Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=-0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on kappa receptor selectivity and potency.

Tyrosine1 and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at kappa receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [D-Ala3]Dyn A(1-11)-NH2 (2) and [Ala3]Dyn A(1-11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central kappa opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1-11)-NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for kappa vs mu and kappa vs delta receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1-11)-NH2 as well as the conformational changes they induce in the message sequence of dynorphin have important effects on potency and selectivity for kappa opioid receptors. To further investigate structure-activity relationships involving the residue at the 3 position of Dyn A(1-11)-NH2, a series of Dyn A analogues with aromatic, charged, and aliphatic side chain substitutions at the 3 position was designed, synthesized, and evaluated for their affinities for kappa, mu, and delta opioid receptors. It was found that analogues with lipophilic amino acids at the 3 position of Dyn A(1-11)-NH2 generally displayed higher affinity but similar selectivities for the kappa receptor than analogues with charged residues at the same position. It is suggested that the structural, configurational, and steric/lipophilic effects of amino acids at position 3 of Dyn A(1-11)-NH2 may play an important role in potency and selectivity for the kappa receptor.

Human absorption of crude coal tar products.

Five normal adult volunteers without cutaneous disease applied 2% crude coal tar to the skin for eight-hour periods on two consecutive days. Blood extracts subjected to gas chromatography and mass spectrometry yielded evidence of absorption in all five volunteers. Phenanthrene, anthracene, pyrene, and fluoranthene, found in four of our volunteers, have been shown to be tumor initiators or cocarcinogens.

The effects of d-amphetamine and diazepam on schedule-induced defecation in rats.

The effects of d-amphetamine (0.32 to 5.6 mg/kg) and diazepam (0.10 to 5.6 mg/kg) on defecation were examined in two groups of rats. One group was exposed to a fixed-time 60-s (FT 60-s) schedule of food delivery and the other group was exposed to massed-food sessions. During vehicle control sessions, rats exposed to the FT 60-s schedule excreted a significantly higher number of fecal boli than rats exposed to massed-food sessions. d-Amphetamine, at doses above 0.56 mg/kg, significantly reduced defecation (boli produced) in both groups, although the magnitude of the drug's effect was larger in the group exposed to the FT 60-s schedule. For both groups, diazepam only produced a significant decrease in defecation at the highest dose (5.6 mg/kg). These results appear to be inconsistent with interpretations of adjunctive behavior that emphasize arousal or emotion as mechanisms.

Trace analysis of 2,6-disubstituted anilines in blood by capillary gas chromatography.

A simple, rapid, and sensitive procedure for the detection of 2,6-disubstituted anilines in the low nanogram range in blood is described. These aromatic amines were extracted from blood and converted to the corresponding N-hepta-fluorobutyramides, which were confirmed by gas chromatography/mass spectrometry (GC/MS). The derivatives yielded excellent electron capture detection (ECD) responses that allowed the identification and detection of these compounds at the low nanogram level by glass capillary GC/ECD. The procedure, which was tested in an in vivo system, is suitable for pharmacokinetic studies and toxicological investigations, and may be adapted for the quantitative determination of other substituted anilines and similar compounds in blood and other body fluids.

Determination of trace levels of hexachlorocyclopentadiene and octachlorocyclopentene in body fluids.

A simple, rapid and sensitive method for the analysis of hexachlorocyclopentadiene (C5-Cl6) and octachlorocyclopentene (C5-Cl8) in blood and urine is described. The procedure requires 5.0 mL of blood or urine, and involves the isolation of the compounds from the sample by liquid-liquid extraction, followed by screening and quantification via glass-capillary column gas chromatography with electron-capture detection and confirmation by gas chromatography-mass spectrometry. The assays are suitable for the detection and identification of nanogram quantities of these compounds in body fluids with a lower detection limit of 50 ng/mL for blood and 10 ng/mL for urine.

Noncontingent reinforcement: effects of satiation versus choice responding.

Recent research findings suggest that the initial reductive effects of noncontingent reinforcement (NCR) schedules on destructive behavior result from the establishing effects of an antecedent stimulus (i.e., the availability of "free" reinforcement) rather than extinction. A number of authors have suggested that these antecedent effects result primarily from reinforcer satiation, but an alternative hypothesis is that the individual attempts to access contingent reinforcement primarily when noncontingent reinforcement is unavailable, but chooses not to access contingent reinforcement when noncontingent reinforcement is available. If the satiation hypothesis is more accurate, then the reductive effects of NCR should increase over the course of a session, especially for denser schedules of NCR, and should occur during both NCR delivery and the NCR inter-reinforcement interval (NCR IRI). If the choice hypothesis is more accurate, then the reductive effects of NCR should be relatively constant over the course of a session for both denser and leaner schedules of NCR and should occur almost exclusively during the NCR interval (rather than the NCR IRI). To evaluate these hypotheses, we examined within-session trends of destructive behavior with denser and leaner schedules of NCR (without extinction), and also measured responding in the NCR interval separate from responding in the NCR IRI. Reductions in destructive behavior were mostly due to the participants choosing not to access contingent reinforcement when NCR was being delivered and only minimally due to reinforcer satiation.

Evaluation of a multiple-stimulus presentation format for assessing reinforcer preferences.

We compared three methods for presenting stimuli during reinforcer-preference assessments: a paired-stimulus format (PS), a multiple-stimulus format in which selections were made with replacement (MSW), and a multiple-stimulus format in which selections were made without replacement (MSWO). Results obtained for 7 participants showed moderate to high rank-order correlations between the MSWO and PS procedures and a similar number of identified reinforcers. In addition, the time to administer the MSWO procedure was comparable to that required for the MSW method and less than half that required to administer the PS procedure. Subsequent tests of reinforcement effects revealed that some stimuli selected in the PS and MSWO procedures, but not selected in the MSW procedure, functioned as reinforcers for arbitrary responses. These preliminary results suggest that the multiple-stimulus procedure without replacement may share the respective advantages of the other methods.

Competition between noncontingent and contingent reinforcement schedules during response acquisition.

We examined the extent to which noncontingent reinforcement (NCR), when used as treatment to reduce problem behavior, might interfere with differential reinforcement contingencies designed to strengthen alternative behavior. After conducting a functional analysis to identify the reinforcers maintaining 2 participants' self-injurious behavior (SIB), we delivered those reinforcers under dense NCR schedules. We delivered the same reinforcers concurrently under differential-reinforcement-of-alternative-behavior (DRA) contingencies in an attempt to strengthen replacement behaviors (mands). Results showed that the NCR plus DRA intervention was associated with a decrease in SIB but little or no increase in appropriate mands. In a subsequent phase, when the NCR schedule was thinned while the DRA schedule remained unchanged, SIB remained low and mands increased. These results suggest that dense NCR schedules may alter establishing operations that result in not only suppression of problem behavior but also interference with the acquisition of appropriate behavior. Thus, the strengthening of socially appropriate behaviors as replacements for problem behavior during NCR interventions might best be achieved if the NCR schedule is first thinned.

Evaluation of the "control over reinforcement" component in functional communication training.

The effectiveness of functional communication training (FCT) as a treatment for behavior disorders has been attributed to a number of variables, one of which is the individual's ability to exert control over the delivery of reinforcement. We evaluated this component of FCT by exposing individuals to conditions in which their behavior either did or did not affect the delivery of reinforcement. Three adults with mental retardation who engaged in self-injurious behavior (SIB) participated. Following a functional analysis of their SIB, the effects of FCT were compared to those of noncontingent reinforcement (NCR) in a multielement design. The amount of reinforcement during both conditions was equated by yoking the schedule of reinforcement during NCR sessions to that in effect during FCT sessions. Results indicated that FCT and NCR were equally effective in reducing the SIB of all participants and suggest that control over reinforcement delivery may not affect the degree to which FCT produces behavioral suppression. However, a different benefit of FCT was evident in the results: More consistent increases in the alternative response were observed during the FCT condition than during the NCR condition.

Displacement of leisure reinforcers by food during preference assessments.

Identification of reinforcers for individuals with developmental disabilities is often based on the outcome of preference assessments in which participants make selections from among a variety of items. We determined the extent to which individuals might show a general preference for food items over leisure items during such assessments and whether leisure items that are "displaced" by food items might nevertheless function as reinforcers. Arrays consisting of food items only and then nonfood items only were presented separately to 14 participants and then were ranked to determined preference. The top selections from these initial assessments were subsequently combined in a third assessment, and preferences were again established. All but 2 participants showed a general preference for food items, such that selection of nonfood items in the combined arrays was displaced downward relative to selection of nonfood in the nonfood-only arrays. Two of the participants were exposed to a condition in which a nonfood item was delivered contingent on the occurrence of an adaptive response, and increased rates of responding by both individuals were observed. Results are discussed in terms of limitations posed by using only food items as reinforcers and the resulting need to take precautionary measures when attempting to identify nonfood reinforcers.

Decreasing signs of negative affect and correlated self-injury in an individual with mental retardation and mood disturbances.

We evaluated the effects of an enriched environment, based on a paired-choice preference assessment, on both rates of self-injurious behavior (SIB) and percentage of session intervals during which signs of negative affect were displayed by a woman with mental retardation and a mood disorder. Results suggested that SIB and signs of negative affect were highly correlated and that the enriched environment effectively reduced both.

Examination of ambiguous stimulus preferences with duration-based measures.

Items that produced ambiguous results in an approach-based preference assessment were reassessed using a duration-based assessment. The reinforcing effects of three items on free-operant responding were subsequently tested. The results suggested that the duration-based assessment produced slightly more differentiated results and that predictions about reinforcer value, based on this assessment, were accurate.

DRO contingencies: an analysis of variable-momentary schedules.

We conducted several comparative analyses to determine the relative effectiveness of variable-momentary differential-reinforcement-of-other-behavior (VM DRO) schedules. Three individuals who had been diagnosed with mental retardation participated. Results of functional analyses indicated that their self-injurious behavior (SIB) was maintained by social-positive reinforcement. Two individuals participated in a two-stage comparative analysis within multielement and multiple baseline designs. Fixed-interval (FI) and variable-interval (VI) DRO were compared in the first stage; VI DRO and VM DRO were compared in the second. All three schedules effectively reduced the participants' SIB. Treatment for the 3rd individual was conducted in a reversal design to examine the effects of VM DRO when it was implemented in isolation, and results indicated that the procedure was effective in reducing SIB. These findings suggest that VM DRO schedules may represent attractive alternatives to traditional FI schedules because momentary schedules do not require continuous monitoring and may result in higher rates of reinforcement.

A comparison of procedures for programming noncontingent reinforcement schedules.

We compared two methods for programming and thinning noncontingent reinforcement (NCR) schedules during the treatment of self-injurious behavior (SIB). The participants were 3 individuals who had been diagnosed with mental retardation. Results of functional analyses indicated that all participants' SIB was maintained by positive reinforcement (i.e., access to attention or food). Following baseline, the effects of two NCR schedule-thinning procedures were compared in multielement designs. One schedule (fixed increment) was initially set at fixed-time 10-s reinforcer deliveries and was also thinned according to fixed-time intervals. The other schedule (adjusting IRT) was initially determined by participants' baseline interresponse times (IRTs) for SIB and was thinned based on IRTs observed during subsequent treatment sessions. Results indicated that both schedules were effective in initially reducing SIB and in maintaining response suppression as the schedules were thinned.

Effects of noncontingent reinforcement on problem behavior and stimulus engagement: the role of satiation, extinction, and alternative reinforcement.

This study examined the effects of noncontingent reinforcement (NCR) with and without extinction on problem behavior and stimulus engagement (consumption of reinforcement) of 4 participants. Reductions in problem behavior using NCR have frequently been attributed to both satiation of the reinforcer and extinction. In the current study, aspects of the NCR treatment effects were difficult to explain based solely on either a satiation or an extinction account. Specifically, it was found that stimulus engagement remained high throughout the NCR treatment analysis, and that problem behavior was reduced to near-zero levels during NCR without extinction. The implications of these findings are discussed with respect to the satiation and extinction hypotheses frequently described in the applied literature. Findings from basic studies examining the effects of response-independent schedules are presented, and are used as the basis for a matching theory account of NCR-related effects. It is proposed that reductions in problem behavior observed during NCR interventions may be a function of the availability of alternative sources of reinforcement.

Treatment of covert food stealing in an individual with Prader-Willi syndrome.

Covert food stealing is common among individuals with Prader-Willi syndrome. We found that verbal reprimands, delivered contingent upon eating prohibited foods, were sufficient to decrease the food stealing of a girl with Prader-Willi syndrome. Warning stimuli were then used to help her discriminate between permitted and prohibited foods during sessions in which food stealing was not directly observed. This procedure resulted in decreases in food stealing from containers labeled with the warning stimuli.

The effects of noncontingent access to single- versus multiple-stimulus sets on self-injurious behavior.

The automatically reinforced self-injury of a girl with autism was treated by providing noncontingent access to a single set of preferred toys during 30-min sessions. The reductive effects of the intervention waned as the session progressed. Rotating toy sets after 10 min or providing access to multiple toy sets resulted in reductions that lasted the entire 30 min.

Examination of relative reinforcement effects of stimuli identified through pretreatment and daily brief preference assessments.

Several brief preference assessments have recently been developed to identify reinforcers for individuals with developmental disabilities. One purported advantage of brief assessments is that they can be administered frequently, thus accommodating shifts in preference and presumably enhancing reinforcement effects. In this study, we initially conducted lengthy paired-choice preference assessments and identified a hierarchy of preferred items for 5 individuals with developmental disabilities. Subsequently, brief multiple-stimulus-without-replacement assessments using the same items were completed each day prior to work sessions. On days when results of the daily brief assessment differed from the one-time lengthy assessment, the relative reinforcing effects of the top items from each assessment were compared in a concurrent-schedule arrangement. The results revealed that when the two assessments differed, participants generally allocated more responses to the task associated with the daily top-ranked item.

Choices between positive and negative reinforcement during treatment for escape-maintained behavior.

Positive reinforcement was more effective than negative reinforcement in promoting compliance and reducing escape-maintained problem behavior for a child with autism. Escape extinction was then added while the child was given a choice between positive or negative reinforcement for compliance and the reinforcement schedule was thinned. When the reinforcement requirement reached 10 consecutive tasks, the treatment effects became inconsistent and reinforcer selection shifted from a strong preference for positive reinforcement to an unstable selection pattern.