Deep brain stimulation: a milestone in neuropsychiatry

Electrical modulation of neuronal circuits is allowing the treatment of an increasing number of diseases for which there is no other treatment option. Since the 1990s, new indications have not ceased to surface, leading to worries of possible excesses in the future. Prof. Pierre Pollak, who has witnessed the development of the technique, reviews twenty-five years of progress.

Laboratoire Traitement du Signal de l'Image (LTSI), équipe MediCIS - © Inserm-LTSI-MEDICIS/LTSI

Implanting electrodes deep within the brain to correct brain function would have seemed like science fiction a century ago. However, this technique begins in the 1960s, to provide relief for patients suffering from intense pain. At the time, it is completely experimental, and the frequencies administered are chosen empirically. Only in the 1990s will this therapeutic approach become reality for specific indications.

From daring and chance

It must be understood that the technique is partly a chance happening! Indeed it is entirely fortuitous that Prof. Alim-Louis Benabid discovered its benefits for treating severe tremors. This was in 1987, at Grenoble University Hospital. While the researcher is operating on a patient in order to destroy a region of the thalamus involved in involuntary movements (as is customary at the time), Alim-Louis Benabid observes that the tremors disappear when he applies a high-frequency stimulus to this area. There is nothing unusual about this experiment, which is actually part of the surgical protocol: a stimulus is applied to the neurons surrounding the area to be ablated in order to test the consequences of the surgical procedure that the surgeon is preparing to perform, and to ensure that this procedure is not liable to damage important functions (motor, language, etc.). However, this stimulation is normally carried out at low frequency. Alim-Louis Benabid thus showed daring because he tested the effect of different frequencies. “At the time, the brain lesions made to reduce the symptoms of patients affected by severe tremors were irreversible. Clinicians dreamed of a new, reversible and adjustable therapeutic approach to improve treatment efficacy and safety. Hence these experiments,” explains Prof. Pierre Pollak, a neurologist in Geneva, who was then working with Alim-Louis Benabid.

Encouraged by this discovery, the physicians test this procedure in other patients affected by tremors of various origin. “Every time we applied a high frequency, between 80 and 100 Hz, the tremors disappeared without any need to injure the brain,” recalls Pierre Pollak. The clinicians then decide to set up a clinical trial to validate this strategy for a patient cohort: they implant two electrodes in the brains of patients (one in each hemisphere in order to control both the left and right sides of the body), connected to an electrical stimulator placed under the skin at thoracic level. The benefit is so substantial that the indication is rapidly approved by the health authorities. This constituted a milestone, leading to “an average 75% reduction in symptoms, in a sustainable manner, and all due to a reversible technique,” adds Pierre Pollak.

Catalogue of indications

Électrodes crâniennes. © Inserm/CRICM - CENIR - Plateforme STIM/Bardinet, Eric

Once deep brain stimulation has been validated as a therapeutic technique for this indication, it is then quickly tested for the treatment of other diseases involving hyperactive brain circuits. This is especially the case for Parkinson’s disease. “During the 1990s, ablation of the subthalamic region, the region responsible for hyperactivity, was strongly discouraged, because of the risk of triggering irreversible involuntary movements. However, deep brain stimulation, with electrodes placed in this location, is immediately shown to work in severely affected patients, and its adverse effects can be controlled,” recalls Pierre Pollak. The stimulation indeed clearly reduces the most severe manifestations of the disease, especially akinesia (reduced movement) and rigidity of the body. A clinical trial promoted by Inserm proves the benefit of this technique in some twenty patients and allows this indication to be recognised by the health authorities from 1993.
Other indications will follow: dystonia, and more recently obsessive compulsive disorders, thanks to a study, also supported by Inserm, in which ten French University Hospitals participated in 2008.

Moreover, the use of deep brain stimulation in the management of other diseases is continuing to undergo evaluation. All the indications being studied involve neuronal dysfunctions that have been identified and located by means of more fundamental studies. “These advances could not have seen the light of day without advances in neurology that have enabled these circuits and their influence in several pathologies to be described,” confirms Pierre Pollak. The method seems promising for the treatment of epilepsy, as well as depression. Other experiments are underway for eating disorders, tics such as occur in Tourette syndrome, and even some types of addiction, especially cocaine, etc. “In depression, deep brain stimulation improves symptoms in 60% of patients. This is extraordinary, considering that these are patients who resist all other treatments,” says Pierre Pollak enthusiastically. “But this also means that 40% of patients are unresponsive, and we must find out why.”

The researchers have actually spent several years looking at the mechanism underlying deep brain stimulation. For the moment it remains quite enigmatic: “Some work suggests a recruitment of inhibitory fibres that might enable control of the local hyperactivity responsible for the symptoms, but this remains hypothetical. The mechanism may in fact vary with the pathology and frequency employed. Studies have, for example, enabled improvement in the walk of disabled individuals with stimulation at a frequency of 25 Hz, whereas 10 Hz is needed to treat essential tremors,” says Pierre Pollak, by way of example.

An invasive technique

Laboratoire Traitement du Signal de l'Image (LTSI) - © Inserm/Patrice Latron

Despite the increased number of potential indications, deep brain stimulation may not be used indiscriminately for all patients. “It is an aggressive surgical technique, which consists of introducing electrodes into deep areas of the brain,” Pierre Pollak reminds us. “It must be carried out on a brain that is in good condition, and reserved for patients who are severely affected, with repercussions on their social and working lives.” It concerns young subjects affected by Parkinson’s disease, for example. There is no question of operating on those older than 75 years. Furthermore, even when patients are properly selected, it causes adverse effects in 2-3% of cases, i.e. mental confusion, hemiparesis, haematoma or infections. Finally, post-operative follow-up is very demanding, with regular visits for nearly six months in order to modify the stimulation with a view to achieving positive results.

 

"Feelgood" electrode

Traitement du parkinson par stimulation cérébrale - © Inserm/Benazzouz, Abdelhamid

Ultimately, only 5-10% of people with Parkinson’s disease currently benefit from deep brain stimulation (approximately 400 patients a year in France), and approximately ten times fewer for other indications (tremor and dystonia). These figures may, however, increase if the technique were to prove effective for serious illnesses affecting young people without alternative treatment options. This is the case with anorexia nervosa, “one of the leading causes of death among young girls,” as Pierre Pollack points out, or addiction. “The indications will increase as researchers discover malfunctions in brain circuits associated with harmful symptoms. The technique will improve with the help of increasingly finer electrodes, which modulate the brain function in a more selective manner. However, we must be careful to set limits. We already know how to increase the capacity of the memory by stimulating the hypocampal system. Maybe we can soon learn to control the circuits governing happiness, pleasure, learning, etc. How can we be sure that, tomorrow, individuals will not be paying for additional memory or pleasure? The risk from progress associated with deep brain stimulation is indeed one of going overboard. It reminds us of the importance of providing an ethical dimension to the regulation of this work,” warns the researcher.

 

Further information

Read the biography of Alim-Louis Benabid on the History of Inserm website (in french)

^ Top of page