Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22.

CONTEXT: Occasionally, 2 or more major neurodegenerative diseases arise simultaneously. An understanding of the genetic bases of combined disorders, such as amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), will likely provide insight into mechanisms of these and related neurodegenerative diseases. OBJECTIVE: To identify loci that contain genes whose defects cause ALS. DESIGN: A genome-wide linkage analysis of 2 data sets from an ongoing study begun in the mid-1980s at 4 university research centers. SUBJECTS: An initial subset of 16 families (549 people) potentially informative for genetic analysis, in which 2 or more individuals were diagnosed as having ALS, identified from a Boston data set of 400 families and 4 families potentially informative (244 people) subsequently identified from a Chicago data set of more than 300 families to test a hypothesis based on findings from the Boston families. MAIN OUTCOME MEASURES: Linkage calculations assuming autosomal dominant inheritance with age-dependent penetrance (a parametric logarithm-of-odds [lod] score of 1.0 or greater required for further study of a potential locus); crossover analysis involving the ALS-FTD locus. RESULTS: In a set of families in which persons develop both ALS and FTD or either ALS or FTD alone, a genetic locus that is linked to ALS with FTD located between markers D9S301 and D9S167 was identified on human chromosome 9q21-q22. Families with ALS alone did not show linkage to this locus. Crossover analysis indicates this region covers approximately 17 cM. CONCLUSION: These data suggest that a defective gene located in the chromosome 9q21-q22 region may be linked to ALS with FTD. JAMA. 2000;284:1664-1669.

Use of integrated, general education, and community settings as primary contexts for skill instruction for students with severe, multiple disabilities.

Four students with severe, multiple disabilities learned to use four to five new skills at critical moments within age-appropriate activities. Instruction was provided only at moments critical to the continuation of the activities when natural cues and consequences delineated the need for the target behaviors. This method of intervention was combined with a more traditional package of antecedent prompt-fade procedures and, in a few instances, time delay. The purpose of the study was to analyze the effects of instruction given only at natural critical moments on the acquisition of basic sensory, motor, social, and communication behaviors. A multiple baseline design across skills within separate activities for four participants was employed. Fifteen of 17 skills were acquired to criterion. In addition, "learning to learn" effects occurred within each activity as instruction of new target behaviors was introduced. The outcomes are important for the participant population because they document the effect of integrated educational models for teaching the most basic skills. Discussion of the motivation provided by activity routines in general education and community settings, as well as interpretation of data when participants have the most severe disabilities, is presented.

Stimulus factors in the training of prepositional usage in three autistic children.

Language deficient, autistic children were trained to use the prepositions "in" and "on". Three subjects were exposed to conditions of training that differed in the method of employment of stimulus objects used to train prepositional usage. Two subjects were trained first with "ambiguous" stimuli, that is, the same stimulus objects were used for training both prepositions. The two subjects were then switched to a training condition with "non-ambiguous" stimulus objects, that is, objects used for training "in" were different than those used for training "on". The two subjects were then switched to the ambiguous stimulus condition and finally returned again to training with non-ambiguous stimuli (four conditions). A third subject began with training on non-ambiguous stimuli, was switched to an ambiguous condition and was then switched back to non-ambiguous stimuli (three conditions). The results for two of the three subjects indicated that accurate usage of the two prepositions was obtained only under training conditions with non-ambiguous stimuli. Results for the third subject suggested that initial training with non-ambiguous stimuli might enhance subsequent accurate responding with ambiguous stimuli.

Reinforcement and generalization of productive plural allomorphs in two retarded children.

Morphological dictates of English usage call for the unvoiced allomorph /-s/ to form the plural of singular nouns with unvoiced endings (e.g., cups). Conversely, the voiced allomorph /-z/ is required to form the plural of nouns with voiced endings (e.g., tree). The study sought to determine the extent to which differential reinforcement could control the acquisition of plural allomorphs in two retarded subjects. In Condition 1, one subject was trained with reinforcement procedures on a list of words calling for the /-s/ allomorph. She was then given unreinforced probe items to determine the extent of generalization to words calling for the /-z/ allomorph. In Condition 2, the procedures were reversed and this subject was trained on a /-z/ list and probed for generalization of /-z/ to words calling for /-s/. A second subject was exposed to the same conditions in the opposite order. The results for the two subjects lent unequivocal support for the hypothesis of generalized training effects. It was concluded that appropriate usage of the linguistic response class "plurals" is susceptible to generalized training effects of differential reinforcement.

Control of tantrum behavior by operant techniques during experimental verbal training.

A technique of controlling undesirable or disruptive behavior during an ongoing program of verbal training with a retardate is described. The technique required that the stimulus materials of the verbal training program be graded according to difficulty, i.e., in terms of the length and complexity of the stimulus materials. (This resulted in an initial grading of the stimulus materials into different levels of probability of reinforcement.) Changes by the experimenter from high-difficulty to low-difficulty stimuli for two trials contingent upon disruptive behavior increased the rate of that behavior; changes from low-difficulty to high-difficulty stimuli for two trials contingent upon disruptive behavior decreased its rate. Thus, contingent alternation of the stimulus materials of the ongoing training program controlled the frequency of undesirable behaviors within the experimental sessions. This technique may comprise an alternative to other procedures which require punishment or timeout from the ongoing program.

An experimental analysis of linguistic development: the productive use of the plural morpheme.

Operant conditioning procedures were used to establish a generative use of the plural morpheme in the speech of a severely retarded girl. During training trials, reinforcement was presented contingent upon correct imitation of singular and plural verbalizations by the experimenter, in response to objects presented to the subject singly and in pairs. A generative productive plural usage resulted, the girl correctly labeling new objects in the singular or plural without further direct training relevant to those objects. After establishing the singular/plural usage, the contingencies were reversed (reinforcement of plural responses to single objects, and vice-versa). This produced a corresponding reversal of response by the child. The original usage was then recovered by returning to the previous contingencies. A second experiment analyzed certain error responses occurring during the first experiment, and further probed the generative nature of the subject's plural usage. It was found that errors were somewhat more likely to occur in the pluralization of words ending in vowels than of words ending in consonants. Furthermore, several words whose plurals had been learned according to the reversed plural rule, when examined later during reinforcement of normal plural usage, were found then to exemplify the normal rule being reinforced, yet without direct training.