Bernard Dan

A report: the definition and classification of cerebral palsy April 2006.

For a variety of reasons, the definition and the clawification of cerebral palsy (CP) need to be reconsidered. Modern brain imaging techniques have shed new light on the nature of the underlying brain injury and studies on the neurobiology of and pathology associated with brain development have further explored etiologic mechanisms. It is now recognized that assessing the extent of activity restriction is part of CP evaluation and that people without activity restriction should not be included in the CP rubric. Also, previous definitions have not given sufficient prominence to the non‐motor neurodevelopmental disabilities of performance and behaviour that commonly accompany CP, nor to the progression of musculoskeletal difficulties that often occurs with advancing age. In order to explore this information, pertinent material was reviewed on July 11–13,2004 at an international workshop in Bethesda, MD (USA) organized by an Executive Committee and participated in by selected leaders in the preclinical and clinical sciences. At the workshop, it was agreed that the concept ‘cerebral palsy’ should be retained. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, health officials, families and the public and would provide a common language for improved communication. Panels organized by the Executive Committee used this information and additional comments from the international community to generate a report on the Definition and Classification of Cerebral Palsy, April 2006. The Executive Committee presents this report with the intent of providing a common conceptualization of CP for use by a broad international audience.

Proposed definition and classification of cerebral palsy, April 2005

Because of the availability of new knowledge about the neurobiology of developmental brain injury, information that epidemiology and modern brain imaging is providing, the availability of more precise measuring instruments of patient performance, and the increase in studies evaluating the efficacy of therapy for the consequences of injury, the need for reconsideration of the definition and classification of cerebral palsy (CP) has become evident. Pertinent material was reviewed at an international symposium participated in by selected leaders in the preclinical and clinical sciences. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, and health officials, and provide a common language for improved communication. With leadership and direction from an Executive Committee, panels utilized this information and have generated a revised Definition and Classification of Cerebral Palsy. The Executive Committee presents this revision and welcomes substantive comments about it.

Somatic mutations in cerebral cortical malformations.

BACKGROUND Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. METHODS Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. RESULTS Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. CONCLUSIONS Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).

Alcohol cues increase cognitive impulsivity in individuals with alcoholism

BackgroundIndividuals with alcoholism are characterized by both attentional bias for alcohol cues and prepotent response inhibition deficit. We tested the hypothesis that alcoholics exhibit greater cognitive disinhibition when the response to be suppressed is associated with alcohol-related information.MethodsForty recently detoxified individuals with alcoholism were compared with 40 healthy non-substance abusers on the “Alcohol-Shifting Task”, a variant of the go/no-go paradigm requiring a motor response to targets and no response to distracters. The aim was to test the ability of alcoholics to discriminate between alcohol-related and neutral words. Sometimes, the alcohol-related words were the targets for the “go” response, with neutral words as distracters, sometimes the reverse. Several shifts in target type occurred during the task.ResultsAlcoholics made significantly more commission errors (i.e., press a key when a distracter displayed) and more omission errors (i.e., not press a key when a target displayed) than controls. Moreover, the number of commission errors was greater in alcoholics when alcohol-related stimuli had to be detected.ConclusionsThese results demonstrate that alcoholics exhibit a basic prepotent response inhibition deficit, which is enhanced when the response to be suppressed is related to alcohol. We discuss clinical and theoretical implications of these findings.

Response inhibition deficit is involved in poor decision making under risk in nonamnesic individuals with alcoholism.

Individuals with alcoholism exhibit poor decision making as reflected by their continued alcohol use despite encountering problems and by low performance in laboratory tasks of decision making. Here, the authors investigated the relative contribution of several distinct processes of executive functions in performance on the Iowa Gambling Task (IGT; A. Bechara, A. R. Damasio, H. Damasio, & S. W. Anderson, 1994) in recently detoxified individuals with alcoholism. Compared to matched healthy participants, individuals with alcoholism showed below-normal scores in the last 20 trials of the IGT as well as on other tasks of executive functions, specifically those assessing the capacity to manipulate information stored in working memory, detect abstract rules, or inhibit prepotent responses. Prepotent response inhibition best predicted performance in the late trials of the IGT, that is, when participants have likely acquired knowledge about the reward/punishment contingencies of the task. These results underline the important role that response inhibition plays in decision making, especially in risky situations, when knowledge of the probability of a given outcome becomes available (i.e. decisions under risk).

Impaired emotional facial expression recognition in alcoholics, opiate dependence subjects, methadone maintained subjects and mixed alcohol-opiate antecedents subjects compared with normal controls.

The present study aims to explore whether an impairment in emotional facial expressions (EFE) decoding is specific to alcoholism compared with opiate dependence. An EFE decoding test consisting of 16 photographs of EFE portraying happiness, anger, sadness and disgust was administered to five different groups of 30 subjects each: recently detoxified alcoholics (RA); opiate addicts under methadone maintenance treatment (OM); detoxified opiate addicts (OA); detoxified subjects with both alcohol and opiate dependence antecedents (DAO); and normal controls (NC). Repeated measures analysis of variance using a multivariate approach was conducted on EFE decoding accuracy scores with group as the between-subjects factor. Accuracy scores were significantly lower in RA and DAO than in OM and OA, which had significantly lower scores than NC. Low accuracy scores in RA and DAO confirm previous results indicating that alcoholism is associated with impaired EFE recognition. Results in OM and OA indicate that opiate dependence is also associated with an impaired EFE decoding but less than in alcoholism. Alcohol and opiate chronic consumption could both exercise a deleterious effect on EFE-decoding brain function, alcohol having the most severe impact. Alternatively, EFE-decoding problems could be present before the development of alcohol and opiate dependence, with an additional effect of chronic alcohol consumption on EFE decoding. In this context, EFE-decoding impairment could reflect a more general emotional intelligence deficit in addicted populations.

Normal Sleep Architecture in Infants and Children

Because the collection of normative sleep data in the pediatric age group largely depends on technical issues, this article discusses various aspects of sleep recordings in infants and children. Polygraphic monitoring of sleep and waking behavior contributes to a better description of maturational stages in children, from the prenatal period to the end of adolescence. This article reviews the general characteristics of normal childrens sleep and the environmental factors that influence these maturational processes. The use of polygraphic recordings to identify neurological deficits and to predict behavioral and neurological outcome in infants and children, however, does not hold great promise. The importance of polysomnographic evaluation is admitted for some major clinical conditions, such as risks for abnormal breathing or narcoleptic attacks.

Impaired emotional facial expression recognition in alcoholism compared with obsessive-compulsive disorder and normal controls.

Emotional facial expression (EFE) decoding skills have been shown to be impaired in recovering alcoholics (RA). The aim of the present study is to replicate these results and to explore whether these abnormalities are specific to alcoholism using two control groups: non-patient controls (NC) and patients with obsessive-compulsive disorder (OC). Twenty-two alcoholic patients at the end of their detoxification process (RA) were compared to 22 OC and 22 NC matched for age, sex and education level. They were presented with 12 photographs of facial expressions portraying different emotions: happiness; anger; and fear. Each emotion was displayed with mild (30%) and moderate (70%) intensity levels. Each EFE was judged on 8 scales labeled happiness, sadness, fear, anger, disgust, surprise, shame and contempt. For each scale, subjects rated the estimated intensity level. RA were less accurate in EFE decoding than OC and NC, particularly for anger and happiness expressions. RA overestimated the emotional intensity for mild intensity level expressions compared with both OC and NC while no significant differences emerged for moderate intensity level expressions. Deficits in EFE decoding skills seem to be specific to RA when compared with OC. Comparison with other psychopathological groups is still needed. Possible consequences of EFE decoding deficits in RA include distorted interpersonal relationships.

Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects.

Pelizaeus–Merzbacher Disease is an X‐linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus–Merzbacher‐Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression. This observation underlines the interest of determining both free T3 and free T4 serum concentrations to screen for MCT8 mutations in young patients (<3 y) with a severe Pelizaeus–Merzbacher‐Like disease presentation or older severe mentally retarded male patients with “hypomyelinated” regions. Ann Neurol 2009;65:114–118

Inactivation of Calcium-Binding Protein Genes Induces 160 Hz Oscillations in the Cerebellar Cortex of Alert Mice

Oscillations in neuronal populations may either be imposed by intrinsically oscillating pacemakers neurons or emerge from specific attributes of a distributed network of connected neurons. Calretinin and calbindin are two calcium-binding proteins involved in the shaping of intraneuronal Ca2+ fluxes. However, although their physiological function has been studied extensively at the level of a single neuron, little is known about their role at the network level. Here we found that null mutations of genes encoding calretinin or calbindin induce 160 Hz local field potential oscillations in the cerebellar cortex of alert mice. These oscillations reached maximum amplitude just beneath the Purkinje cell bodies and are reinforced in the cerebellum of mice deficient in both calretinin and calbindin. Purkinje cells fired simple spikes phase locked to the oscillations and synchronized along the parallel fiber axis. The oscillations reversibly disappeared when gap junctions or either GABAA or NMDA receptors were blocked. Cutaneous stimulation of the whisker region transiently suppressed the oscillations. However, the intrinsic somatic excitability of Purkinje cells recorded in slice preparation was not significantly altered in mutant mice. Functionally, these results suggest that 160 Hz oscillation emerges from a network mechanism combining synchronization of Purkinje cell assemblies through parallel fiber excitation and the network of coupled interneurons of the molecular layer. These findings demonstrate that subtle genetically induced modifications of Ca2+ homeostasis in specific neuron types can alter the observed dynamics of the global network.