Bidirectional variation in glutamate efflux in the medial prefrontal cortex induced by selective positive and negative allosteric mGluR5 modulators.

Dysregulation of prefrontal cortical glutamatergic signalling via NMDA receptor hypofunction has been implicated in cognitive dysfunction and impaired inhibitory control in such neuropsychiatric disorders as schizophrenia, attention-deficit hyperactivity disorder and drug addiction. Although NMDA receptors functionally interact with metabotropic glutamate receptor 5 (mGluR5), the consequence of this interaction for glutamate release in the prefrontal cortex (PFC) remains unknown. We therefore investigated the effects of positive and negative allosteric mGluR5 modulation on changes in extracellular glutamate efflux in the medial PFC (mPFC) induced by systemic administration of the non-competitive NMDA receptor antagonist dizocilpine (or MK801) in rats. Extracellular glutamate efflux was measured following systemic administration of the positive allosteric mGluR5 modulator [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone] (ADX47273; 100 mg/kg, p.o.) and negative allosteric mGluR5 modulator [2-chloro-4-{[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-yl]ethynyl}pyridine] (RO4917523; 0.3 mg/kg, p.o.), using a wireless glutamate biosensor in awake, freely moving rats. The effect of MK801 (0.03-0.06 mg/kg, s.c.) on mPFC glutamate efflux was also investigated in addition to the effects of MK801 (0.03 mg/kg, s.c.) following ADX47273 (100 mg/kg, p.o.) pre-treatment. ADX47273 produced a sustained increase in glutamate efflux and increased the effect of NMDA receptor antagonism on glutamate efflux in the mPFC. In contrast, negative allosteric mGluR5 modulation with RO4917523 decreased glutamate efflux in the mPFC. These findings indicate that positive and negative allosteric mGluR5 modulators produce long lasting and opposing actions on extracellular glutamate efflux in the mPFC. Positive and negative allosteric modulators of mGluR5 may therefore be viable therapeutic agents to correct abnormalities in glutamatergic signalling present in a range of neuropsychiatric disorders.

Semantic congruency of auditory warnings.

The aim of this study was to explore operator experience and performance for semantically congruent and incongruent auditory icons and abstract alarm sounds. It was expected that performance advantages for congruent sounds would be present initially but would reduce over time for both alarm types. Twenty-four participants (12M/12F) were placed into auditory icon or abstract alarm groupings. For each group both congruent and incongruent alarms were used to represent different driving task scenarios. Once sounded, participants were required to respond to each alarm by selecting a corresponding driving scenario. User performance for all sound types improved over time, however even with experience a decrement in speed of response remained for the incongruent iconic sounds and in accuracy of performance for the abstract warning sounds when compared to the congruent auditory icons. Semantic congruency was found to be of more importance for auditory icons than for abstract sounds. Practitioner Summary: Alarms are used in many operating systems as emergency, alerting, or continuous monitoring signals for instance. This study found that the type and representativeness of an auditory warning will influence operator performance over time. Semantically congruent iconic sounds produced performance advantages over both incongruent iconic sounds and abstract warnings.

Balance appointment information leaflets: employing performance-based user-testing to improve understanding.

OBJECTIVE: To use performance-based user-testing to evaluate the effectiveness of balance appointment patient information leaflets (PILs) in conveying important information. DESIGN: The study used a sequential groups design. Twenty participants were asked to find and demonstrate understanding of 11 key points of information contained within two NHS leaflets, A and B (10 participants each), through individual structured-interviews. Participants' views of the leaflets were explored through a short semi-structured interview. Following analysis, a revised leaflet was developed and tested on a further 20 participants. STUDY SAMPLE: 40 participants (25F/15M, aged 46-72) with no experience of balance problems or balance assessment appointments. RESULTS: Participants exhibited difficulties with finding and/or understanding 5/11 and 6/11 points of information within leaflets A and B, respectively. Five out of eleven points of the revised leaflet also posed problems. Ten out of eleven points were understood by > 90% of participants testing the revised leaflet compared with 6/11 points for leaflets A and B. CONCLUSIONS: Some balance appointment PILs contain information which is difficult to find and/or understand for some readers. PILs should be evaluated prior to use using performance-based methods, since poor information provision may lead to increased patient anxiety and appointment non-attendance, cancellation, or postponement.

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity.

BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.

Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism.

RATIONALE: Impaired N-methyl-D-aspartate (NMDA) receptor signalling underlies several psychiatric disorders that express high levels of impulsivity. Although synergistic interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5), the significance of this interaction for impulsivity is unknown. OBJECTIVE: This study aims to investigate the effects of negative and positive allosteric mGluR5 modulation (NAM/PAM) on trait impulsivity and impulsivity evoked by NMDA receptor antagonism in rats. METHODS: Motor and choice impulsivity were assessed using the five-choice serial reaction time task (5-CSRTT) and delayed-discounting task (DDT), respectively. The effects of RO4917523 and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (NAMs) and ADX47273 (PAM) were investigated in non-impulsive rats and in trait high- and low-impulsive rats. The effects of these compounds on impulsivity induced by NMDA receptor antagonism (MK801) in the 5-CSRTT were also investigated. RESULTS: RO4917523 (0.1-1 mg/kg) decreased premature responding and increased omissions but had no effect on locomotor activity up to 0.1 mg/kg. MTEP significantly increased omissions, decreased accuracy and slowed responding but had no effect on premature responding. ADX47273 decreased premature responding at doses that had no effect on locomotor activity. MK801 increased premature responding and impaired attentional accuracy; these deficits were dose dependently rescued by ADX47273 pre-treatment. Allosteric modulation of mGluR5 had no significant effect on choice impulsivity, nor did it modulate general task performance. CONCLUSIONS: These findings demonstrate that mGluR5 allosteric modulation selectively dissociates motor and choice impulsivity. We further show that mGluR5 PAMs may have therapeutic utility in selectively targeting specific aspects of impulsivity and executive dysfunction.

Cell-based screening of traditional Chinese medicines for proliferation enhancers of mouse embryonic stem cells.

A high-throughput cell-based method was developed for screening traditional Chinese herbal medicines (TCHMs) for potential stem cell growth promoters. Mouse embryonic stem (mES) cells expressing enhanced green fluorescent protein (EGFP) were cultured in growth media supplemented with various TCHM extracts. The dosage-dependent effects of TCHM extracts on cell growth, including proliferation and cytotoxicity, were assessed via EGFP fluorescence measurement. Seven TCHMs were investigated, and among them Panax notoginseng (PN), Rhizoma Atractylodis macrocephalae, Rhizoma chuanxiong, and Ganoderma lucidum spores (GLS) showed potential to improve mES cell proliferation. Eleven mixtures of these four TCHMs were then studied, and the results showed that the mixture of PN and GLS had the strongest growth promoting effect, increasing the specific growth rate of mES cells by 29.5% at a low dosage of 0.01% (wt/vol) PN/GLS (P<0.01) and 34.2% at 0.1% (wt/vol) PN/GLS (P<0.05) compared to the control. The growth promoting effect of PN/GLS was further confirmed with ES cells cultured in spinner flasks. A 29.3-fold increase in the total cell number was achieved in the medium supplemented with 0.01% PN/GLS after 5 days, while the control culture only gave a 16.8-fold increase. This cell-based screening method thus can provide an efficient and high-throughput way to explore potential stem cell growth promoters from TCHMs.

Hearing aid instruction booklets: employing usability testing to determine effectiveness.

PURPOSE: This study implemented performance-based usability and literature testing to determine whether people could use 2 instruction booklets for hearing aids (HAs) to carry out basic maintenance tasks and find and understand key facts. METHOD: Using a cross-sectional study design, researchers recruited 40 participants (25 women, 15 men, ages 46-72 years) with no experience of HAs or audiology services to test instruction booklets for a Danalogic and Unitron HA (20 participants each). Participants were asked to follow instructions provided within the booklets to complete common HA tasks (e.g., cleaning the HA and mold and changing the battery) and demonstrate understanding of information. Participants' views of the booklets were then obtained within a short individual interview. RESULTS: Participants experienced problems in completing all tasks while following instructions provided by the Danalogic and Unitron booklets. Individual interviews highlighted further issues regarding layout, diagrams, and content, including missing information. CONCLUSIONS: Some HA instruction booklets contain information that some users may find difficult to find, understand, and follow. These limitations may negatively impact on HA satisfaction and use. It is recommended that written information for clients be evaluated prior to use. This study supports the premise that performance-based usability and literature testing are appropriate methods to use.

Auditory displays as occasion setters.

OBJECTIVE: The aim of this study was to evaluate whether representational sounds that capture the richness of experience of a collision enhance performance in braking to avoid a collision relative to other forms of warnings in a driving simulator. BACKGROUND: There is increasing interest in auditory warnings that are informative about their referents. But as well as providing information about some intended object, warnings may be designed to set the occasion for a rich body of information about the outcomes of behavior in a particular context. These richly informative warnings may offer performance advantages, as they may be rapidly processed by users. METHOD: An auditory occasion setter for a collision (a recording of screeching brakes indicating imminent collision) was compared with two other auditory warnings (an abstract and an "environmental" sound), a speech message, a visual display, and no warning in a fixed-base driving simulator as interfaces to a collision avoidance system. The main measure was braking response times at each of two headways (1.5 s and 3 s) to a lead vehicle. RESULTS: The occasion setter demonstrated statistically significantly faster braking responses at each headway in 8 out of 10 comparisons (with braking responses equally fast to the abstract warning at 1.5 s and the environmental warning at 3 s). CONCLUSION: Auditory displays that set the occasion for an outcome in a particular setting and for particular behaviors may offer small but critical performance enhancements in time-critical applications. APPLICATION: The occasion setter could be applied in settings where speed of response by users is of the essence.

What's in a name? The role of graphics, functions, and their interrelationships in icon identification.

Communication using icons is now commonplace. It is therefore important to understand the processes involved in icon comprehension and the stimulus cues that individuals utilize to facilitate identification. In this study, we examined predictors of icon identification as participants gained experience with icons over a series of learning trials. A dynamic pattern of findings emerged in which the primary predictors of identification changed as learning progressed. In early learning trials, semantic distance (the closeness of the relationship between icon and function) was the best predictor of performance, accounting for up to 55% of the variance observed, whereas familiarity with the function was more important in later trials. Other stimulus characteristics, such as our familiarity with the graphic in the icon and its concreteness, were also found to be important for icon design. The theoretical implications of these findings are discussed, with particular emphasis on the parallels with picture naming. The icon identification norms from this study may be downloaded from brm.psychonomic-journals.org/content/supplemental.

Mapping candidate within-vehicle auditory displays to their referents.

OBJECTIVE: This study investigated speech, environmental sounds (naturally occurring sounds with arbitrary meanings), auditory icons (natural or synthetic sounds with specific meanings), and abstract synthetic warnings as candidates for within-vehicle interfaces. BACKGROUND: Auditory displays and warnings must satisfy certain criteria, such as being appropriately urgent and commanding appropriately fast response times. However, a semiotic analysis suggests that displays, as signals interpreted by users, should also be mapped successfully onto their referents. METHOD: Response times and accuracy were recorded in a computer task of identifying learned mappings of candidate displays to a range of referent driving events (such as "headway closing"); perceived urgency and pleasantness were assessed separately. RESULTS: Speech and auditory icons produced near-ceiling performance in response times and identification accuracy. Abstract sounds produced notably slower response times and less accuracy. Environmental sounds showed an intermediate pattern of performance for accuracy, but the response times were similar to those of the abstract sounds. Speech utterances were similarly and consistently rated as pleasant but also of intermediate perceived urgency. The three other sound types showed a consistent mapping of their perceived urgency to the situational urgency of their referents; for these sounds, perceived urgency and pleasantness were negatively correlated. CONCLUSION: The results point to the importance of considering the role of signal-referent relationships in designing auditory displays. APPLICATION: The results have applicability for auditory displays in the vehicle interface, whereas the theoretical framework is of value in auditory display design in a broader context.

Icon identification in context: the changing role of icon characteristics with user experience.

OBJECTIVE: This research examined the relative importance of icon characteristics in determining the speed and accuracy of icon identification. BACKGROUND: Studies to date have focused on the role of one or two icon characteristics when users first experience an icon set. This means that little is known about the relative importance of icon characteristics or how the role of icon characteristics might change as users gain experience with icons. METHODS: Thirty participants carried out an icon identification task over a long series of trials to simulate learning through experience. Icon characteristics investigated included semantic distance, concreteness, familiarity, and visual complexity. RESULTS: Icon characteristics were major determinants of performance, accounting for up to 69% of the variance observed in performance. However, the importance of icon characteristics changed with experience: Semantic distance is crucial initially while icon-function relationships are learned, but familiarity is important later because it has lasting effects on access to long-term memory representations. CONCLUSION: These findings suggest that icon concreteness may not be of primary importance when identifying icons and that semantic distance and familiarity may be more important. APPLICATION: Designers need to take into account icon characteristics other than concreteness when creating icons, particularly semantic distance and familiarity. The precise importance of the latter characteristics will vary depending on whether icons are rarely encountered or frequently used.