Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline

Rationale: Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. Objective: In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Methods: Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/− mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Results: Once stable performance had been achieved, Map2k7+/− mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline—a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia—signs of improvement in attentional performance were detected. Conclusions: Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline

The Formyl Peptide Receptor 2 Regulates Microglial Phenotype Through Immunometabolism: Implications for Alzheimer’s Disease

Microglia are key players in the pathology of Alzheimer’s disease (AD), driving chronic inflammation, oxidative stress, and the altered metabolism seen in the brains of patients. With clinical trials continuing to fail, new approaches towards drug development are critical. Strategies to reduce microglial activation may therefore be a viable therapeutic approach to tackling AD. Formyl peptide receptor 2 (Fpr2), which drives peripheral inflammatory resolution, is expressed in microglia. However, its functional role in neuroinflammation is unclear. This thesis provides evidence to support the peripheral findings of Fpr2 stimulation, wherein it may also hold promise for exploitation as a therapeutic for neurodegenerative disorders, including AD. We also highlight novel findings surrounding the modulation of both oxidative stress and microglial metabolism associated with Fpr2 activation. Under inflammatory conditions, we report that selective agonists for Fpr2 modulate the microglial inflammatory response, actively shifting from a pro-inflammatory to a pro-resolving phenotype, emphasised by the reduction of pro-inflammatory cytokines and concomitant increases in both pro-resolving cytokines and phagocytosis. Metabolic shifting away from glycolysis was also observed for pro-resolving microglia. Moreover, we describe for the first time that Fpr2 completely reverses reactive oxygen species (ROS) production from the mitochondria and NADPH oxidase enzymes following an inflammatory stimulus. We also highlight that the toxic oligomeric amyloid (oAβ) facilitates microglial ROS production and subsequent metabolic changes without triggering an inflammatory response. oAβ facilitated NADPH oxidase activation, which in turn resulted in the activation of glucose 6-phosphate dehydrogenase (G6PD), the rate limiting step for the pentose phosphate pathway. This metabolic pathway is responsible for producing NADPH, which in turn NADPH oxidases exploit for further ROS production. These changes resulted in noticeable reductions in both microglial glycolysis and oxidative phosphorylation. We present data underlining that Fpr2/3 stimulation reverses oAβ-induced ROS production, with a resultant reduction in G6PD activity and the return of homeostatic glycolysis. These oAβ-induced microglial changes triggered the apoptosis of SH-SY5Y cells in co-culture with BV-2 microglia. However, supporting our interest in Fpr2/3 for therapeutic approaches to neurodegenerative diseases, post-treatment with a select agonist for the receptor successfully prevented apoptosis of these neuronal like SH-SY5Y cells. This original data unveils novel functions of Fpr2/3 in the central nervous system (CNS), supplementing the well-established pro-resolving functions the receptor facilitates within the periphery. The combination of pro-resolving, anti-oxidative, immunometabolic and anti-apoptotic functions of Fpr2/3 support the exploitation of this receptor for therapeutic research into multiple different CNS disorders, including AD

EDAMUX : A method for measuring User Experience

Background: User experience (UX) is seen as an important quality of a successful product and software companies are becoming increasingly interested in the field of UX. As UX has the goal to improve the experience of users, there is a need for better methods in measuring the actual experience. One aspect of UX is to understand the emotional aspect of experience. Psychophysiology studies the relations between emotions and physiology and electrodermal activity (EDA) has been found to be a physiological measurement of emotional arousal. Aims: The aim of this thesis is researching the utility of measuring EDA to identify moments of emotional arousal during human-computer interaction. By studying peaks in EDA during software interaction we expect to find issues in the software that work as triggers or stimuli for the peaks. Method: We used the design science methodology to develop EDAMUX. EDAMUX is a method to unobtrusively observe users, while gathering significant interaction moments through self reporting and EDA. A qualitative single-case study was conducted to evaluate the utility of EDAMUX. Results: We found that we can discover causes of bad user experience with EDAMUX. Moments of emotional arousal, derived from EDA, was found in conjunction with performance issues, usability issues and bugs. Emotional arousal was also observed during software interaction where the user was blaming themself. Conclusions: EDAMUX shows potential in discovering issues in software that are difficult to find with methods that rely on subjective self-reporting. Having the potential to objectively study emotional reactions is seen as valuable in complementing existing methods of measuring user experience

Matching bias in syllogistic reasoning: Evidence for a dual-process account from response times and confidence ratings

We examined matching bias in syllogistic reasoning by analysing response times, confidence ratings, and individual differences. Roberts’ (2005) “negations paradigm” was used to generate conflict between the surface features of problems and the logical status of conclusions. The experiment replicated matching bias effects in conclusion evaluation (Stupple & Waterhouse, 2009), revealing increased processing times for matching/logic “conflict problems”. Results paralleled chronometric evidence from the belief bias paradigm indicating that logic/belief conflict problems take longer to process than non-conflict problems (Stupple, Ball, Evans, & Kamal-Smith, 2011). Individuals’ response times for conflict problems also showed patterns of association with the degree of overall normative responding. Acceptance rates, response times, metacognitive confidence judgements, and individual differences all converged in supporting dual-process theory. This is noteworthy because dual-process predictions about heuristic/analytic conflict in syllogistic reasoning generalised from the belief bias paradigm to a situation where matching features of conclusions, rather than beliefs, were set in opposition to logic

Virtual Reality Games for Motor Rehabilitation

This paper presents a fuzzy logic based method to track user satisfaction without the need for devices to monitor users physiological conditions. User satisfaction is the key to any product’s acceptance; computer applications and video games provide a unique opportunity to provide a tailored environment for each user to better suit their needs. We have implemented a non-adaptive fuzzy logic model of emotion, based on the emotional component of the Fuzzy Logic Adaptive Model of Emotion (FLAME) proposed by El-Nasr, to estimate player emotion in UnrealTournament 2004. In this paper we describe the implementation of this system and present the results of one of several play tests. Our research contradicts the current literature that suggests physiological measurements are needed. We show that it is possible to use a software only method to estimate user emotion

Modelling students' effort using behavioral data

International audienceStudents' effort is often considered a key factor for students' success. It has several related definitions, none of which is widely adopted. In this paper, we define students' effort as the experienced cognitive load, which is the total amount of cognitive resources used during the execution of a given task. We propose an effort model to quantify students' effort based on this construct. Our approach uses behavioral measures (i.e., interaction and eye gaze data). Our preliminary results show that the eye gaze measures have an intermediary relationship with effort, while the interaction measures have a weak relationship with effort and seem slightly complementary to eye gaze measures