In a sentence reading task, words that occurred out of context were associated with specific types of event-related brain potentials. Words that were physically aberrant (larger than normal) elecited a late positive series of potentials, whereas semantically inappropriate words elicited a late negative wave (N400). The N400 wave may be an electrophysiological sign of the "reprocessing" of semantically anomalous information.

https://science.sciencemag.org/content/sci/207/4427/203.full.pdf

Reading senseless sentences: brain potentials reflect semantic incongruity

To understand the endogenous components of the event-related brain potential (ERP), we must use data about the components' antecedent conditions to form hypotheses about the information-processing function of the underlying brain activity These hypotheses, in turn, generate testable predictions about the consequences of the component We review the application of this approach to the analysis of the P300 component The amplitude of the P300 is controlled multiplicatively by the subjective probability and the task relevance of the eliciting events, whereas its latency depends on the duration of stimulus evaluation These and other factors suggest that the P300 is a manifestation of activity occurring whenever one's model of the environment must be revised Tests of three predictions based on this “context updating” model are reviewed Verleger's critique is based on a misconstrual of the model as well as a partial and misleading reading of the relevant literature

Is the P300 component a manifestation of context updating

This paper reviews the literature on the Nl wave of the human auditory evoked potential. It concludes that at least six different cerebral processes can contribute to (he negative wave recorded from the scalp with a peak latency between 50 and 150 ms: a component generated in the auditory-cortex on the supratemporal plane, a component generated in the association cortex on the lateral aspect of the temporal and parietal cortex, a component generated in the motor and premotor cortices, the mismatch negativity, a temporal component of the processing negativity, and a frontal component of the processing negativity, The first three, which can be considered ‘true’ N1 components, are controlled by the physical and temporal aspects of the stimulus and by the general state of the subject. The other three components are not necessarily elicited by a stimulus but depend on the conditions in which the stimulus occurs. They often last much longer than the true N1 components that they overlap.

The N1 wave of the human electric and magnetic response to sound: a review and an analysis of the component structure

Anatomical, physiological and functional neuroimaging studies suggest that the cerebellum participates in the organization of higher order function, but there are very few descriptions of clinically relevant cases that address this possibility. We performed neurological examinations, bedside mental state tests, neuropsychological studies and anatomical neuroimaging on 20 patients with diseases confined to the cerebellum, and evaluated the nature and severity of the changes in neurological and mental function. Behavioural changes were clinically prominent in patients with lesions involving the posterior lobe of the cerebellum and the vermis, and in some cases they were the most noticeable aspects of the presentation. These changes were characterized by: impairment of executive functions such as planning, set-shifting, verbal fluency, abstract reasoning and working memory; difficulties with spatial cognition including visual-spatial organization and memory; personality change with blunting of affect or disinhibited and inappropriate behaviour; and language deficits including agrammatism and dysprosodia. Lesions of the anterior lobe of the cerebellum produced only minor changes in executive and visual-spatial functions. We have called this newly defined clinical entity the 'cerebellar cognitive affective syndrome'. The constellation of deficits is suggestive of disruption of the cerebellar modulation of neural circuits that link prefrontal, posterior parietal, superior temporal and limbic cortices with the cerebellum.

/pdf/the-cerebellar-cognitive-affective-syndrome-2qlts0j1w1.pdf

The cerebellar cognitive affective syndrome.

Autism is a severe neurobehavioral syndrome, arising largely as an inherited disorder, which can arise from several diseases. Despite recent advances in identifying some genes that can cause autism, its underlying neurological mechanisms are uncertain. Autism is best conceptualized by considering the neural systems that may be defective in autistic individuals. Recent advances in understanding neural systems that process sensory information, various types of memories and social and emotional behaviors are reviewed and compared with known abnormalities in autism. Then, specific genetic abnormalities that are linked with autism are examined. Synthesis of this information leads to a model that postulates that some forms of autism are caused by an increased ratio of excitation/inhibition in sensory, mnemonic, social and emotional systems. The model further postulates that the increased ratio of excitation/inhibition can be caused by combinatorial effects of genetic and environmental variables that impinge upon a given neural system. Furthermore, the model suggests potential therapeutic interventions.

https://onlinelibrary.wiley.com/doi/epdf/10.1034/j.1601-183X.2003.00037.x

Model of autism: increased ratio of excitation/inhibition in key neural systems

Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for 1 affected family member; 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.

The Genetics of Autism

The cerebro-hepato-renal syndrome is a rare familial malady with cerebral, renal, and skeletal abnormalities, severe hypotonia, cirrhosis, iron and lipid storage, and death within 6 months. Correlated electron microscopic, histochemical, and biochemical studies demonstrate defects in two oxidative organelles. Peroxisomes cannot be found in hepatocytes and renal proximal tubules. In hepatocytes and cortical astrocytes, mitochondria are distorted in their appearance and glycogen stores are increased. Oxygen consumnption of brain and liver mitochondrial preparations with succinate and with substrates reducing nicotinamide adenine dinucleotide is markedly diminished, but the consumption is normal with ascorbate and tetramethylphenylenediamine, which suggests a defect in electron transport prior to the cytochromes. Histochemical studies of mitochondrial oxidation point to a defect between the succinate dehydrogenase flavoprotein and coenzyme Q, possibly in the region of nonheme iron protein.

https://science.sciencemag.org/content/sci/182/4107/62.full.pdf

Peroxisomal and Mitochondrial Defects in the Cerebro-Hepato-Renal Syndrome

Summary There is an increased but variable risk of epilepsy in autism. Three main factors—age, cognitive level, and type of language disorder—account for variability in the reported prevalence of epilepsy. The prevalence is highest in studies that have included adolescents and young adults, individuals with moderate to severe mental retardation and those with motor deficits, and individuals with severe receptive language deficits. The association of autism with clinical or subclinical epilepsy might denote common genetic factors in some cases. Whether subclinical epilepsy has adverse effects on cognition, language, and behaviour is debated, as is the relation of autistic regression with an epileptiform electroencephalogram to Landau-Kleffner syndrome. There is no evidence-based treatment recommendation for individuals with autism, regression, and subclinical epilepsy. Double-blind studies with sufficient power to resolve this issue are urgently needed.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(02)00160-6.pdf

Epilepsy in autism

Background. Approximately one third of the parents of children with pervasive developmental disorders or autistic spectrum disorders reports an early regression of unknown cause in their children9s language, sociability, and play. Seizures or an epileptiform electroencephalogram (EEG) are associated with language regression in acquired epileptic aphasia (Landau–Kleffner syndrome) and some other pediatric epileptic syndromes. The importance of epilepsy or epileptic EEGs as contributors to autistic regression is not known. Method. Subjects were 482 boys and 103 girls on the autistic spectrum seen consecutively in consultation by one child neurologist. Data on autistic regression, seizures, sleep EEGs, and cognitive function were entered prospectively into a data base. Results. Of the 585 children, 176 (30%) had a history of regression, and 66 children (11%) had a history of epilepsy, defined as two or more unprovoked seizures. Among 392 children with available sleep EEGs, the EEG was epileptiform in 59% of the 66 epileptic children and 8% of the 335 nonepileptic children. Regression had occurred equally among children without seizures and in those with epilepsy. Regression was associated with an epileptiform EEG in 14% of 155 nonepileptic children who had undergone a regression, as opposed to 6% of 364 children with neither regression nor epilepsy. Mean age at regression was 21 months. There was no difference in the proportion of children with epilepsy or epileptiform EEGs who had regressed before or after 2 years of age. Approximately half of the epileptiform discharges were centrotemporal, whether or not the child was epileptic or had regressed. Children with lower cognitive function were more likely to have undergone regression than those with better cognitive skills (34% vs 20%). Conclusion. Epilepsy or epileptiform EEGs occur in a significant minority of autistic children with a history of regression and in a smaller minority without regression. Prompt recognition of regression and recording of prolonged sleep EEGs is recommended, even though information on the potential efficacy of antiepileptic treatment to improve language and behavior in autistic children with epilepsy or an epileptiform EEG is still lacking.

Regression in Pervasive Developmental Disorders: Seizures and Epileptiform Electroencephalogram Correlates

UMMARY
In an attempt to delineate causal factors in dyslexia, 113 children and young adults (age-range eight to 18 years) were divided into three groups: those with brain damage who could read (n = 31), those with brain damage who were dyslexic (n = 53), and those without brain damage who were dyslexic (n = 29). A battery of neuropsychological tests was presented to each participant.

No significant differences were found between the two dyslexic groups. Three syndromes -language disorder, articulation and graphomotor dysco-ordination, and visuo-perceptual disorder—were found among the great majority of those with dyslexia. The results support a model of dyslexia as being caused by multiple independent defects in higher cortical functioning, as opposed to the theory of a single causal defect. A clinical description of each syndrome is given and models of dyslexia are discussed. The authors stress the desirability of including brain-damaged readers as a control group in any future study on causal factors in dyslexia.

RESUME
Dyslexie chez les enfants et les adolescents: trois syndromes neuropsychologiques independants

Dans le but de determiner les facteurs en cause dans la dyslexie, 113 enfants et adolescents (ages de 8 a 18 ans) ont ete divises en trois groupes: ceux qui pouvaient lire malgre une lesion cerebrale (n = 31), ceux qui presentaient une lesion cerebrale et une dyslexie (n = 53) et ceux qui sans lesion cerebrale avaient une dyslexie (n 29). Une batterie de tests neuropsychologiques ont ete proposes a chaque sujet.

Aucune difference significative n'a ete trouvee entre les deux groupes dyslexiques. Trois syndromes: troubles du langage, incoordination de l'articulation et de la graphomotricite, et troubles visuo-perceptif ont ete notes chez la grande majorite des dyslexiques. Ces resultats sont en faveur d'une conception de la dyslexie causee par de multiples facteurs independants dans le fonctionnement cortical haut et non d'une conception d'une cause unique. Une description clinique de chaque syndrome est donnee et des modeles de dyslexie sont discutes. Les auteurs insistent sur la necessite d'inclure des lecteurs atteints de troubles cerebraux comme groupe controle dans toute etude ulterieure sur les facteurs en cause dans la dyslexie.

ZUSAMMENFASSUNG
Leseschwache bei Kindern und Heraimachsenden: drei unabhangige neuropsychologische Syndrome

Um die Kausalfaktoren der Dyslexie zu beschreiben, wurden 113 Kinder und Heran-wachsende (Alter 8–18 Jahre) in der Untersuchung in drei Gruppen geteilt: solche mit Hirnschaden, die aber lesen konnten (n = 31), solche mit Hirnschaden und Dyslexie (n = 53) und solche ohne Hirnschaden mit Dyslexie (n = 29). Jeder Versuchsteilnehmer wurde einer Reihe neuropsychologischer Tests unterzogen.

Zwischen den leseschwachen Gruppen fand sich keine signifikante Differenz. Bei der grosen Mehrheit derer mit Dyslexie fanden sich drei Symtome—Sprachstorungen, Artikulations- und graphomotorische Dyskoordination und visuell-perzeptive Storungen. Die Ergebnisse unterstutzen eine Modellvorstellung der Dyslexie, die sie durch multiple voneinander unabhangige Defekte hoherer corticaler Funktionen verursacht ansieht, im Gegensatz zu der Theorie eines einzelnen kausalen Defekts. Es wird eine klinische Beschreibung eines jeden Syndroms gegeben und Modelle der Dyslexie werden diskutiert. Die Autoren betonen, das es wunschenswert ist bei jeder weiteren Studie uber Kausalfaktoren der Dyslexie Hirngeschadigte, die lesen konnen, als eine Kontrollgruppe mit einzubeziehen.

RESUMEN
Dislexia en ninos y jovenes adultos: Tres sindromes neuropsicologicos independientes

En un intento de delinear los factores causales en la dislexia, 113 ninos y adultos jovenes (de edad entre 8 y 18 anos) fueron divididos en tres grupos: Unos con lesion cerebral y que podian leer (n = 31), otros con lesion cerebral pero que eran dislexicos (n = 53) y otros sin lesion cerebral y que eran dislexicos (n = 29). A cada participante se le presento una bateria de tests neuropsicologicos.

No se hallo ninguna diferencia significativa entre los dos grupos dislexicos. Tres sindromes (alteracion en el lenguaje, discoordinacion de la articulacion y grafomotora y alteracion visuo-perceptiva) fueron hallados en la gran mayoria de los que padecian dislexia. Los resultados apoyan la idea de que la dislexia esta causada por multiples defectos independientes de las funciones corticales superiores, en oposicion a la teoria de un unico defecto causal. Se da una descripcion clinica de cada sindrome y se discuten los modelos de dislexia. Los autores subrayan el deseo de incluir a los lectores con lesion cerebral como un grupo control en estudios futuros que se hagan sobre los factores causales de la dislexia.

Isabelle Rapin

Papers

The Genetics of Autism

Peroxisomal and Mitochondrial Defects in the Cerebro-Hepato-Renal Syndrome

Epilepsy in autism

Regression in Pervasive Developmental Disorders: Seizures and Epileptiform Electroencephalogram Correlates

Dyslexia in Children and Young Adults: Three Independent Neuropsychological Syndromes