Biomarkers in bipolar disorder : a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

Corticospinal excitability following short-term motor imagery training of a strength task

Motor imagery and actual movement engage similar neural structures, however, whether they produce similar training-related corticospinal adaptations has yet to be established. The aim of this study was to compare changes in strength and corticospinal excitability following short-term motor imagery strength training and short-term strength training. Transcranial magnetic stimulation (TMS) was applied over the contralateral motor cortex (M1) to elicit motor-evoked potentials in the dominant biceps brachii muscle prior to and following 3-week strength training using actual bicep curls or motor imagery of bicep curls. The strength training (n = 6) and motor imagery (n = 6) groups underwent three supervised training sessions per week for 3 weeks. Participants completed four sets of six to eight repetitions (actual or imagined) at a training load of 80% of their one-repetition maximum. The control group (n = 6) were required to maintain their current level of physical activity. Both training groups exhibited large performance gains in strength (p < 0.001; strength training 39% improvement, imagery 16% improvement), which were significantly different between groups (p = 0.027). TMS revealed that the performance improvements observed in both imagery and strength training were accompanied by increases in corticospinal excitability (p < 0.001), however, these differences were not significantly different between groups (p = 0.920). Our findings suggest that both strength training and motor imagery training utilised similar neural substrates within the primary M1, however, strength training resulted in greater gains in strength than motor imagery strength training. This difference in strength increases may be attributed to adaptations during strength training that are not confined to the primary M1. These findings have theoretical implications for functional equivalent views of motor imagery as well as important therapeutic implications.

The task of designing tasks for teacher education and development

Posing, adapting, and creating worthwhile tasks that support student learning are significant pedagogical practices of teachers. However in mathematics education, task design and curriculum development are not often the responsibility of practicing teachers. Textbooks can become the main source of mathematics problems and teachers often follow the text and its sequence of problems. Although mathematics teachers can benefit from access to research-based curriculum resources, limited opportunities to adapt and design tasks can make it challenging to meet the diverse needs and interests of their students. More opportunities for learning to create problems are needed for both practicing and beginning mathematics teachers. What then is involved in learning to pose, adapt and create worthwhile mathematics tasks? More specifically, how can teacher educators design tasks that support teacher candidates in learning to create mathematical tasks? As teacher educators we have, over the past few years, used our own courses as sites in Australia and Canada for investigating various contexts to support preservice teachers in their learning to adapt and create mathematical tasks. Our research includes both large scale and small qualitative studies to explore the perspectives of teacher candidates on learning to create and pose mathematical problems, the kinds of problems they pose, and the opportunities and challenges this offers us as teacher educators. Our work is inspired by Variation Theory that focuses on learning as the act of awareness and discernment of variation. We are exploring both how variation theory can be useful for preservice teachers in their designing, posing and adapting of mathematical tasks and for teacher educators in their design of such pedagogical tasks. The results of our work support the argument that tasks to design, adapt and pose mathematical problems enhance their pedagogical understanding and should be a feature of teacher education courses. This is a new area for research and practice; further exploration of the suitability of particular tasks in elementary mathematics teacher education is recommended.

Voluntary demand for auditing by farm businesses: an Australian perspective

 This study investigates voluntary demand for auditing by Australian farm businesses, a significant but relatively unexplored segment of the economy. Most farms operate as family partnerships or sole proprietors and we thus focus on incentives to audit arising from internal sources (owner-manager), controlling for traditional incentives arising from external contractual constraints (i.e., debt), organisational characteristics (i.e., size), and agency conflict. We hypothesise that an external audit assists management in enhancing internal control by complementing the process of profit planning and control (budgeting) and that increased family conflict provides an incentive to engage external audit. Of the 457 survey questionnaire respondents, 27% voluntarily engage an external auditor and 66% conduct some formal written planning. Results from logistic regression analyses support the predicted impact of both size and debt on audit, and further support the hypothesised impact of budgeting. The positive association between budgeting and audit confirms the complementary relationship. More importantly, this relationship is not confounded by the combined impact of size and budgeting and debt and budgeting on voluntary audit. In addition, family conflict has no impact on voluntary demand for auditing by farm business.

Are voluntary wheel running and open-field behavior correlated in mice? Different answers from comparative and artificial selection approaches

Voluntary wheel running and open-field behavior are probably the two most widely used measures of locomotion in laboratory rodents. We tested whether these two behaviors are correlated in mice using two approaches: the phylogenetic comparative method using inbred strains of mice and an ongoing artificial selection experiment on voluntary wheel running. After taking into account the measurement error and phylogenetic relationships among inbred strains, we obtained a significant positive correlation between distance run on wheels and distance moved in the open-field for both sexes. Thigmotaxis was negatively correlated with distance run on wheels in females but not in males. By contrast, mice from four replicate lines bred for high wheel running did not differ in either distance covered or thigmotaxis in the open field as compared with mice from four non-selected control lines. Overall, results obtained in the selection experiment were generally opposite to those observed among inbred strains. Possible reasons for this discrepancy are discussed.

Understanding of mental states in later childhood: an investigation of theory of mind in autism spectrum disorder and typical development with a novel task

The developmental trajectories of Theory of Mind (ToM) in later childhood and into adolescence have not been thoroughly investigated, partly due to a lack of sensitive paradigms that can chart development in typical populations or in individuals with a core deficit in ToM, such as those with autism spectrum disorder (ASD). The present study assessed understanding of emotions, beliefs, and intentions using both an established ToM task (Baron‐Cohen et al., 2001) and the more recently developed Comic Strip Task (CST; Cornish et al., 2010). Participants comprised 12 typically-developing (TD) children (mean age: 12·0 years, range: 9·9‐14·8 years) and 12 high-functioning children with ASD (mean age: 11·0 years, range: 9·1‐13·6 years). Results indicated that the ASD group were not impaired on any of the ToM tasks relative to TD children. It was concluded that although children with high-functioning ASD appear to develop basic ToM skills, they do not generalize these to naturalistic situations. The comic-strip paradigm is suggested as a promising way to approach the measurement of ToM across childhood in typical children and those with ASD.

Dynamic control of skilled and unskilled labour task assignments

Efficient allocation of skilled and non-skilled workers allow a company to improve productivity and usually requires an understanding of personnel capability, operating conditions and resource availability. This paper examines a labour control strategy that optimises labour skill level, utilisation, task execution time and processing error. The proposed controller manages different labour groups in a multiple work cell environment, providing real-time job assignment, as well as guiding and navigation features. These features can be used to enhance the performance of existing MRP-based or Just-In-Time production systems. A discrete event simulation-based manufacturing model has been developed to assess the performance of the labour controller. Experiments conducted for the selected production scenarios have demonstrated a productivity improvement when using the proposed control. A second experiment has shown that when a skilled labour uses the labour controller to guide them through the job, their utilisation also increases. The proposed controller also has potential application in other domains, such as minimising the shopping time at a supermarket

The international society for bipolar disorders (ISBD) task force report on antidepressant use in bipolar diosrders

Objective:
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.

Method:  
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.

Results:  
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.

Conclusions:
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Comparable effects of nicotine in smokers and nonsmokers on a prospective memory task

In a double-blind placebo-controlled study, we examined the effect of nicotine, a cholinergic agonist, on performance of a prospective memory (ProM) task in young adult volunteers.

Volunteers were required to complete an ongoing lexical decision task while maintaining the ProM task (responding with a different button press to items containing particular target letters). Half of the volunteers were smokers, half were nonsmokers. Half of each group received a single dose (1 mg) of nicotine nasal spray before completing the task; the remaining volunteers received a matched inactive placebo spray.

Nicotine improved performance on the ProM task when volunteers were able to devote resources to that task. Under a variant procedure, where volunteers completed a concurrent auditory monitoring task, ProM performance was impaired under nicotine. Results are discussed in terms of the resource model of ProM, and the arousal model of drug effects.

Procedural learning deficits in specific language impairment (SLI): a meta-analysis of serial reaction time task performance

Meta-analysis and meta-regression were used to evaluate whether evidence to date demonstrates deficits in procedural memory in individuals with specific language impairment (SLI), and to examine reasons for inconsistencies of findings across studies. The Procedural Deficit Hypothesis (PDH) proposes that SLI is largely explained by abnormal functioning of the frontal-basal ganglia circuits that support procedural memory. It has also been suggested that declarative memory can compensate for at least some of the problems observed in individuals with SLI. A number of studies have used Serial Reaction Time (SRT) tasks to investigate procedural learning in SLI. In this report, results from eight studies that collectively examined 186 participants with SLI and 203 typically-developing peers were submitted to a meta-analysis. The average mean effect size was .328 (CI95: .071, .584) and was significant. This suggests SLI is associated with impairments of procedural learning as measured by the SRT task. Differences among individual study effect sizes, examined with meta-regression, indicated that smaller effect sizes were found in studies with older participants, and in studies that had a larger number of trials on the SRT task. The contributions of age and SRT task characteristics to learning are discussed with respect to impaired and compensatory neural mechanisms in SLI.

The impact of working memory load on task execution and online plan adjustment during multitasking in a virtual environment

Three experiments investigated the impact of working memory load on online plan adjustment during a test of multitasking in young, nonexpert, adult participants. Multitasking was assessed using the Edinburgh Virtual Errands Test (EVET). Participants were asked to memorize either good or poor plans for performing multiple errands and were assessed both on task completion and on the extent to which they modified their plans during EVET performance. EVET was performed twice, with and without a secondary task loading a component of working memory. In Experiment 1, articulatory suppression was used to load the phonological loop. In Experiment 2, oral random generation was used to load executive functions. In Experiment 3, spatial working memory was loaded with an auditory spatial localization task. EVET performance for both good- and poor-planning groups was disrupted by random generation and sound localization, but not by articulatory suppression. Additionally, people given a poor plan were able to overcome this initial disadvantage by modifying their plans online. It was concluded that, in addition to executive functions, multiple errands performance draws heavily on spatial, but not verbal, working memory resources but can be successfully completed on the basis of modifying plans online, despite a secondary task load.