Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals.

Drugs of abuse hijack brain-reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting nonexocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties, which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to 2 h. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration, and frequency of spontaneous dopamine transients, the naturally occurring, nonelectrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sugar reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sugar-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify upregulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling.

Perceptual and memory biases for health-related information in hypochondriacal individuals.

Problematic health concerns characteristic of hypochondriasis may be better understood with the aid of cognitive, information processing theories. We investigated whether hypochondriacal individuals show perceptual and explicit memory biases favoring health-related information. A clinical sample of hypochondriacs (n=18) and healthy controls (n=22), and a sample of hypochondriacal (n=22) and nonhypochondriacal (n=67) patients referred for Holter monitoring, completed a computerized test of perceiving difficult-to-read words and then an encoding task followed by recall of those words. Contrary to our prediction, hypochondriacal individuals in the clinical sample did not perceive more health-related words than words not related to health. Hypochondriacal individuals in the Holter-monitoring sample showed an unexpected bias against reporting health-related words. Social class may account for some of the group differences in this sample. Hypochondriacal individuals in both samples showed better memory for health-related than nonhealth words.

Organizational strategies mediate nonverbal memory impairment in obsessive-compulsive disorder.

BACKGROUND: Previous neuropsychological studies of obsessive-compulsive disorder (OCD) have indicated impaired executive functioning and nonverbal memory. The extent to which impaired executive functioning impacts nonverbal memory has not been established. The current study investigated the mediating effects of organizational strategies used when copying a figure on subsequent nonverbal memory for that figure. METHODS: We examined neuropsychological performance in 20 unmedicated subjects with OCD and 20 matched normal control subjects. Subjects were administered the Rey-Osterrieth Complex Figure Test (RCFT) and neuropsychological tests assessing various aspects of executive function. RESULTS: OCD subjects differed significantly from healthy control subjects in the organizational strategies used to copy the RCFT figure, and they recalled significantly less information on both immediate and delayed testing. Multiple regression analyses indicated that group differences in immediate percent recall were significantly mediated by copy organizational strategies. Further exploratory analyses indicated that organizational problems in OCD may be related to difficulties shifting mental and/or spatial set. CONCLUSIONS: Immediate nonverbal memory problems in OCD subjects were mediated by impaired organizational strategies used during the initial copy of the RCFT figure. Thus, the primary deficit was one affecting executive function, which then had a secondary effect on immediate memory. These findings are consistent with current theories proposing frontal-striatal system dysfunction in OCD.

Aging and the scope of visual attention.

OBJECTIVE: To discover whether some cognitive deficits associated with aging could be related to a restricted scope of visual attention. DESIGN: Cross-sectional study, with subjects in each age group receiving the same four conditions. SUBJECTS: 24 elderly (mean age 65.2 years, 12 men and 12 women) and 24 young (mean age 21.8 years, 12 men and 12 women) matched for handedness, gender, and education level. METHODS: SUBJECTS viewed a display that contained four light-gray squares arranged as if on the tips of a plus sign, then black X marks appeared and the subjects indicated whether one or two Xs appeared in the squares as quickly and accurately as possible. The time to respond and accuracy level were recorded. Two types of displays were used; one with squares spread out over a large area and one with squares condensed into a small area. In two thirds of the trials the size remained the same (with half being large, and half small), and in one third it changed (with half of these trials changing from large-to-small and half from small-to-large). RESULTS: In the trials that had a consistent display size, the elderly subjects performed the task better with the smaller display, whereas the young subjects performed equally well with both sized displays. In addition, the elderly found it easier to shift from large to small scope than to maintain attention at the large scope; in contrast, the younger subjects found it easiest to maintain attention on a static display size. CONCLUSIONS: The elderly prefer to focus attention on a smaller region of space than do younger people.

Decisions about prenatal testing for chromosomal disorders: perceptions of a diverse group of pregnant women.

We conducted a study to elucidate factors influencing women's decisions regarding prenatal genetic screening for and diagnosis of chromosomal disorders and to learn about their experiences with these tests and with the medical system. Using focus group interviews and questionnaire assessments, we obtained detailed impressions of a diverse group of 75 pregnant women. Participants varied with respect to race/ethnicity, religious background, and reproductive history, as well as in their decisions about use of prenatal screening and diagnostic testing. Substantial variation surfaced in attitudes toward testing. Factors influencing women's views included available resources, feelings about having a child with Down syndrome, moral beliefs, family and social influences, perceptions of one's own health, the difficulty of becoming pregnant, and willingness to put the fetus at elevated miscarriage risk. Such findings indicate that age-based policies regarding access to prenatal diagnoses that, among other reasons, are based on the balance of risks between bearing a child with a chromosomal abnormality versus procedure-related loss are incompatible with the range of concerns that women bring to this decision and the weight individual women may assign to the outcomes.

Aging and scanning of imagined and perceived visual images.

The authors examined adult age differences in the proficiency of visually scanning across perceived and imagined displays. Participants were asked to indicate whether an arrow in the central region of a square grid ring pointed to a target square. The distance between arrow and target was varied, and all participants showed the expected increase in response times and error rates as scanning distance increased. The arrow and grid display either remained visible until the participant responded (perceptual condition) or disappeared after 50 ms (imagery condition). In both conditions, older participants required more time to scan and made more errors as distance increased than did younger participants. These findings conflict with previous studies showing that perceptual and imagery scanning are preserved with aging. Although methodological factors may have contributed to these differences, further research is needed to elucidate effects of aging on visual scanning.

Reverse-micelle model: pH, electromagnetic field and inhibitor enzyme interaction.

The reverse micelle is one of many models thought to have properties more nearly resembling the biological cellular environment, than does the traditional dilute-solution biochemical reaction system. In order to evaluate the results of EMF perturbation of enzyme-catalyzed reactions, the description of the AOT reverse-micelle model, with respect to its internal pH, effect of chemical inhibitors, temperature, and electromagnetic-field perturbation has herein been extended. Acetylcholinesterase and NADPH cytochrome-P450 reductase, reacting within the AOT reverse-micelle, exhibit a temperature vs. activity profile equivalent to the same reaction in a buffered dilute-solution environment. In reverse micelles, some inhibitors of AChE (propidium, and d-tubocurarine) have much less effect upon indophenol-acetate hydrolysis than they do in a dilute solution environment. Other inhibitors act in the same manner within the structured environment of the reverse micelle as in the conventional dilute solution reaction model. These differences are explicable in terms of mechanism of action of the individual inhibitors. Perturbation by low-intensity microwave fields has a similar inhibitory effect upon dilute-solution reactions, as those in the 'low-water-activity' environment of the reverse micelle. However, the interactions between physical and chemical perturbants are differently limited by the structure of the aqueous phase of the reverse micelle. pH of the 'internal' reverse-micelle environment is a function of the availability of H-ions supplied by system components. Use of indicator dyes show that the low-molarity buffers which are compatible with reverse-micelle stability, are often insufficient to maintain a constant pH. Too, in the reverse micelle, reaction rate, for proton yielding reactions, is dramatically greater than the rate of the same reaction in dilute solution at the same acidic pH.

Striatal recruitment during an implicit sequence learning task as measured by functional magnetic resonance imaging.

Prior research has repeatedly implicated the striatum in implicit sequence learning; however, imaging findings have been inconclusive with respect to the sub-territories and laterality involved. Using functional magnetic resonance imaging (fMRI), we studied brain activation profiles associated with performance of the serial reaction time task (SRT) in 10 normal right-handed males. Behavioral results indicate that significant implicit learning occurred, uncontaminated by significant explicit knowledge. Concatenated fMRI data from the entire cohort revealed significant right-lateralized activation in both the caudate and putamen. Analysis of fMRI data from individual subjects showed inter-individual variability as to the precise territories involved, including right as well as left caudate and putamen. Interestingly, all seven subjects who manifested robust learning effects exhibited significant activation within the putamen. Moreover, among those seven subjects, the magnitude of signal intensity change within the putamen correlated significantly with the magnitude of reaction time advantage achieved. These findings demonstrate right-sided striatal activation across subjects during implicit sequence learning, but also highlight interindividual variability with respect to the laterality and striatal subterritories involved. In particular, results from individual subjects suggest that, during the SRT, the reaction time advantage garnered via implicit sequence learning might be predominantly associated with activity within the putamen.

Probing striatal function in obsessive-compulsive disorder: a PET study of implicit sequence learning.

Positron emission tomography was employed to contrast the brain activation pattern in patients with obsessive-compulsive disorder (OCD) to that of matched control subjects while they performed an implicit learning task. Although patients and control subjects evidenced comparable learning, imaging data from control subjects indicated bilateral inferior striatal activation, whereas OCD patients did not activate right or left inferior striatum and instead showed bilateral medial temporal activation. The findings further implicate corticostriatal dysfunction in obsessive-compulsive disorder. Furthermore, when OCD patients are confronted with stimuli that call for recruitment of corticostriatal systems, they instead appear to access brain regions normally associated with explicit (conscious) information processing.

Recall and recognition memory in obsessive-compulsive disorder.

This study examined recall and recognition memory in 20 nonmedicated patients with obsessive-compulsive disorder (OCD) and 20 matched control subjects. As hypothesized, OCD subjects showed abnormalities affecting delayed recall of nonverbal information but showed normal recognition. These results are interpreted as providing preliminary evidence of a nonverbal memory retrieval deficit consistent with proposed corticostriatal system dysfunction in OCD.

Can patients with obsessive-compulsive disorder discriminate between percepts and mental images? A signal detection analysis.

Signal detection analysis was used to test three hypotheses for repetitive thoughts and behaviors characteristic of obsessive-compulsive disorder (OCD). Patients might have (a) low sensitivity for the difference between having seen something or having imagined seeing it, (b) a high criterion for this discrimination, or (c) difficulty associating context with information in memory. Subjects judged viewed words or imagined words and later indicated which were actually seen. Patients with OCD discriminated seen from imaged words significantly better than normal control subjects, as evidenced by higher d' scores on a recognition memory task. Groups did not differ in response criterion, beta, used to decide whether words had been seen or imaged. Implications for the study of OCD from an information-processing perspective are discussed.

Cerebral lateralization.

Recent findings suggest that cerebral laterality will not be understood in terms of simple dichotomies, such as the idea that the left hemisphere is analytic and the right holistic. Rather, hemisphere differences can be better explained in terms of relatively specific principles that extend over limited domains. For visual perception and mental imagery, the left hemisphere appears to be relatively better than the right at encoding component parts, representing visual categories, and encoding categorical spatial relations; in contrast, the right hemisphere appears to be relatively better at encoding overall patterns, representing specific instances, and encoding coordinate metric spatial relations. Recent neural network models support a hypothesis that ties together these disparate findings.

Mixed function oxidase demethylase and dealkylase activity in an electromagnetic field.

In contrast to the increase in reaction rate of microsomal NADPH-cytochrome-P450 reductase activity resulting from low-level microwave perturbation (reported earlier) transformations involving the entire MFO-pathway were inhibited by a microwave field. Dealkylation of 7-ethoxycoumarin was inhibited 25% and demethylation of p-nitroanisole was inhibited 40% when the reaction was carried forward in a 9.14 GHz CW field. Microsomal preparations from the liver of mature chickens had enzymic characteristics (kinetic constants, inhibitor-response spectrum) for these substrates similar to those reported for rodent and human MFO complex.

EM-field effect upon properties of NADPH-cytochrome P-450 reductase with model substrates.

Artificial substrates, including ferricyanide and dichlorophenol indophenol (IP), are frequently used to model the activity of NADPH-cytochrome P-450 reductase, in the xenobiotic-metabolic pathway catalyzed by the P-450 complex. Here, the two oxidants were compared in a microsomal preparation from chicken liver. Low-energy 9.14 GHz perturbation affected both reactions similarly, though the IP reaction may be more sensitive to extremely low energy levels. The reactions of the two oxidants differed from each other in their response to the prior incubation of the microsomes with carbon monoxide and to the presence of superoxide dismutase. The mechanics of the reduction of ferricyanide and the reduction of IP are not identical and the electron-flow paths may be dissimilar. Microwave effect cannot be attributed a temperature change in the reaction medium; it appears to occur at the level of the electron-flow path across the dual-flavin reductase.

Ouabain inhibition of kidney ATPase is altered by 9.14 GHz radiation.

At each of several stabilized temperatures between 7.0 and 43.8 degrees C, increases in dog-kidney, Na(+)-, K(+)-ATPase catalytic activity were usually observed in association with exposure for 5 min to 9.14 GHz CW microwave radiation in a thin tubular reactor. However, at 24.9 degrees C, a 23% decrease occurred. Comparisons of activity of ouabain-inhibited reactions revealed that the efficacy of the cardiac glycoside as an inhibitor of ATPase activity was severely diminished by the microwave field. The ouabain-site control mechanism may be a specific microwave target at this exposure frequency. Experimental results can be interpreted in terms of molecular structural changes or direct energy input. The estimated SAR of energy that was incident on preparations is 20 W/kg.

Microwave effect upon chlorpromazine-inhibited kidney ATPase.

Presence of chlorpromazine, a non-active-site inhibitor of Na(+)-K(+)-ATPase catalytic activity, in a reaction system exposed to 9.14 GHz CW radiation, resulted in approximately 23% inhibition. This effect was temperature-independent within the normal range for this protein. A low-level microwave field also inhibited the enzyme catalytic rate. Loci of chlorpromazine inhibition and of low-level microwave inhibition appear to be distinct and non-interactive under the conditions of this study. Use of enzyme reaction systems as models for microwave causation of leukemia and the possible involvement of pharmacological agents, such as ouabain and chlorpromazine, in this process has been considered.

Use of plasmid analysis to determine the source of bacterial invasion of the urinary tract.

Gram negative colonisation and infection of the urinary tract is a well recognised complication of the neuropathic bladder caused by spinal cord injury (SCI). K. pneumoniae accounts for one third of all urinary tract infections in hospitalised SCI patients. Plasmid analysis has been shown to reliably fingerprint bacterial strains, particularly K. pneumoniae, so that growth from two separate locations in or on the body can be accurately analysed as to migration from a reservoir to a target location. Eighty seven hospitalised SCI patients on intermittent catheterisation for a total of 586 patient-weeks were studied. Twice weekly catheterised urine specimens and once weekly rectal swab cultures were taken from each patient. Thirty seven patients experienced at least one clinically significant (colony count greater than 10,000/mL) urinary tract colonisation caused by K. pneumoniae, representing 66 total colonisations. Further analysis of 31 of these 37 patients revealed: K. pneumoniae in all of their stool cultures (p less than 0.05) and the identical strain of K. pneumoniae in the urine as well as the stool in 72% of the 66 colonisations (p less than 0.05). Analysis of 14 patients without K. pneumoniae urinary colonisations showed absence of faecal K. pneumoniae in 3, and predominant growth in only 4. In 22 of the 37 patients, multiple K. pneumoniae urinary colonisations were noted, representing 27 pairs of colonisation. Fifteen of the pairs were found to be relapsing (caused by two identical bacterial strains), and 12 were recurrent (caused by two different bacterial strains). Thirteen of the 15 relapsing pairs also had identical urine and stool K. pneumonia strains (p less than 0.05). All colonisations were treated with appropriate antibiotics based on culture and sensitivity reports. Fourteen of the 15 relapsing colonisation pairs have identical antibiograms (p less than 0.05), while all 12 of the recurrent colonisation pairs had different antibiograms (p less than 0.05). The differences noted on sensitivity patterns (antibiograms) correlated with differences among strains of K. pneumoniae based upon plasmid analysis. Treatment of bacteriuria did not affect the nature of repeated colonisations regardless of the antibiotic chosen, the route of administration or the duration of treatment.

Gram staining apparatus for space station applications.

A self-contained, portable Gram staining apparatus (GSA) has been developed for use in the microgravity environment on board the Space Station Freedom. Accuracy and reproducibility of this apparatus compared with the conventional Gram staining method were evaluated by using gram-negative and gram-positive controls and different species of bacteria grown in pure cultures. A subsequent study was designed to assess the performance of the GSA with actual specimens. A set of 60 human and environmental specimens was evaluated with the GSA and the conventional Gram staining procedure. Data obtained from these studies indicated that the GSA will provide the Gram staining capability needed for the microgravity environment of space.

Bacterial challenge study of a porous carbon percutaneous implant.

Numerous percutaneous devices for power transmission and control to electrically powered, intracorporeal blood pumps have been used for periods ranging from 12 months to 4 yrs; however, consistent and reliable performance has not been achieved, due most frequently to the development of infection and sinus tracts at the percutaneous lead exit site. The present study showed that percutaneous devices fabricated from porous vitreous carbon can function satisfactorily in vivo over extended periods. The implant sites successfully resisted infection by normal flora bacteria for as long as 48 months, although superficial surface colonization and infection did occur after deliberate application of pathogens.