Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis

Background: Genetically determined Intellectual Disability (ID) is an intractable condition that involves severe impairment of mental abilities such as learning, reasoning and predicting the future. As of today, little is known about the placebo response in patients with ID. Objective: To determine if placebo response exists in patients with genetically determined ID. Data sources and Study selection We searched Medline/PubMed, EMBASE, CENTRAL and PsycINFO to find all placebo-controlled double-blind randomized clinical trials (RCTs) in patients with genetically determined ID, published up to April 2013, focusing on core ID symptoms. Data extraction and synthesis Two investigators extracted outcome data independently. Main outcomes and measures Bias-corrected standardized mean difference (Hedge’s g) was computed for each outcome measure, using the Comprehensive Meta-Analysis software. A priori defined patient sub-groups were analyzed using a mixed-effect model. The relationship between pre-defined continuous variable moderators (age, IQ, year of publication and trial duration) and effect size was analyzed using meta-regression Results: Twenty-two placebo-controlled double-blind RCTs met the inclusion criteria (n = 721, mean age = 17.1 years, 62% men, mean trial duration = 35 weeks). There was a significant overall placebo response from pre- to post-treatment in patients with ID (g = 0.468, p = 0.002), both for “subjective outcomes” (a third-person’s evaluation of the patient) (g = 0.563, p = 0.022) and “objective outcomes” (direct evaluation of the patient’s abilities) (g = 0.434, p = 0.036). Individuals with higher IQ had higher response to placebo (p = 0.02) and no placebo response was observed in ID patients with comorbid dementia. A significant effect of age (p = 0.02) was found, indicating higher placebo responses in treatment of younger patients. Conclusions and relevance Results suggest that patients with genetically determined ID improve in the placebo arm of RCTs. Several mechanisms may contribute to placebo effects in ID, including expectancy, implicit learning and “placebo-by-proxy” induced by clinicians/family members. As the condition is refractory, there is little risk that improvements are explained by spontaneous remission. While new avenues for treatment of genetically determined ID are emerging, our results demonstrate how contextual factors can affect clinical outcomes and emphasize the importance of being vigilant on the role of placebos when testing novel treatments in ID

Certainty of genuine treatment increases drug responses among intellectually disabled patients

Objective: To determine the placebo component of treatment responses in patients with intellectual disability (ID). Methods: A statistical meta-analysis comparing bias-corrected effect sizes (Hedges g) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiving genuine treatment (100% vs 50%). Studies in fragile X, Down, Prader-Willi, and Williams syndrome published before June 2015 were considered. Results: Seventeen open-label trials (n = 261, 65% male; mean age 23.6 years; mean trial duration 38 weeks) and 22 placebo-controlled trials (n = 721, 62% male; mean age 17.1 years; mean trial duration 35 weeks) were included. The overall effect size from pre to post treatment in open-label studies was g = 0.602 (p = 0.001). The effect of trial type was statistically significant (p = 0.001), and revealed higher effect sizes in studies with 100% likelihood of getting active drug, compared to both the drug and placebo arm of placebo-controlled trials. We thus provide evidence for genuine placebo effects, not explainable by natural history or regression toward the mean, among patients with ID. Conclusions: Our data suggest that clinical trials in patients with severe cognitive deficits are influenced by the certainty of receiving genuine medication, and open-label design should thus not be used to evaluate the effect of pharmacologic treatments in ID, as the results will be biased by an enhanced placebo component

Study of neuronal networks and cognitive mecanisms involved in X linked intellectual disability

Grâce aux progrès de la génétique moléculaire qui ont permis d’identifier de nouveaux gènes de déficience intellectuelle liée à l’X, il nous a été possible de travailler sur des groupes homogènes de malades présentant une mutation dans le même gène. Nous avons d’une part, pu mettre en évidence un dysfonctionnement du circuit cérébello-thalamo-préfrontal grâce à une étude en IRM morphométrique réalisée chez des patients ayant une mutation dans le gène Rab-GDI. D’autre part, nous avons identifié un phénotype tout à fait spécifique lié aux mutations du gène ARX, tant clinique que neuropsychologique, et cinématique, associant une atteinte très particulière de la motricité distale des membres supérieurs et du langage. La préhension des patients est pathognomonique, avec une préférence pour la pince pouce-majeur, une difficulté accrue pour l’utilisation du bord cubital de la main, et un trouble de la pronosupination. Sur le plan neuroanatomique, il existe une diminution de volume des noyaux gris centraux et des épaisseurs corticales des régions contrôlant la motricité, bien corrélées au paramètres de cinématique. Enfin, nous avons exploré les stratégies de raisonnement des patients déficients intellectuels atteints du syndrome de l’X fragile, d’une mutation du gène ARX ou de trisomie 21 en élaborant un paradigme de raisonnement visuel analogique issu des matrices de Raven. Nous en avons établi la trajectoire développementale. Les stratégies utilisées par les patients (étude en eyetracking) sont différentes de celles des contrôles y compris de même âge mental, avec un défaut d’inhibition majeur, encore plus franc chez les patients X fragiles que ceux porteurs de trisomie 21Thanks to progress in molecular genetics, that allowed identification of new genes responsible for X linked intellectual disability, we studied on homogeneous groups of patients presenting with a mutation in one or the other gene. In the first section, we showed dysfunction of cerebello-thalamo-prefrontal networks, thanks to morphological MRI study performed on patients with a mutation in the Rab-GDI gene. In the second section, we highlighted a very specific phenotype related to ARX gene mutations, clinically, neuropsychologically, and kinematically, with a very peculiar impairment of upper limbs distal motricity, and language disorder. Patients hand-grip is pathognomonic, with a preference for the middle finger instead of the index for the grip of object, major impairment of fourth finger use, and lack of pronation movements. Neuroimaging study showed decreased volume of basal ganglia, and cortical thickness of motor regions, well correlated to kinematic parameters. In the third section, we explored reasoning strategies in three groups of patients with intellectual deficiency: fragile X, ARX mutated and Down syndrome patients and controls (both chronological and mental age-matched subjects). We notably elaborated a visual analogical reasoning paradigm, inspired from Raven’s matrices. We established a developmental trajectory of this paradigm. The strategy used by patients (eyetracking study) was different from the one used by controls, with a huge lack of inhibition, even greater for fragile X patients than for Down syndrome patient

Etude clinique de 35 patients présentant une déficience mentale liée au gène ARX

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Epigenetic Modification of the FMR1 Gene in Fragile X Syndrome Is Associated with Differential Response to the mGluR5 Antagonist AFQ056

International audienc

Dispositif d'évaluation des capacités cognitives d'un patient

L'invention concerne un dispositif (1) d'évaluation des capacités cognitives, comprenant: - un dispositif d'affichage (3) ; - un dispositif de test (2) configuré pour localiser l'emplacement du dispositif d'affichage fixé par un oeil du patient et effectuer automatiquement la séquence suivante: - l'affichage (3) d'un visuel de test ; - déterminer le nombre de transitions du regard entre une matrice et des propositions de réponse ; - répéter la séquence pour plusieurs visuels de test

A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations

Contains fulltext : 192462.pdf (Publisher’s version ) (Open Access

Motor resonance facilitates movement execution: an ERP and kinematic study

International audienceAction observation, simulation and execution share neural mechanisms that allow for a common motor representation. It is known that when these overlapping mechanisms are simultaneously activated by action observation and execution, motor performance is influenced by observation and vice versa. To understand the neural dynamics underlying this influence and to measure how variations in brain activity impact the precise kinematics of motor behavior, we coupled kinematics and electrophysiological recordings of participants while they performed and observed congruent or non-congruent actions or during action execution alone. We found that movement velocities and the trajectory deviations of the executed actions increased during the observation of congruent actions compared to the observation of non-congruent actions or action execution alone. This facilitation was also discernible in the motor-related potentials of the participants; the motor-related potentials were transiently more negative in the congruent condition around the onset of the executed movement, which occurred 300 ms after the onset of the observed movement. This facilitation seemed to depend not only on spatial congruency but also on the optimal temporal relationship of the observation and execution events

Simultaneous action execution and observation optimise grasping actions.

International audienceAction observation and execution share overlapping neural resonating mechanisms. In the present study, we sought to examine the effect of the activation of this system during concurrent movement observation and execution in a prehension task, when no a priori information about the requirements of grasping action was available. Although it is known that simultaneous activation by observation and execution influences motor performance, the importance of the delays of these two events and the specific effect of movement observation itself (and not the prediction of the to-be-observed movement) on action performance are poorly known. Fine-grained kinematic analysis of both the transport and grasp components of the movement should provide knowledge about the influence of movement observation on the precision and the performance of the executed movement. The experiment involved two real participants who were asked to grasp a different side of a single object that was composed of a large and a small part. In the first experiment, we measured how the transport component and the grasp component were affected by movement observation. We tested whether this influence was greater if the observed movement occurred just before the onset of movement (200 ms) or well before the onset of movement (1 s). In a second experiment, to reproduce the previous experiment and to verify the specificity of the grasping movements, we also included a condition consisting of pointing towards the object. Both experiments showed two main results. A general facilitation of the transport component was found when observing a simultaneous action, independent of its congruency. Moreover, a specific facilitation of the grasp component was present during the observation of a congruent action when movement execution and observation were nearly synchronised. While the general facilitation may arise from a competition between the two participants as they reached for the object, the specific facilitation of the grasp component seems to be directly related to mirror neuron system activity induced by action observation itself. Moreover, the time course of the events appears to be an essential factor for this modulation, implying the transitory activation of the mirror neuron system

Long-term follow-up in 12 children with pulmonary arteriovenous malformations : Confirmation of hereditary hemorrhagic telangiectasia in all cases

International audienceObjective To assess whether pulmonary arteriovenous malformation (PAVM) is associated with hereditary hemorrhagic telangiectasia (HI-IT). Study design This study wits a review of 12 children (sex ratio = 1) including family history, mutation analysis, and long-term follow-up. Results Five children were under age 3 years when PAVM was diagnosed. Presentations included pulmonary, symptoms (11 8), cerebral abscess (n = 2), and transient ischemic attack (TIA) (n = 1); 1 patient was asymptomatic. Nine of the 12 children (75%) had a family history of PAVM The diagnosis of HHT was con finned in all cases. A mutation in ENG was found in 9 of the 10 children available for testing. No mutation in ACVRL1 was found. During long-term follow-up (mean, 16 years), the following complications occurred: TIA (n = 2), hemoptysis (n = 2), and cerebral abscess (n = 2). Nine children experienced recurrence of PAVM The children with no recurrence were those without a family history of PAVM. Conclusions The diagnosis of HHT should be considered in a child with an apparently isolated PAVM. Because serious complications may occur at any age, we recommend screening for PAVM and long-term follow-up in children from families with HHT, especially those with air ENG mutation