity is a predictive element of the stimulation’s effectiveness. However, the molecular effects of tDCS still need to be clarified in order to unearth the inner workings.

And the long-term impact?

For the moment, the researchers from the Coma Science Group are studying the impact of repeated stimulation (20 minutes a day for a week) in patients in a minimally conscious state receptive to tDCS.  The goal is to prolong and maintain the benefits generated by this technique on cognitive and motor skills in the people concerned in the long term. “The ease of use and relatively low cost of this new technique makes it a good candidate for aftercare in daily clinical practice, in order to stimulate the recovery of patients who have survived a coma”, says Professor Laureys. He adds that it could also be useful to improve the evolution of patients plunged into a chronic minimally conscious state.

It was commonly thought that the brain lost all its plasticity beyond the acute phase of an altered state of consciousness. The work of the Coma Science Group underlines the fact that this is not the case, and that it maintains a certain plasticity for years. "However, we shouldn’t deduce from this that everything is possible", insists the head of the team in Liège. “The clinical reality is that there are patients who remain very handicapped. Consequently, our discovery doesn’t fundamentally reopen the debate on the end of life of patients in a chronic altered state of consciousness."

(1) Aurore Thibaut, Marie-Aurélie Bruno, Didier Ledoux, Athena Demertzi, Steven Laureys, tDCS in patients with disorders of consciousness: sham-controlled randomized double blind study, Neurology, 2014 Apr 1;82(13):1112-8.