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.
To determine if placebo response exists in patients with genetically determined ID.
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.
Two investigators extracted outcome data independently.
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.
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.
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.
Successful non-verbal social interaction between human beings requires dynamic and efficient encoding of others′ gestures. Our study aimed at identifying neural markers of social interaction and goal ...variations in a non-verbal task. For this, we recorded simultaneously the electroencephalogram from two participants (dual-EEG), an actor and an observer, and their arm/hand kinematics in a real face-to-face paradigm. The observer watched “biological actions” performed by the human actor and “non-biological actions” performed by a robot. All actions occurred within an interactive or non-interactive context depending on whether the observer had to perform a complementary action or not (e.g., the actor presents a saucer and the observer either places the corresponding cup or does nothing). We analysed the EEG signals of both participants (i.e., beta (~20Hz) oscillations as an index of cortical motor activity and motor related potentials (MRPs)). We identified markers of social interactions by synchronising EEG to the onset of the actor′s movement. Movement kinematics did not differ in the two context conditions and the MRPs of the actor were similar in the two conditions. For the observer, however, an observation-related MRP was measured in all conditions but was more negative in the interactive context over fronto-central electrodes. Moreover, this feature was specific to biological actions. Concurrently, the suppression of beta oscillations was observed in the actor's EEG and the observer's EEG rapidly after the onset of the actor's movement. Critically, this suppression was stronger in the interactive than in the non-interactive context despite the fact that movement kinematics did not differ in the two context conditions. For the observer, this modulation was observed independently of whether the actor was a human or a robot. Our results suggest that acting in a social context induced analogous modulations of motor and sensorimotor regions in observer and actor. Sharing a common goal during an interaction seems thus to evoke a common representation of the global action that includes both actor and observer movements.
•We recorded Dual-EEG and arm kinematics of two interacting participants.•Beta rhythm and Motor Potentials of an actor and an observer were measured.•Beta suppressions was stronger in interactive context for the actor and for the observer.•Acting in social context led to similar motor system modulations in both participants.•The modulations could represent a common motor representation.
Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease ...between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and deterioration of the central nervous system. Treatment with cysteamine if started early can delay the progression of the disease. Little is known about the neurological impairment which occurs later. The goal of the present study was to find a possible neuroanatomical dysmorphic pattern that could help to explain the cognitive profile of cystinosis patients. We also performed a detailed review of the literature on neurocognitive complications associated with cystinosis.
17 patients (mean age = 17.6 years, 5.4-33.3) with cystinosis were included in the study. Neuropsychological assessment was performed including intelligence (Intelligence Quotient (IQ) with Wechsler's scale), memory (Children Memory Scale and Wechsler Memory Scale), visuo-spatial (Rey's figure test) and visuo-perceptual skills assessments. Structural brain MRI (3 T) was also performed in 16 out of 17 patients, with high resolution 3D T1-weighted, 3D FLAIR and spectroscopy sequences.
Intellectual efficiency was normal in patients with cystinosis (mean Total IQ = 93). However the Perceptual Reasoning Index (mean = 87, 63-109) was significantly lower than the Verbal Comprehension Index (mean = 100, 59-138, p = 0.003). Memory assessment showed no difference between visual and verbal memory. But the working memory was significantly impaired in comparison with the general memory skills (p = 0.003). Visuospatial skills assessment revealed copy and reproduction scores below the 50th percentile rank in more than 70% of the patients. Brain MRI showed cortical and sub-cortical cerebral atrophy, especially in the parieto-occipital region and FLAIR hypersignals in parietal, occipital and brain stem/cerebellum. Patients with atrophic brain had lower Total IQ scores compared to non-atrophic cystinosis patients.
Patients with cystinosis have a specific neuropsychological and neuroanatomical profile. We suggest performing a systematic neuropsychological assessment in such children aiming at considering adequate management.
Evidence that the motor and the linguistic systems share common syntactic representations would open new perspectives on language evolution. Here, crossing disciplinary boundaries, we explore ...potential parallels between the structure of simple actions and that of sentences. First, examining Typically Developing (TD) children displacing a bottle with or without knowledge of its weight prior to movement onset, we provide kinematic evidence that the sub-phases of this displacing action (reaching + moving the bottle) manifest a structure akin to linguistic embedded dependencies. Then, using the same motor task, we reveal that children suffering from specific language impairment (SLI), whose core deficit affects syntactic embedding and dependencies, manifest specific structural motor anomalies parallel to their linguistic deficits. In contrast to TD children, SLI children performed the displacing-action as if its sub-phases were juxtaposed rather than embedded. The specificity of SLI's structural motor deficit was confirmed by testing an additional control group: Fragile-X Syndrome patients, whose language capacity, though delayed, comparatively spares embedded dependencies, displayed slower but structurally normal motor performances. By identifying the presence of structural representations and dependency computations in the motor system and by showing their selective deficit in SLI patients, these findings point to a potential motor origin for language syntax.
Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are ...emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials.
We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients.
We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2).
Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups.
We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.
The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and ...for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a duplication of 24 base pairs (c.429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA).
In this study, we first present ARX expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although ARX expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 ARX patients carrying c.429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that ARX patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip.
As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in ARX dup24 patients is very likely the anatomical substrate of this developmental form of LKA.
•c.429_452dup24 in ARX is responsible for ID with Limb Kinetic Apraxia.•During human brain development, ARX is expressed in GABAergic neuronal progenitors.•ARX patients have a significantly decreased caudate nucleus volume by MRI.•This caudate nucleus volume reduction is correlated with motor impairment severity.•These anatomic findings may explain this developmental form of Limb Kinetic Apraxia.
Abstract Background Kawasaki disease is an acute and time-limited systemic vasculitis primarily affecting young children. Patient We describe an 18-month-old girl with Kawasaki disease who developed ...cerebral infarction following complete occlusion of her right internal carotid artery. Results The occlusion occurred 10 days after the onset of fever, while she was on high-dose aspirin, and the day after she received intravenous immunoglobulin treatment. We present the first literature review on this very rare complication. Conclusion Stroke is a rare neurological complication in Kawasaki disease. Optimal treatment should be begun as soon as possible after diagnosis. Intravenous immunoglobulins seem to reduce the cerebrovascular complications, but evaluation of hydration status is strongly recommended before performing such treatment.
Objective To assess whether pulmonary arteriovenous malformation (PAVM) is associated with hereditary hemorrhagic telangiectasia (HHT). Study design This study was 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 (n = 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 confirmed 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 an ENG mutation.
Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form ...of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABA
receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.
Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with neurodevelopmental disorders. Here, we ...review the placebo effect in autism spectrum disorder (ASD). Placebo responses are widely evident in ASD clinical trials and could partly operate via so‐called placebo‐by‐proxy, whereby caregivers or clinicians indirectly shape patient outcomes. Understanding the role of placebo effects in ASD may help discern genuine treatment effects from contextual factors in clinical trials. The much less studied nocebo effect, or negative placebo, might contribute to the experience of side effects in ASD treatments but empirical data is missing. Better knowledge about placebo and nocebo mechanisms may contribute to the development of more effective research designs, such as three‐armed designs that account for natural history, and improved treatments for ASD symptoms. At a clinical level, deeper knowledge about placebo and nocebo effects may optimize the delivery of care for individuals with ASD in the future.
What this paper adds
Placebo responses are evident in autism spectrum disorder (ASD) clinical trials.
Placebo responses in ASD are likely dependent on a placebo‐by‐proxy mechanism.
What this paper adds
Placebo responses are evident in autism spectrum disorder (ASD) clinical trials.
Placebo responses in ASD are likely dependent on a placebo‐by‐proxy mechanism.
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