Effects of X-ray radiation on complex visual discrimination learning and social recognition memory in rats.

The present report describes an animal model for examining the effects of radiation on a range of neurocognitive functions in rodents that are similar to a number of basic human cognitive functions. Fourteen male Long-Evans rats were trained to perform an automated intra-dimensional set shifting task that consisted of their learning a basic discrimination between two stimulus shapes followed by more complex discrimination stages (e.g., a discrimination reversal, a compound discrimination, a compound reversal, a new shape discrimination, and an intra-dimensional stimulus discrimination reversal). One group of rats was exposed to head-only X-ray radiation (2.3 Gy at a dose rate of 1.9 Gy/min), while a second group received a sham-radiation exposure using the same anesthesia protocol. The irradiated group responded less, had elevated numbers of omitted trials, increased errors, and greater response latencies compared to the sham-irradiated control group. Additionally, social odor recognition memory was tested after radiation exposure by assessing the degree to which rats explored wooden beads impregnated with either their own odors or with the odors of novel, unfamiliar rats; however, no significant effects of radiation on social odor recognition memory were observed. These data suggest that rodent tasks assessing higher-level human cognitive domains are useful in examining the effects of radiation on the CNS, and may be applicable in approximating CNS risks from radiation exposure in clinical populations receiving whole brain irradiation.

Neurobehavioral effects of head-only gamma-radiation exposure in rats.

The present report describes initial steps in the development of an animal model for assessing the effects of low levels of radiation encountered in the space environment on human cognitive function by examining the effects of radiation on a range of neurobehavioral functions in rodents that are similar to a number of basic human cognitive functions. The present report presents baseline data on the effects of gamma radiation on neurobehavioral functions in rodents (psychomotor speed, discrimination accuracy and inhibitory control) that are similar to those in humans. Two groups of eight Long-Evans rats were trained to perform a reaction-time task that required them to depress a lever for 1-3 s and to release the lever within 1.5 s of a release stimulus (correct trial) to receive a reward. Releasing the lever prior to the release stimulus (error) terminated the trial. One group was exposed to head-only gamma radiation (5 Gy at a dose rate of 1 Gy/min), while the second group was sham-irradiated using the same anesthesia protocol. The irradiated group showed significant deficits in both performance accuracy (percentage correct scores) and performance reliability (false alarm scores) from 1 to 4 months after irradiation, indicating clear performance impairments. The increase in false alarm scores is consistent with reduced inhibitory control and a shift toward increased anticipatory responses at the cost of decreased accuracy. The nonirradiated group showed no such changes over the same period.

A randomized controlled trial of interim methadone maintenance.

CONTEXT: Effective alternatives to long waiting lists for entry into methadone hydrochloride maintenance treatment are needed to reduce the complications of continuing heroin dependence and to increase methadone treatment entry. OBJECTIVE: To compare the effectiveness of interim methadone maintenance with that of the usual waiting list condition in facilitating methadone treatment entry and reducing heroin and cocaine use and criminal behavior. DESIGN: Randomized, controlled, clinical trial using 2 conditions, with treatment assignment on a 3:2 basis to interim maintenance-waiting list control. SETTING: A methadone treatment program in Baltimore. PARTICIPANTS: A total of 319 individuals meeting the criteria for current heroin dependence and methadone maintenance treatment. INTERVENTIONS: Participants were randomly assigned to either interim methadone maintenance, consisting of an individually determined methadone dose and emergency counseling only for up to 120 days, or referral to community-based methadone treatment programs. MAIN OUTCOME MEASURES: Entry into comprehensive methadone maintenance therapy at 4 months from baseline; self-reported days of heroin use, cocaine use, and criminal behavior; and number of urine drug test results positive for heroin and cocaine at the follow-up interview conducted at time of entry into comprehensive methadone treatment (or at 4 months from baseline for participants who did not enter regular treatment). RESULTS: Significantly more participants assigned to the interim methadone maintenance condition entered comprehensive methadone maintenance treatment by the 120th day from baseline (75.9%) than those assigned to the waiting list control condition (20.8%) (P<.001). Overall, in the past 30 days at follow-up, interim participants reported significantly fewer days of heroin use (P<.001), had a significant reduction in heroin-positive drug test results (P<.001), reported spending less money on drugs (P<.001), and received less illegal income (P<.02) than the waiting list participants. CONCLUSION: Interim methadone maintenance results in a substantial increase in the likelihood of entry into comprehensive treatment, and is an effective means of reducing heroin use and criminal behavior among opioid-dependent individuals awaiting entry into a comprehensive methadone treatment program.

Crewmember performance before, during, and after spaceflight.

The development of technologies for monitoring the welfare of crewmembers is a critical requirement for extended spaceflight. Behavior analytic methodologies provide a framework for studying the performance of individuals and groups, and brief computerized tests have been used successfully to examine the impairing effects of sleep, drug, and nutrition manipulations on human behavior. The purpose of the present study was to evaluate the feasibility and sensitivity of repeated performance testing during spaceflight. Four National Aeronautics and Space Administration crewmembers were trained to complete computerized questionnaires and performance tasks at repeated regular intervals before and after a 10-day shuttle mission and at times that interfered minimally with other mission activities during spaceflight. Two types of performance, Digit-Symbol Substitution trial completion rates and response times during the most complex Number Recognition trials, were altered slightly during spaceflight. All other dimensions of the performance tasks remained essentially unchanged over the course of the study. Verbal ratings of Fatigue increased slightly during spaceflight and decreased during the postflight test sessions. Arousal ratings increased during spaceflight and decreased postflight. No other consistent changes in rating-scale measures were observed over the course of the study. Crewmembers completed all mission requirements in an efficient manner with no indication of clinically significant behavioral impairment during the 10-day spaceflight. These results support the feasibility and utility of computerized task performances and questionnaire rating scales for repeated measurement of behavior during spaceflight.

Behavioral health: the propaedeutic requirement.

Concern about the behavioral effects of spaceflight can be traced back a half century to the earliest preparatory bioastronautics experiments in the mid-1 950s. A central focus of the first primate suborbital flights, as well as the orbital chimpanzee pretest flights of Project Mercury, was the effects of such stressful ventures on the learned performances of these space behavioral health pioneers. The hiatus in spaceflight behavioral health experimental investments that followed these early initiatives began with the advent of the 'human astronaut' era of the mid-1960s, and has dominated the last several decades. Contemporary concerns in this regard have most recently been articulated by a turn-of-the-century Committee of the Institute of Medicine, National Academy of Sciences, providing a visionary view of space medicine during travel beyond Earth orbit. This 2-yr study focused on those most complex behavioral health interactions involving humans in extreme, isolated, and confined microsocieties-areas that have not received the necessary level of attention. The evident behavioral health issues raised by the prospect of long-duration exploratory missions beyond Earth orbit, including performance and general living conditions, recovery and support systems, and the screening, selection, and training of candidate participants are reviewed and discussed.

Distributed interactive communication in simulated space-dwelling groups.

This report describes the development and preliminary application of an experimental test bed for modeling human behavior in the context of a computer generated environment to analyze the effects of variations in communication modalities, incentives and stressful conditions. In addition to detailing the methodological development of a simulated task environment that provides for electronic monitoring and recording of individual and group behavior, the initial substantive findings from an experimental analysis of distributed interactive communication in simulated space dwelling groups are described. Crews of three members each (male and female) participated in simulated "planetary missions" based upon a synthetic scenario task that required identification, collection, and analysis of geologic specimens with a range of grade values. The results of these preliminary studies showed clearly that cooperative and productive interactions were maintained between individually isolated and distributed individuals communicating and problem-solving effectively in a computer-generated "planetary" environment over extended time intervals without benefit of one another's physical presence. Studies on communication channel constraints confirmed the functional interchangeability between available modalities with the highest degree of interchangeability occurring between Audio and Text modes of communication. The effects of task-related incentives were determined by the conditions under which they were available with Positive Incentives effectively attenuating decrements in performance under stressful time pressure.

Central nervous system correlates of behavioral deficits following simian immunodeficiency virus infection.

Despite the high incidence of cognitive and motor impairment in acquired immunodeficiency syndrome (AIDS) patients, the mechanisms of AIDS-related central nervous system (CNS) pathology are not completely understood. Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS, including human immunodeficiency virus (HIV)-induced CNS pathology and cognitive/behavioral impairment. Co-inoculation with two SIV strains, SIV/17E-Fr and SIV/DeltaB670, accelerates SIV CNS disease, producing SIV encephalitis in over 90% of pig-tailed macaques within 3 months. In the present study, this SIV model was employed to identify cellular and viral correlates of behavioral impairment following SIV infection. Measures of psychomotor speed (simple reaction time), fine motor control (bimanual motor task), and general motor activity (home cage movement) were all adversely affected by SIV disease. Prior to euthanasia, performance was significantly impaired in both a simple reaction time task in 6 of 12 monkeys and a bimanual motor task in 5 of 6 monkeys. All monkeys evaluated (11 of 11) showed significant reductions in spontaneous motor activity. Significant correlations were found between impaired performance on the bimanual motor test and axonal damage (accumulation of beta-amyloid precursor protein in the corpus callosum) as well as increased microglial activation and macrophage infiltration (levels of CD68 and Ham56 immunostaining). These results suggest that axonal damage is related to the behavioral impairment induced by infection with SIV. The axonal damage may result from neuroimmune responses, including microglial and macrophage activation. Therefore, axonal damage may be a morphologic manifestation of neuronal dysfunction that underlies development of behavioral impairment in HIV/SIV CNS infection.

Assessing abuse liability in clinical trials.

In this article, the use of data collected in registration-focused clinical trials to provide information concerning abuse liability of compounds under development is discussed. Registration-focused trials are limited by the small and select sample chosen for study participation and design constraints. However, most compounds under development are first administered to humans during the conduct of registration-focused trials, so this presents an opportunity to collect potentially important information about the effects of drugs in humans. At present, information concerning subjective effects and symptoms associated with drug discontinuation are not collected systematically. Reports are generally considered as adverse events (AEs) and are recorded on the case report forms (CRFs) in the investigators own language. There is generally no rating of drug "liking". The authors suggest strategies that could be implemented in registration-focused clinical trials to improve the information gathered with regard to subjective effects, abuse liability and discontinuation-emergent symptoms. Importantly, there remains much groundwork to be done in developing and validating appropriate assessment instruments and determining "threshold" levels for concern. Under the best of circumstances, registration-focused clinical trials have limited potential to detect abuse liability because of the small number of patients seen and the exclusion of many subjects who might be particularly vulnerable to the abuse of marketed compounds (i.e. individuals with substance use disorders). In cases where there are reasons to suspect that a drug under development has abuse potential, systematic exploration with a series of studies specifically designed to assess abuse potential must be conducted.

Cocaine's effects on detection, discrimination, and identification of auditory stimuli by baboons.

The perceptual effects of cocaine were examined under conditions that required baboons to detect the presence of tones as well as to identify tones of different pitches, and the results compared to the results of prior studies on cocaine's effects on the detection of tones, the discrimination of different tone pitches, and the discrimination of different human vowel sounds of similar pitch. A reaction time procedure was employed in which baboons were trained to press a lever in the presence of a visual "ready" signal, and release the lever only when one tone pitch occurred, but not release the lever when a second, different tone pitch occurred. Changes in the percentage of correct detections and median reaction times for each tone were measured following intramuscular administration of cocaine (0.01-1.0 mg/kg). Cocaine impaired tone identification and shortened reaction times to the tones in all baboons. Cocaine's effects on accuracy, however, were primarily due to elevations in false alarm rates, as opposed to detection of the stimuli themselves. The results demonstrate that cocaine impairs the discriminability of tone pitches in baboons, and that such impairments can depend upon the type of stimuli employed (tones vs. speech sounds) and the type of procedure employed (discrimination vs. identification).

Cocaine's effects on the discrimination of simple and complex auditory stimuli by baboons.

The effects of cocaine on tone frequency discriminations by baboons were examined and compared with previous data for more complex acoustic stimuli (speech sounds) to see if cocaine's perceptual effects on these discriminations depends upon the type of stimulus employed (i.e., tones vs. speech sounds). Baboons pressed a lever to produce one repeating "standard" tone and released the lever only when one of four other "comparison" tones occasionally occurred in place of the standard tone. Cocaine's effects were assessed once or twice weekly by giving an intramuscular injection of cocaine hydrochloride (0.01-0.56 mg/kg) immediately prior to performing the task and by examining correct detections and reaction times for each tone following drug administration. Cocaine impaired tone discriminability, with greater impairments occurring for those tones that were more similar in frequency to the standard tone. Cocaine's perceptual effects occurred within 20-70 min following drug administration. Cocaine also impaired or facilitated the speed of responding to auditory stimuli, depending upon the drug dose and subject. The results demonstrate that cocaine can impair auditory discriminations involving simple tones, as well as speech sounds, and further supports the suggestion that cocaine's effects are focused on CNS mechanisms related to the use of pitch cues.