History of psychosurgery at Sainte-Anne Hospital, Paris, France, through translational interactions between psychiatrists and neurosurgeons.

Sainte-Anne Hospital is the largest psychiatric hospital in Paris. Its long and fascinating history began in the 18th century. In 1952, it was at Sainte-Anne Hospital that Jean Delay and Pierre Deniker used the first neuroleptic, chlorpromazine, to cure psychiatric patients, putting an end to the expansion of psychosurgery. The Department of Neuro-psychosurgery was created in 1941. The works of successive heads of the Neurosurgery Department at Sainte-Anne Hospital summarized the history of psychosurgery in France. Pierre Puech defined psychosurgery as the necessary cooperation between neurosurgeons and psychiatrists to treat the conditions causing psychiatric symptoms, from brain tumors to mental health disorders. He reported the results of his series of 369 cases and underlined the necessity for proper follow-up and postoperative re-education, illustrating the relative caution of French neurosurgeons concerning psychosurgery. Marcel David and his assistants tried to follow their patients closely postoperatively; this resulted in numerous publications with significant follow-up and conclusions. As early as 1955, David reported intellectual degradation 2 years after prefrontal leucotomies. Jean Talairach, a psychiatrist who eventually trained as a neurosurgeon, was the first to describe anterior capsulotomy in 1949. He operated in several hospitals outside of Paris, including the Sarthe Psychiatric Hospital and the Public Institution of Mental Health in the Lille region. He developed stereotactic surgery, notably stereo-electroencephalography, for epilepsy surgery but also to treat psychiatric patients using stereotactic lesioning with radiofrequency ablation or radioactive seeds of yttrium-90. The evolution of functional neurosurgery has been marked by the development of deep brain stimulation, in particular for obsessive-compulsive disorder, replacing the former lesional stereotactic procedures. The history of Sainte-Anne Hospital's Neurosurgery Department sheds light on the initiation-yet fast reconsideration-of psychosurgery in France. This relatively more prudent attitude toward the practice of psychosurgery compared with other countries was probably due to the historically strong collaboration between psychiatrists and neurosurgeons in France.

Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate.

High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the Acb target was stimulated for all patients, three of whom exhibited a significant response. A decrease in glucose metabolism was observed after Acb stimulation, in the posterior cingulate gyrus, left frontal lobe, superior and medial gyrus, and bilateral cerebellum. An increase in metabolism was observed in the bilateral frontal lobe (superior gyrus), left frontal lobe (medial gyrus), and right limbic lobe (anterior cingulate gyrus). The results of this trial suggest that Acb is a more promising target than the caudate. NCT01569711.

Neuronal activity correlated with checking behaviour in the subthalamic nucleus of patients with obsessive-compulsive disorder.

Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.

Why don't you try harder? An investigation of effort production in major depression.

Depression is mainly characterized as an emotional disorder, associated with reduced approach behavior. It remains unclear whether the difficulty in energising behavior relates to abnormal emotional states or to a flattened response to potential rewards, as suggested by several neuroimaging studies. Here, we aimed to demonstrate a specific incentive motivation deficit in major depression, independent of patients' emotional state. We employed a behavioral paradigm designed to measure physical effort in response to both emotional modulation and incentive motivation. Patients did exert more effort following emotionally arousing pictures (whether positive or negative) but not for higher monetary incentives, contrary to healthy controls. These results show that emotional and motivational sources of effort production are dissociable in pathological conditions. In addition, patients' ratings of perceived effort increased for high incentives, whereas controls' ratings were decreased. Thus, depressed patients objectively behave as if they do not want to gain larger rewards, but subjectively feel that they try harder. We suggest that incentive motivation impairment is a core deficit of major depression, which may render everyday tasks abnormally effortful for patients.

A video Clinical Global Impression (CGI) in obsessive compulsive disorder.

The Clinical Global Impression scale (CGI) is frequently used in clinical research because of its face validity and ease of use but data on its reliability are scarce. Our goal was to estimate the reliability of the scale and compare reliability between face-to-face and video scoring. We analyzed 50 different video interviews recorded during 5 visits of a crossover trial to study the effect of subthalamic nucleus stimulation. Six specialized clinicians rated the CGI using these videos, providing 300 different ratings. The intraclass correlation was lower at inclusion (0.30 [0.13-0.50]) than at later visits (0.68 [0.61-0.80]). Reliability was not influenced by the patients' stimulation status. The mean of at least two independent evaluations of the video is needed to achieve an ICC greater than 0.8. The video CGI is a valid clinical outcome measure suitable for clinical trials (ClinicalTrials.gov number, NCT00169377).

Neurological soft signs in OCD patients with early age at onset, versus patients with schizophrenia and healthy subjects.

Compelling evidence suggests that both schizophrenia and obsessive compulsive disorder (OCD) are related to deviant neurodevelopment. Neurological soft signs (NSS) have been proposed to be a marker of abnormal brain development in schizophrenia. The purpose of this study is to examine whether NSS are also a marker in patients with OCD, in particular, in early-onset OCD. The authors included 162 subjects and compared patients with OCD, patients with schizophrenia (SCZ), and healthy control subjects. They were all examined for NSS (Krebs' Scale), extrapyramidal symptoms (Simpson-Angus Scale), and were rated on the Abnormal Involuntary Movements Scale (AIMS). The authors found no differences between NSS total scores and subscores in OCD versus controls, whereas total NSS, motor coordination, and motor integration were significantly lower in OCD than in SCZ. OCD patients with early-onset (before age 13) did not differ from those with later-onset OCD. These results support the idea that NSS, as determined by current scales, is relatively specific to schizophrenia, although they do not preclude the existence of a neurological dysfunction in OCD. Further studies are required to determine the type of neurological signs that could be useful trait-markers in the phenotypic characterization of subtype OCD.

Decrease of prefrontal metabolism after subthalamic stimulation in obsessive-compulsive disorder: a positron emission tomography study.

BACKGROUND: High-frequency bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is a promising treatment in refractory obsessive-compulsive disorder (OCD). METHOD: Using the crossover, randomized, and double-blind procedure adopted by the STOC study, 10 patients treated with high-frequency bilateral STN DBS underwent am 18-fluorodeoxyglucose positron emission tomography (PET) investigation to highlight the neural substratum of this therapeutic approach. RESULTS: The median Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores for all 10 patients were 31 (minimum = 18, maximum = 36) with "Off-Stimulation" status and 19 (minimum = 0, maximum = 30) with "On-Stimulation" status (p = .05). The OCD patients in Off-Stimulation status showed a hypermetabolism in the right frontal middle and superior gyri, right parietal lobe, postcentral gyrus, and bilateral putamen compared with healthy control subjects. A significant decrease in cerebral metabolism was observed in the left cingulate gyrus and the left frontal medial gyrus in On-Stimulation conditions compared with Off-Stimulation conditions. In addition, the improvement assessed by Y-BOCS scores during the On-Stimulation conditions was positively correlated with PET signal changes at the boundary of the orbitofrontal cortex and the medial prefrontal cortex, between PET signal changes and the Y-BOCS scores modifications in On-Stimulation status. CONCLUSION: This study suggests that the therapeutic effect of STN DBS is related to a decrease in prefrontal cortex metabolism.

Dysfunction of the subthalamic nucleus induces behavioral and movement disorders in monkeys.

High-frequency stimulation of the subthalamic nucleus (STN) in parkinsonian patients is reported to induce psychiatric effects. The likely explanation for these effects is the partitioning of the STN into sensorimotor, associative, and limbic anatomo-functional territories. Thus, a specific neuronal dysfunction of the STN sensorimotor territory could lead to abnormal movements, whereas a dysfunction of the associative or limbic territory could lead to behavioral disturbances. To test this hypothesis, neuronal dysfunction of the STN was induced by microinjections of the GABA agonist muscimol, or antagonist bicucculline, in various parts of the nucleus in three monkeys. Stereotyped behaviors (licking and biting fingers) and/or violent hyperactivity were obtained with bicuculline injected into the anteromedial, associative, and limbic territories, whereas injections of muscimol induced no major effects. Abnormal limb movements (contralateral ballism) were obtained after muscimol or bicuculline injections into the posterolateral, sensorimotor territory. Control injections localized around the STN induced other effects (mainly torticollis), which underlines the specificity of STN injection effects. Our study supports the hypothesis that the anteromedial part of the STN is involved in behavioral control.

Behavioral and movement disorders induced by local inhibitory dysfunction in primate striatum.

The current model of basal ganglia organization postulates their functional division into sensorimotor, associative, and limbic territories, implicated, respectively, in motor, cognitive, and motivational aspects of behavior. Based on this model, we previously demonstrated, in the external segment of globus pallidus of monkeys, that the same neuronal dysfunction induced dyskinesia or abnormal behavior depending on the functional territory. To extend these findings, we performed bicuculline microinjections into the different functional territories of the striatum in 6 monkeys. Abnormal movements were observed after microinjections into the posterior putamen, corresponding to the sensorimotor territory, and into the dorsal part of the anterior striatum, corresponding to the associative functional territory. Within the ventral striatum, referred to as the limbic functional territory, we identified 3 subregions corresponding to different types of abnormal behaviors. Simultaneous neuronal recordings performed close to the microinjection sites confirmed that bicuculline produced a focal increase of neuronal activity surrounded by a zone with neuronal hypoactivity. This study provides new evidence for the involvement of specific striatal regions in movement as well as in a large spectrum of behavioral disorders and suggests that local inhibitory dysfunction could be a pathological mechanism of various neurological and psychiatric disorders.

Subthalamic nucleus stimulation in severe obsessive-compulsive disorder.

BACKGROUND: Severe, refractory obsessive-compulsive disorder (OCD) is a disabling condition. Stimulation of the subthalamic nucleus, a procedure that is already validated for the treatment of movement disorders, has been proposed as a therapeutic option. METHODS: In this 10-month, crossover, double-blind, multicenter study assessing the efficacy and safety of stimulation of the subthalamic nucleus, we randomly assigned eight patients with highly refractory OCD to undergo active stimulation of the subthalamic nucleus followed by sham stimulation and eight to undergo sham stimulation followed by active stimulation. The primary outcome measure was the severity of OCD, as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), at the end of two 3-month periods. General psychopathologic findings, functioning, and tolerance were assessed with the use of standardized psychiatric scales, the Global Assessment of Functioning (GAF) scale, and neuropsychological tests. RESULTS: After active stimulation of the subthalamic nucleus, the Y-BOCS score (on a scale from 0 to 40, with lower scores indicating less severe symptoms) was significantly lower than the score after sham stimulation (mean [+/-SD], 19+/-8 vs. 28+/-7; P=0.01), and the GAF score (on a scale from 1 to 90, with higher scores indicating higher levels of functioning) was significantly higher (56+/-14 vs. 43+/-8, P=0.005). The ratings of neuropsychological measures, depression, and anxiety were not modified by stimulation. There were 15 serious adverse events overall, including 1 intracerebral hemorrhage and 2 infections; there were also 23 nonserious adverse events. CONCLUSIONS: These preliminary findings suggest that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events. (ClinicalTrials.gov number, NCT00169377.)

High-frequency stimulation of the anterior subthalamic nucleus reduces stereotyped behaviors in primates.

Growing evidence shows that dysfunction of the limbic basal ganglia (BG) network is implicated in repetitive behaviors, such as obsessive compulsive disorder (OCD) and Tourette's syndrome (TS), in humans. Because deep brain stimulation (DBS) of the posterior subthalamic nucleus (STN), which modulates the sensorimotor BG network, is beneficial in movement disorders, stimulation of the anterior, limbic STN might improve intractable behavioral disorders. We therefore evaluated the effect of anterior STN stimulation on the repetitive behaviors induced in two monkeys after bicuculline-induced dysfunction of the limbic external globus pallidus. DBS in the anterior STN dramatically reduced the stereotypies, but had no effect on the performance of a simple food retrieval task. Stimulations outside the STN were less effective in reducing the stereotypies. Electrode trajectories, reconstructed postmortem, confirmed that the effective contacts were in the anterior STN. DBS in the limbic STN might therefore provide relief from the severe stereotyped behaviors observed in OCD and TS.

[Clinical aspects of obsessive-compulsive disorder]. / Reconnaître un trouble obsessionnel compulsif.

Obsessive-compulsive disorder is a frequent and chronic disorder accompanied by a marked distress and dysfunction. It is characterised by intrusive thoughts or images (obsessions) which increase anxiety, and by repetitive and ritualistic actions (compulsions) which decrease anxiety. Obsessive-compulsive disorder is frequently complicated by major depressive disorder or other psychiatrics disorders. Unfortunately, it is frequently underdiagnosed and undertreated despite the efficacity of treatments by selective serotonine reuptake inhibitors associated with behavioural and cognitive therapy. Diagnosis of this disorder is easy but needs a good knowledge of symptoms because of the clinical heterogeneity.