Learning Outcomes Report

Aim of the study The learning outcomes study, conducted as part of WP3 of the BioApp project, has as objectives: (a) generating a comprehensive list of the learning outcomes; (b) reaching an agreement on the scope and priority of the learning outcomes, and (c) making suggestions for the further development of the Biomedical Design module. Method To address the objectives of the study, the group concept mapping approach was applied. Group Concept Mapping (GCM) is a systematic approach that objectively identifies an expert group’s shared vision on a particular issue, in our case the Biomedical Design module learning outcomes. The method involved the participants in activities that most professionals are used to: idea generation, sorting of ideas into groups and rating the ideas on some values (e.g., importance and difficulty to achieve). The analysis applied multi-dimensional scaling and cluster analysis to visually depict the experts’ shared representations on the learning outcomes as thematic groups. One of the distinguishing characteristics of GCM is the visualisation of the results from the analysis. Visualisation allows the emerging data structures and their interrelationships to be grasped. This facilitates decision making. Group Concept Mapping produces three main types of visualisations: conceptual maps, pattern matches and go-zones. Results The following thematic groups (clusters) of learning outcomes emerged from the data: ‘Attention to the end user’, ‘New approaches to design’, ‘Design process’, ‘Regulation and Ethics’, ‘Commercialisation’, ‘Knowledge integration’, ‘Communication’, ‘Collaboration’, ‘Higher order skills’, ‘Problem solving process’, ‘Connecting domains’, and ‘Learning goals’. Five more global areas of interest could be identified after conceptually related clusters were combined: ‘Design’ ( including ‘Design process’, ‘New approaches’, and ‘Attention to end user’); ‘Marketing’ (containing ‘Commercialization’ and ‘Regulation and Ethics’); ‘Interdisciplinary group dynamics’ (comprised of ‘Communication’ and ‘Collaboration’); ‘Learning objectives’ (consisting of ‘Learning goals’, ‘Higher order skills’ and ‘Problem solving process’) and ‘Creative combination’ (which includes ‘Knowledge integration’ and ‘Connecting domains’). Furthermore, the learning outcomes could be classified into two major categories: a) technical skills (new advancements in design process with special attention to users, also commercialisation and standardisation), and b) transversal skills, which include working effectively in teams (‘communication’ and ‘collaboration’) and creative problem solving (‘problem solving process’). The rating results indicate that the most important groups of learning outcomes are ‘Higher order skills’ and ‘Communication’. At the same time, however, these outcomes are deemed to be the most difficult to achieve. Other difficult to achieve learning outcomes are ‘Learning goals’, ‘Problem solving process’ and ‘Connecting domains’. The least important group of learning outcomes is ‘Commercialization’ and the easiest to achieve is ‘Regulation and Ethics’. The framework of learning outcomes consists of not only learning outcomes related to traditional topics such as ‘Design process’ and ‘Creative problem solving’, but also themes not very popular in curriculums on design such as ‘Commercialisation’, ‘Standardisation’, ‘Regulations’, and ‘Ethics’. The results also show there is a moderate correlation between the two values of importance and difficulty to achieve on the cluster level. The clusters ‘Problem solving process’, ‘Connecting domains’ and ‘Commercialization’ score lower on importance but higher on difficulty to achieve. In contrast, ‘Regulation and Ethics’ scores higher on importance but relatively lower on difficulty to achieve. Conclusions This study provided not only an empirical basis for identifying the main learning outcomes areas for an educational module on Biomedical Design, but also suggested how to operationally define them (through the statements in each cluster). The study emphasizes the need for addressing the highest level of learning taxonomy (analysis, synthesis, problem solving, creativity) when defining learning outcomes. It further reveals the need to teach students to integrate knowledge from different professional domains. However, the overall conclusion must be that the study not only identified learning outcomes for the Biomedical Design module when considered in isolation from the encompassing curriculum, but that the identified learning outcomes can only be effectively achieved when further integration of the module in the curriculum is allowed

Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2) deficient mice: Do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms?

Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner's 'two-headed' model indicates that antipsychotics not only reverse LI disruption, 'disrupted LI', but also potentiate LI when low/absent in controls, 'persistent' LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1 -/- and wild-type mice, indicating no such moderation in Drd1 -/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis

Dysregulation of specialized delay/interference-dependent working memory following loss of dysbindin-1A in schizophrenia-related phenotypes

Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A -/-, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A -/-showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A -/-provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects

Mutant mouse models in evaluating novel approaches to antipsychotic treatment

In this review we consider the application of mutant mouse phenotypes to the study of psychotic illness in general and schizophrenia in particular, as they relate to behavioral, psychopharmacological, and cellular phenotypes of putative import for antipsychotic drug development. Mutant models appear to be heuristic at two main levels; firstly, by indicating the functional roles of neuronal components thought to be of relevance to the putative pathobiology of psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those neuronal components; secondly, by indicating the functional roles of genes associated with risk for psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those risk genes. We focus initially on models of dopaminergic and glutamatergic dysfunction. Then, we consider advances in the genetics of schizophrenia and mutant models relating to replicable risk genes. Lastly, we extend this discussion by exemplifying two new variant approaches in mutant mice that may serve as prototypes for advancing antipsychotic drug development. There is continuing need not only to address numerous technical challenges but also to develop more “real-world” paradigms that reflect the milieu of gene × environment and gene × gene interactions that characterize psychotic illness and its response to antipsychotic drugs

Modeling schizophrenia: uncovering novel therapeutic targets

The vague relationship between diagnosis, underlying etiology and a rudimentary understanding of the pathophysiology of psychosis, particularly schizophrenia, has made it difficult to develop and validate suitable disease models for such disorders. Despite recent technological advancements, animal models have yet to yield a revolutionary treatment for schizophrenia. Refinement and standardization of assessment methods in the preclinical domain and streamlining of concepts from which animal models are generated are required, particularly in relation to models that recapitulate cognitive and negative symptoms of schizophrenia. In this review, caveats of current treatments for schizophrenia and current animal modeling strategies are examined in the context of their validity and potential for discovery of novel therapies, and finally, future prospects for the field are considered

Catechol-O-methyl transferase as a drug target for schizophrenia

Current antipsychotic drugs lack material efficacy against the negative symptoms and cognitive deficits of schizophrenia. There is considerable uncertainty regarding the optimal pharmacotherapeutic strategy for treating these and other aspects of psychotic illness. The present review summarises clinical, mutant, and psychopharmacological data related to catechol-O-methyltransferase (COMT), an enzyme involved in the catabolism of catecholamine neurotransmitters, with a view to establishing the antipsychotic potential of compounds targeting the action of this enzyme. The review examines clinical and preclinical genetic data linking COMT gene variation with risk for schizophrenia or specific symptoms or disease endophenotypes. We then summarise data concerning the behavioural effects of COMT inhibitors. These genetic and pharmacological data relating to COMT as a therapeutic target have implications for the development of individualised treatments for treatment-resistant symptoms of schizophrenia, including cognitive dysfunction and, potentially, negative symptoms

Susceptibility genes for schizophrenia: mutant models, endophenotypes and psychobiology

Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models

Physiological and behavioural responsivity to stress and anxiogenic stimuli in COMT-deficient mice

Catechol-O-methyltransferase, an enzyme involved in regulating brain catecholamine levels, has been implicated in anxiety, pain and/or stress responsivity. Elements of this putative association remain unclarified, notably whether: (a) COMT variation modulates responses to acute and/or chronic stress equally; (b) acute pharmacological inhibition of COMT produces comparable effects on anxiety to that observed after deletion of the COMT gene; (c) COMT genotype modulates action of anxiolytic drugs.<p></p> We aimed to further investigate the relationship between reduced COMT function, anxiety and stress responsivity in mice.<p></p> To compare the effect of acute vs. chronic restraint stress in female COMT KO vs. WT mice, serum corticosterone and cytokine concentrations were measured [Experiment 1]. Sensitivity to the benzodiazepines midazolam and chlordiazepoxide in the light–dark test was assessed in female COMT KO vs. WT mice [Experiment 2]. Effects of acute administration of the COMT inhibitor tolcapone, and of these same benzodiazepines thereon, in the light–dark test were assessed in female C57BL/6 mice [Experiment 3].<p></p> COMT KO mice demonstrated an increased corticosterone response to acute but not chronic stress, and a modified cytokine profile after chronic, but not acute stress. COMT KO mice showed increased anxiety, but benzodiazepine sensitivity was affected by COMT genotype. Whilst tolcapone had no effect on light/dark performance in C57BL6/J mice it decreased benzodiazepine sensitivity.<p></p> These data elaborate earlier findings of increased anxiety in female COMT KO mice and also clarify a role for COMT in modulating stress-related hormonal and immune parameters in a manner that depends on chronicity of the stressor