A very encouraging clinical trial for patients with OCD

November 12 2008

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In 2002, thanks to a chance observation in patients suffering from Parkinson's disease, Inserm researchers found a potential treatment for the most serious forms of obsessive compulsive disorder (OCD). Following neurosurgical treatment, two patients had a substantial decrease in their OCD. Today, only 6 years after this first discovery, a clinical trial involving the teams of 10 university hospital centers was coordinated by the Avenir team "Behavior, Emotion, and Basal Ganglia" of Dr Mallet at Pitié-Salpêtrière Hospital. This study, carried out with 16 patients, produced spectacular results. In some patients the disorders almost totally disappeared. This research was published in the November 13, 2008 edition of the New England Journal of Medicine.

OCD(1) affects 2 % of the population and is considered a psychiatric disorder. It is the number four psychiatric pathology in terms of frequency following phobias, disorders relating to alcohol and drugs, and depression. The people affected are obsessed with cleanliness, order, and symmetry, or are overcome by doubts and irrational fears. In order to reduce their anxiety, they carry out rituals of tidying, washing or verification for several hours a day in the most serious cases. These signs reflect major suffering and a serious handicap that often last for years, and should not be confused with obsessive, perfectionist and meticulous personality traits. One third of patients are resistant to the usual treatment, a combination of cognitive behavior therapy and anti-depressants (serotonin reuptake inhibitors). Hypotheses in favor of a dysfunction of the striato-pallido-thalamo-cortical cerebral circuits encouraged experimental attempts at psychosurgical treatment (destruction of certain parts of the incriminated cerebral areas or of their connections) in patients with the most serious cases. But the efficacy of these trials, which were never evaluated in a rigorous manner, is unclear because of uncertainty in the choice of the cerebral targets. Furthermore, the lesion is irreversible and thus open to criticism from an ethical standpoint. After several attempts, some neurosurgery teams tried to reproduce the effect of the lesions with the deep stimulation technique (see box). Despite interesting observations, a serious lack of precision concerning the choice of the anatomical target was reported.

In order to propose a reliable therapeutic alternative for the most severe forms of OCD, French researchers chose a different study approach. A small area of the brain that is involved in motor disturbances in Parkinson's Disease (the subthalamic nuclei) drew their attention. Stimulating it led to a substantial reduction in behavior disorders in two Parkinson's patients. In Parkinson's patients, the insertion of an electrode at the center of the subthalamic nucleus eliminates motor disturbances. But when the site of the stimulation is shifted by a few millimeters, changes in the psychic state and behavior of patients are observed. They may for example become hyperactive, insomniac or irritable. If the contact is changed again, these effects disappear. Previous research by Luc Mallet and his colleagues showed that depending on the precise localization of the electrode, one of the various aspects of behavior, motor, social or affective, could be modified.

A national study carried out at 10 university hospital centers

Deep cerebral stimulation was thus proposed as a therapeutic alternative for people with severe OCD in whom pharmacological and psychological treatments had no effect. This technique has the advantage of being reversible. It also allows for precise adjustment of the various stimulation parameters (frequency, voltage, pulse duration) to obtain the best result possible.

Sixteen patients, divided among 10 French university hospital centers, were selected for surgical implantation of an electrode in each subthalamic nucleus. Over the course of 10 months, they were monitored by the doctors, psychiatrists and researchers involved in the protocol for which AP-HP was the sponsor and the main investigator. The stimulator connected to the electrodes was activated and then deactivated in a randomized manner (order determined randomly): eight patients underwent a period of active stimulation followed by a period of "placebo" stimulation while eight others received "placebo" stimulation followed by real stimulation. "This was a double blind test, i.e. neither the patients nor the doctors knew the periods of stimulation," Luc Mallet explained.

There are various tools for the diagnosis of obsessive compulsive disorder. The researchers used them to objectively measure the evolution of the disorders in their patients. The suffering caused by the obsessions and compulsions, the time devoted to them, and the capacity of the patients to control these thoughts and behaviors were evaluated with a specific scale. The results were quite convincing. After the surgery and at the end of 3 months of active stimulation, 7 patients out of 10 showed a response to the treatment and an improvement in their condition: more than 25% of their symptoms had disappeared. The evaluation of the efficacy of the treatment also focused on the capacity of the patient to return to normal family life, to form new social ties, or to go back to work. After 3 months of active stimulation, 6 patients out of 10 reached satisfactory overall functioning with only moderate discomfort due to the illness. Only 12% of them reached this level with placebo stimulation.

French researchers are leaders in the field, due particularly to close collaboration between several high-level teams in different disciplines(3). This clinical trial was very encouraging. "Among the patients monitored, some experienced a return to a social, affective and professional life that had been abandoned for years because of the illness," Luc Mallet said.

These results require further adjustment however. Prudence is necessary given the possible behavioral effects. While these are rapidly reversible, dealing with them requires an excellent knowledge of the technique and perfect coordination of the medical teams. The researchers and clinicians must further refine the stimulation parameters. They must also continue to acquire very precise knowledge of the cartography of the subthalamic nuclei. Very regular psychiatric and psychological oversight is always indispensable, before and after the operation.

What is deep cerebral stimulation?
Deep brain stimulation is a neurosurgery technique that involves implanting two electrodes in the brain and connecting them to a stimulator implanted under the skin. This stimulator acts as a pacemaker, delivering a direct electrical current which modulates the sequences of abnormal signals emitted by the brain. The electrode contains 4 different contacts spaced two millimeters apart. Each contact can be stimulated independently of the others. This technique has been used with success since the end of the 1980's in the treatment of Parkinson's disease. The Inserm researchers proved that it is also effective in treating the most severe forms of obsessive compulsive disorder. However, deep brain stimulation is still an operation and involves the risks inherent in any neurosurgery.

Top view of the nuclei located in the depth of the

Top view of the nuclei located in the depth of the cerebral hemispheres and involved in the development of the symptoms of Tourette Syndrome (MGT) and obsessive compulsive disorder (OCD). The precise targets in which the stimulation electrodes are implanted are located in the internal globus pallidus for Tourette Syndrome and the subthalamic nucleus for OCD. Each of these nuclei has a limbic territory (yellow), an associative territory (violet) and a sensorimotor territory (green). The other nuclei that make up the basal ganglia are the caudate nucleus (dark blue), and the putamen (light blue). In the insert: the entire skull with the caudate nuclei and two electrodes implanted in the subthalamic nuclei.


Results for Tourette Syndrome

Tourette Syndrome is the resultant of a joint dysfunction of the limbic territories and the basal ganglia. This disease is characterized by motor and vocal tics. In patients with the most severe forms, medication has no effect.

Three people benefited from the deep brain stimulation technique. The electrodes were implanted in the limbic zones of 2 deep structures, a nucleus of the thalamus and the internal globus pallidus, in order to compare their respective efficacy in a double-blind protocol. Here too, the technique was successful. The best results were obtained by stimulating the anterior part of the internal globus pallidus, with improvement in symptoms on the order of 70%. Prolonged monitoring of patients (6 years of monitoring for the first patient operated) shows that the effects are maintained over time, allowing them to resume working and to have a normal social life. A multi-center trial is now in progress on a larger number of patients. Researchers will now try to determine that this treatment can become a therapeutic option that is usable outside of a research setting.

This research, carried out by the same team of researchers, demonstrates the considerable therapeutic potential of deep brain stimulation. When it is applied with precision, it allows for fine regulation of neuronal systems, the dysfunctions of which lead to pathological repetitive behaviors in humans.

(1) OCD is an obsessional neurosis. The symptoms include obsessive thought and involuntary and irrepressible compulsions (repetitive acts).
(3) In order to reinforce the excellence of the French research teams and to increase their visibility on the international level, the Institute for Brain and Spinal Cord Disorders (ICM) is to be established in 2010 on the site of the Pitié Salpêtrière. The team of Dr Mallet, which is likely to become part of the ICM, will then be working with 600 researchers from all over the world in a 22,000 m2 space devoted to neuroscience research.

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Know more


Subthalamic Nucleus Stimulation in Severe Obsessive Compulsive Disorder
Mallet L, Polosan M, Jaafari N, Baup N, Welter ML, Fontaine D, Tezenas du Montcel S, Yelnik J, Chéreau I, Arbus C, Raoul S, Aouizerate B, Damier P, Chabardès S, Czernecki V, Ardouin C, Krebs MO, Bardinet E, Chaynes P, Burbaud P, Cornu P, Derost P, Bougerol T, Bataille B, Mattei V, Dormont D, Devaux B, Vérin M, Houeto JL, Pollak P, Benabid A-L, Agid Y, Krack P, Millet B and Pelissolo A.
New England Journal of Medicine, Volume 359, Issue 20: November 13, 2008

Internal pallidal and thalamic stimulation in patients with Tourette's syndrome
Welter ML, Mallet L, Houeto JL, Karachi C, Czernecki V, Cornu P, Navarro S, Pidoux B, Dormont D, Bardinet E, Yelnik J, Damier P and Agid Y.
Archives of Neurology 2008; 65(7):952-957

Compulsions, Parkinson's disease, and stimulation
Mallet L, Mesnage V, Houeto JL, Pelissolo A, Yelnik J, Behar C, Gargiulo M, Welter ML, Bonnet AM, Pillon B, Cornu P, Dormont D, Pidoux B, Allilaire JF and Agid Y.
Lancet 2002, 360(9342):1302-4

Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior
Mallet L, Schupbach M, N'Diaye K, Remy P, Bardinet E, Czernecki V, Welter ML, Pelissolo A, Ruberg M, Agid Y and Yelnik J.
The Proceedings of the National Academy of Sciences 2007, 104(25):10661-6

List of the 10 participating university hospital centers:
Hôpital de la Pitié-Salpêtrière (Paris 6), Hôpital Saint-Anne (Paris 5), CHU of Bordeaux, Clermont-Ferrand, Grenoble, Nantes, Nice, Poitiers, Rennes, Toulouse.

Researcher contacts
Luc Mallet
Inserm Avenir Team IFR 70 - Behavior, Emotion, and Basal Ganglia
Clinical Investigation Center - CHU Pitié-Salpêtrière
Tel: 01 42 16 19 50/ 12 33

Antoine Pelissolo
Adult Psychiatry Department - CHU Pitié-Salpêtrière
Tel: 01 42 16 12 33/ 18 25

Site of the Institute for Brain and Spinal Cord Disorders: http://http://www.icm-institute.org

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