Importance of reward and prefrontal circuitry in hunger and satiety: Prader-Willi syndrome vs simple obesity.

BACKGROUND: The majority of research on obesity (OB) has focused primarily on clinical features (eating behavior, adiposity measures) or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions that are associated with appetite-regulatory hormones are also involved in the development and maintenance of OB. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic OB. Simple (non-PWS) OB represents an OB-control state. OBJECTIVE: This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (that is, hypothalamus, amygdala) and prefrontal regions associated with cognitive control (that is, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC) after eating. DESIGN AND PARTICIPANTS: A total of 14 individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC and DLPFC. RESULTS: Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in the hypothalamus and hippocampus in response to food (vs non-food) images pre-meal. Post meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared with OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control. CONCLUSION: In PWS, compared with OB per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple OB.

Obese children show hyperactivation to food pictures in brain networks linked to motivation, reward and cognitive control.

OBJECTIVE: To investigate the neural mechanisms of food motivation in children and adolescents, and examine brain activation differences between healthy weight (HW) and obese participants. SUBJECTS: Ten HW children (ages 11-16; BMI < 85%ile) and 10 obese children (ages 10-17; BMI >95%ile) matched for age, gender and years of education. MEASUREMENTS: Functional magnetic resonance imaging (fMRI) scans were conducted twice: when participants were hungry (pre-meal) and immediately after a standardized meal (post-meal). During the fMRI scans, the participants passively viewed blocked images of food, non-food (animals) and blurred baseline control. RESULTS: Both groups of children showed brain activation to food images in the limbic and paralimbic regions (PFC/OFC). The obese group showed significantly greater activation to food pictures in the PFC (pre-meal) and OFC (post-meal) than the HW group. In addition, the obese group showed less post-meal reduction of activation (vs pre-meal) in the PFC, limbic and the reward-processing regions, including the nucleus accumbens. CONCLUSION: Limbic and paralimbic activation in high food motivation states was noted in both groups of participants. However, obese children were hyper-responsive to food stimuli as compared with HW children. In addition, unlike HW children, brain activations in response to food stimuli in obese children failed to diminish significantly after eating. This study provides initial evidence that obesity, even among children, is associated with abnormalities in neural networks involved in food motivation, and that the origins of neural circuitry dysfunction associated with obesity may begin early in life.

Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome.

BACKGROUND: Differences in behavioral phenotypes between the two most common subtypes of Prader-Willi syndrome (PWS) (chromosome 15q deletions and maternal uniparental disomy 15 (UPD) indicate that distinct neural networks may be affected. Though both subtypes display hyperphagia, the deletion subgroup shows reduced behavioral inhibition around food, whereas those with UPD are generally more able to maintain cognitive control over food intake impulses. OBJECTIVE: To examine the neural basis of phenotypic differences to better understand relationships between genetic subtypes and behavioral outcomes. We predicted greater food motivation circuitry activity in the deletion subtype and greater activity in higher order cognitive regions in the UPD group, especially after eating. DESIGN AND PARTICIPANTS: Nine individuals with PWS due to UPD and nine individuals with PWS due to (type 2) deletion, matched for age, gender and body mass index, underwent functional magnetic resonance imaging (fMRI) while viewing food images during two food motivation states: one before (pre-meal) and one after (post-meal) eating a standardized 500 kcal meal. RESULTS: Both PWS subgroups showed greater activity in response to food pre- and post-meal compared with the healthy-weight group. Compared with UPD, the deletion subtype showed increased food motivation network activation both pre- and post-meal, especially in the medial prefrontal cortex (mPFC) and amygdala. In contrast, the UPD group showed greater activation than the deletion subtype post-meal in the dorsolateral prefrontal cortex (DLPFC) and parahippocampal gyrus (PHG). CONCLUSION: These preliminary findings are the first functional neuroimaging findings to support divergent neural mechanisms associated with behavioral phenotypes in genetic subtypes of PWS. Results are discussed within the framework of genetic mechanisms such as haploinsufficiency and gene dosage effects and their differential influence on deletion and UPD subtypes, respectively.

Measurement of problem behaviour during medication evaluations.

BACKGROUND: The focus of this review is on methods that are currently being used to evaluate the behavioural effects of medication for individuals with intellectual disabilities. First we describe what has been identified as the ideal criteria for conducting clinical trials and how these criteria may be adapted to do less controlled evaluations. The central theme is a review of the biological measures (e.g. labs, drug levels), behavioural rating scales and direct observation measures that are often used to evaluate medication effects. Issues related to how the side effects of medication can affect behaviour will also be discussed. CONCLUSION: The importance of encouraging communication and collaboration across all systems of care and the use of socially valid measures are discussed.

The relationship between compulsive behaviour and academic achievement across the three genetic subtypes of Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic syndrome associated with several physical, cognitive and behavioural characteristics. For many individuals with this syndrome, compulsive behaviour is often noted in both food and non-food situations. The focus of this paper is on the non-food-related compulsions in individuals with PWS and comparing differences across the three genetic subtypes of the syndrome. METHODS: Compulsive behaviours in 73 people with PWS were assessed using the Yale-Brown Obsessive Compulsive Scale and the Compulsive Behavior Checklist. Compulsive behaviour and its relation to IQ and academic achievement also were evaluated. Phenotypic differences were characterized for the three most common genetic subtypes of the disorder: 16 individuals with the long Type I (TI) 15q deletion, 26 individuals with the short Type II (TII) 15q deletion and 31 individuals with maternal disomy 15. RESULTS: There appeared to be important differences between the two deletion subtypes. Specifically, individuals with the TI deletion had more compulsions regarding personal cleanliness (i.e. excessive bathing/grooming), and their compulsions were more difficult to interrupt and interfered with social activities more than the other subtypes. Individuals with the TII deletion were more likely to have compulsions related to specific academic areas (i.e. rereading, erasing answers and counting objects or numbers). CONCLUSIONS: These findings may help clinicians and researchers identify possible intervention strategies and supports based on the behavioural phenotype associated with genetic subtype in individuals with PWS.

A measure of food seeking in individuals with Prader-Willi syndrome.

BACKGROUND: Individuals with Prader-Willi syndrome (PWS), a chromosome 15 genetic disorder, often have a significant preoccupation with food and problem behaviour related to food seeking is often prevalent. METHODS: In the present study, we compared how individuals with PWS responded on a survey regarding the acceptability of food in various locations that varied according to degree of appropriateness for human consumption (e.g. food on a plate, food in a garbage can). For a subgroup of participants, we observed how they actually responded when placed in a room with food items placed in the same locations depicted in the survey. In the first part of the study, three groups (25 typically developing individuals, 7 individuals with intellectual disability (ID), and 19 individuals with PWS) responded to a visual survey to determine the degree of acceptability of food items in various locations (e.g. on a table near a hairbrush, on the floor behind a toy box, in a trash can). In the second part of the study, these food items (popcorn, jelly beans) were placed in the 12 locations described above. Nine individuals diagnosed with PWS (deletion type) and three individuals with ID were given some break time in the room for 15 min. The amount of food consumed, the time spent food seeking, and time spent interacting with materials were measured. RESULTS: Results of the survey indicated that the PWS group differed significantly with regard to how they responded on the survey from the typically developing group, but did not differ significantly from the ID group. Results of the food seeking observations indicated that only three individuals with PWS ate a significant number of items. The three individuals did not differ from the rest of the group according to IQ or compulsivity score; however, they had significantly lower body mass index (BMI) scores and were younger than the other participants. CONCLUSIONS: The findings from the survey indicate that individuals with PWS are able to discriminate the appropriateness of eating items in more or less contaminated areas; however, the amount of time spent seeking food and the amount of food covertly consumed appeared to depend more directly on age and BMI.

Using the Diagnostic Assessment of the Severely Handicapped-II (DASH-II) to measure the therapeutic effects of risperidone.

BACKGROUND: Within the scope of a double-blind, placebo-controlled, crossover medication study, the Diagnostic Assessment of the Severely Handicapped-II (DASH-II) was evaluated as a measurement for determining the effectiveness of the medication risperidone in treating the problem behaviour of 21 people with intellectual disabilities (ID). METHOD: Participants' caregivers completed the DASH-II during the placebo/baseline phase of the study and the maintenance phase of the study, and completed the Aberrant Behavior Checklist - Community (ABC-C) weekly throughout the entire study. The results obtained using the DASH-II were compared to those obtained using the ABC-C, an instrument shown to be well correlated with the DASH-II. RESULTS: Results suggest that while the DASH-II and the ABC-C were well correlated during the placebo/baseline phase of the current study, they were not well correlated at completion of the 6-month maintenance phase of the medication trial. CONCLUSION: The DASH-II, while appropriate for assisting in the diagnosis of psychopathology in people with ID, does not appear to monitor changes in problem behaviour as a result of risperidone use as well as the ABC-C. Differences in the frequency of problem behaviour that each measure evaluated and the applicability of using the DASH-II to measure medication effects on problem behaviour are discussed.

Effects of risperidone on aberrant behavior of persons with developmental disabilities: I. A double-blind crossover study using multiple measures.

The efficacy of the atypical antipsychotic risperidone was evaluated in the treatment of aberrant behavior (e.g., aggression, self-injury) in 20 individuals with developmental disabilities. A double-blind, crossover design was used to compare risperidone with placebo in a 22-week trial with a 6-month follow-up phase. Based on a 50% reduction in mean Aberrant Behavior Checklist--Community total scores, 50% of the participants were identified as responders. Naturalistic observations of a subset of five individuals showed that for 4 out of 5 participants, risperidone was effective in reducing aberrant behavior. Side effects included weight gain (84% of participants) and sedation (40% of participants). The advantages of conducting a comprehensive analysis of the effects of medication on aberrant behavior are discussed.

Revictimization and information processing in women survivors of childhood sexual abuse.

This study examined the effect of sexual revictimization on information processing of trauma-related stimuli in a sample of child sexual abuse (CSA) survivors diagnosed with posttraumatic stress disorder (PTSD). Fifty-one treatment-seeking women participated in this study. Participants completed the Sexual Experiences Survey regarding sexual revictimization in the last 6 months and performed a modified emotional Stroop task in which they named the colors of neutral words (e.g., apple), general threat words (e.g., malignant and death), and sexual/victimization words (e.g., penis and abuser). As predicted, the revictimized participants (n = 16) took significantly longer to color-name sexual/victimization words than did the nonrevictimized participants. These results suggest that revictimization serves to prime preexisting "trauma" memory networks, thereby amplifying the impact of childhood sexual trauma on selective attention toward trauma-related stimuli.

Weight gain in a controlled study of risperidone in children, adolescents and adults with mental retardation and autism.

As part of an ongoing, prospective, ABA design, double-blind crossover study of risperidone versus placebo for the treatment of aggressive, destructive and self-injurious behavior in persons aged 6-65 years with mental retardation (MR) and autism, we measured the weight of 19 subjects at each study visit. We compared mean weight gain during the 16-week acute phase and 24-week open maintenance phase with that during the initial and middle placebo phases statistically, using a linear mixed model procedure. Results of the linear mixed model analysis showed that relative weight gain observed during the acute and maintenance drug phases was significantly greater than that observed during the initial and middle placebo phases respectively (p = .0001 and p = .0001). Over approximately a year, children aged 8-12 (n = 5) gained a mean of 8.2 kg (range = 2.7-17.7 kg); adolescents (n = 6) aged 13-16 gained a mean of 8.4 kg (range 3.6-15.5 kg); adults aged 21-51 (n = 8) gained a mean of 5.4 kg (range 0-9.5 kg). Weight gain observed in this controlled study of risperidone treatment in children, adolescents, and adults with MR and autism was significant. It may be greater in this population than in others reported and in this study was not limited to an acute effect only. Rate of weight gain diminished rapidly on tapering and stopping the drug. Further studies are urgently needed, including those incorporating diet and exercise programming.

Acute necrotizing torsion of the gallbladder.

Torsion of the gallbladder is an extremely rare cause of acute surgical abdomen. Although gallbladder torsion has been reported the diagnosis remains elusive and is often missed. A case of necrotizing gallbladder torsion is examined, and the literature is reviewed by the authors. History peak incidence and pathophysiology are discussed, and possible risk factors are identified. We conclude that torsion of the gallbladder is a condition that has minimal clinical findings.

A brief method for conducting a negative-reinforcement assessment.

A brief negative-reinforcement assessment was conducted with developmentally disabled children with severe destructive behavior. Five children were trained to engage in a simple escape response (e.g., a hand clap). Then each child was presented with a variety of stimuli or tasks that ranged on a scale from preferred to nonpreferred, based on parent ranking. The participant received a brief break from the stimuli or task, contingent on each escape response. For one child, an avoidance contingency was also implemented in which he could engage in the response to avoid the presentation of stimuli. Results showed that for each child, several stimuli were identified that may serve as effective negative reinforcers. Results also indicated that the procedure did not elicit any negative side effects for four children and low rates of destructive behavior for the fifth child. For one child, the results of the negative-reinforcement assessment were used to develop an effective treatment for destructive behavior. Additional applications of the reinforcement assessment to treatment interventions is discussed, as well as limitations to the procedure.

Functional analysis and treatment of destructive behavior maintained by termination of "don't" (and symmetrical "do") requests.

We used descriptive assessment information to generate hypotheses regarding the function of destructive behavior for 2 individuals who displayed near-zero rates of problem behavior during an experimental functional analysis using methods similar to Iwata, Dorsey, Slifer, Bauman, and Richman (1982/1994). The descriptive data suggested that destructive behavior occurred primarily when caregivers issued requests to the participants that interfered with ongoing high-probability (and presumably highly preferred) behaviors (i.e., a "don't" or a symmetrical "do" request). Subsequent experimental analyses showed that destructive behavior was maintained by contingent termination of "don't" and symmetrical "do" requests but not by termination of topographically similar "do" requests. These results suggested that destructive behavior may have been maintained by positive reinforcement (i.e., termination of the "don't" request allowed the individual to return to a highly preferred activity). Finally, a treatment (functional communication training plus extinction) developed on the basis of these analyses reduced destructive behavior to near-zero levels.

Analysis of free-time contingencies as positive versus negative reinforcement.

Providing a short break contingent on completed work may increase responding through positive reinforcement (e.g., access to preferred activities) or negative reinforcement (e.g., escape form work). In this investigation, three analyses conducted with a boy with profound mental retardation showed that (a) a 20-s break increased responding more than a positive reinforcer (cola) did, and (b) the reinforcing effect of a 20-s break were affected by the availability of positive reinforcers during the break were affected by the availability of positive reinforcers during the break.

Pyramidal staff training in the extension of treatment for severe behavior disorders.

We implemented a pyramidal training procedure for staff working with individuals who exhibited self-injurious behavior (SIB), aggression, and disruption. Two adults with developmental disabilities and their direct-care staff and supervisors participated. Following successful treatment by the experimenters, two types of baselines were conducted with the clients and their direct-care staff. During an initial baseline, the staff implemented preexisting procedures. Staff members then received instruction on the new treatment procedures using training methods common throughout the institution, and data were collected during this "post-in-service" baseline. Experimenters then taught unit supervisors to implement treatment, collect and interpret data, and provide similar instructions and feedback to the staff members. The supervisor training was implemented in a multiple baseline design across subjects (clients and direct-care staff). Results showed little change following in-service training but noticeable improvements in direct-care staff behaviors and corresponding decreases in the clients' inappropriate behavior following the pyramidal training intervention with supervisors. Six additional clients (along with their direct-care staff and supervisors) participated in pre- and posttreatment replication designs, and their results provided additional support for the efficacy of the supervisor training procedures.

A sequential, test-control methodology for conducting functional analyses of self-injurious behavior.

Multielement and reversal designs used to identify maintaining variables for behavior disorders such as self-injury have several potential limitations, including interaction effects (multielement), inefficiency (reversal), and lack of a continuous control (reversal). This article describes a methodology that minimizes these problems yet captures the best features of both designs. This design consists of several phases implemented in a sequential (A-B-C) fashion, as in the reversal design. However, each phase consists of two conditions, a test and a control, presented concurrently in a multielement format. Five subjects' self-injury was assessed using both the multielement design and the sequential, test-control (or pairwise) design. Results for two subjects indicated that the multielement design produced clear assessment outcomes, and similar findings were obtained using the pairwise design. For two other subjects, the multielement assessments were somewhat undifferentiated, and clearer results were obtained using the pairwise design. The fifth subject's self-injury showed cyclical patterns using both assessment techniques. Benefits and limitations of the sequential assessment methodology are discussed.

Momentum and extinction effects on self-injurious escape behavior and noncompliance.

Previous research on applications of behavioral momentum has indicated that a high-probability (high-p) instructional sequence, in which a series of instructions for which there is a high probability of compliance is presented immediately before an instruction for which there is a low probability of compliance, is an effective method for increasing compliance. It is not clear, however, whether the procedure is effective when individuals actively attempt to escape from the instructional situation. In this study, we examined the effects of the high-p sequence, when implemented first alone and then later with an extinction component, as treatment for the self-injurious escape behavior of 2 individuals. Results showed that when the instructional sequence was implemented without extinction, rates of self-injury increased and percentage of compliance decreased. In addition, the percentage of trials occasioning escape behavior increased for both high- and low-probability instructions. When an extinction component was added to the high-p sequence, rates of self-injury and the percentage of trials containing self-injury decreased, and compliance increased. These findings suggest that extinction may be an important component of treatment when escape behavior such as self-injury accompanies noncompliance in instructional contexts and competes with compliant behavior.

Assessment of stereotypic and self-injurious behavior as adjunctive responses.

Certain responses of both humans and nonhumans appear to be maintained indirectly by intermittent reinforcement schedules and have been referred to collectively as adjunctive behavior. Although basic research has examined adjunctive behavior extensively, relatively few studies have been conducted with humans, particularly those with developmental disabilities who often engage in frequent and varied stereotypic behavior. This study assessed possible adjunctive characteristics of self-injurious and stereotypic behaviors using a multielement design containing two types of control conditions. Four subjects who engaged in both self-injurious behavior and stereotypy participated after variables maintaining their self-injury were identified via functional analyses. Each day, subjects were exposed to three 15-min sessions in random order: (a) noncontingent presentation of food on a fixed-time schedule (e.g., FT 30 s), (b) a massed-reinforcement (food) control, and (c) a no-reinforcement control. A variety of fixed-time schedules were examined during different experimental phases. Results of this preliminary study suggested that self-injury was not induced by intermittent reinforcement schedules, whereas the stereotypic behavior of some individuals showed characteristics of adjunctive behavior. The importance of research on adjunctive behavior and suggestions for future studies are discussed.

The functions of self-injurious behavior: an experimental-epidemiological analysis.

Data are summarized from 152 single-subject analyses of the reinforcing functions of self-injurious behavior (SIB). Individuals with developmental disabilities referred for assessment and/or treatment over an 11-year period were exposed to a series of conditions in which the effects of antecedent and consequent events on SIB were examined systematically by way of multielement, reversal, or combined designs. Data were collected during approximately 4,000 experimental sessions (1,000 hr), with the length of assessment for individuals ranging from 8 to 66 sessions (M = 26.2) conducted over 2 to 16.5 hr (M = 6.5). Differential or uniformly high responding was observed in 145 (95.4%) of the cases. Social-negative reinforcement (escape from task demands or other sources of aversive stimulation) accounted for 58 cases, which was the largest proportion of the sample (38.1%). Social-positive reinforcement (either attention or access to food or materials) accounted for 40 (26.3%) of the cases, automatic (sensory) reinforcement accounted for 39 (25.7%), and multiple controlling variables accounted for 8 (5.3%). Seven sets of data (4.6%) showed either cyclical or inconsistent patterns of responding that were uninterpretable. Overall results indicated that functional analysis methodologies are extremely effective in identifying the environmental determinants of SIB on an individual basis and, subsequently, in guiding the process of treatment selection. Furthermore, an accumulation of assessment data from such analyses across a large number of individuals provides perhaps the most rigorous approach to an epidemiological study of behavioral function.

Reemergence and extinction of self-injurious escape behavior during stimulus (instructional) fading.

Based on results of a functional analysis indicating that the self-injurious behavior (SIB) of 3 individuals was maintained by negative reinforcement (escape from instructional situations), the effects of stimulus (instructional) fading were evaluated in a multiple baseline design across subjects. The rate of instructions was reduced to zero at the beginning of treatment and was gradually increased (faded in) across sessions as long as SIB remained low. However, if SIB remained high for 10 consecutive sessions, extinction was implemented until SIB decreased, at which point extinction was withdrawn and fading was resumed. Treatment was completed when the rate of instructions was the same as in baseline (two per minute), and SIB remained below 0.5 responses per minute for two consecutive sessions. Results showed that instructional fading (without extinction) virtually eliminated SIB initially, but these effects were not maintained. All 3 subjects required multiple exposures to extinction and over 150 treatment sessions in order to meet the end-of-treatment criteria. Advantages and limitations of fading procedures without an extinction component, as well as extensions of both interventions to other clinical problems, are discussed.