Cortical AAV-CNTF gene therapy combined with intraspinal mesenchymal precursor cell transplantation promotes functional and morphological outcomes after spinal cord injury in adult rats

Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations

A general dissipativity constraint for feedback system design, with emphasis on MPC

A ‘General Dissipativity Constraint’ (GDC) is introduced to facilitate the design of stable feedback systems. A primary application is to MPC controllers when it is preferred to avoid the use of ‘stabilising ingredients’ such as terminal constraint sets or long prediction horizons. Some very general convergence results are proved under mild conditions. The use of quadratic functions, replacing GDC by ‘Quadratic Dissipation Constraint’ (QDC), is introduced to allow implementation using linear matrix inequalities. The use of QDC is illustrated for several scenarios: state feedback for a linear time-invariant system, MPC of a linear system, MPC of an input-affine system, and MPC with persistent disturbances. The stability that is guaranteed by GDC is weaker than Lyapunov stability, being ‘Lagrange stability plus convergence’. Input-to-state stability is obtained if the control law is continuous in the state. An example involving an open-loop unstable helicopter illustrates the efficacy of the approach in practice.National Research Foundation Singapor

Measuring outcomes from a peer-led social communication skills intervention for adults following acquired brain injury

Background: Reduced social competence and social integration following acquired brain injury (ABI) is well-documented. There is evidence that group social communication interventions for people with ABI and training for neuro-typical communication partners can be more effective than training the person with ABI alone. This study explores the effectiveness of a peer-led group intervention based on claims that peer models are a more powerful mechanism for learning and behaviour change than interventions led by a clinician. A peer-led training model for social communication has not previously been tested in ABI. Method: Twenty-four participants with severe ABI were recruited from a residential post-acute neurorehabilitation centre. An experimental parallel group design was used to compare a peer-led group intervention to a social activity group (usual care). A pilot study tested the feasibility of the approach followed by a main study. The groups ran for 8 weeks. A peer facilitator was trained in sixteen individual sessions over 4 weeks with a clinician. Behaviour was measured twice at baseline, after intervention and at maintenance. Four primary outcome measures, including the Adapted Measure of Participation in Conversation (MPC), and a newly devised measure of conversational interaction evaluated change in group communication behaviours. Results: Groups did not differ in baseline behaviour. There were significant differences in the treated group on the MPC and the measure of conversational interaction post-intervention. The treated group showed a more balanced interaction post-intervention and at follow-up. However, outcome measures showed differential sensitivity. Conclusion: There is preliminary evidence of advantage for peer-led groups in ABI intervention. The new conversational measure shows promise as a method to detect change in group communication behaviour

Antidepressant-like Effects of Peripheral Reelin Administration in a Preclinical Model of Depression

Depression is a serious psychiatric disorder characterized by a range of debilitating symptoms. Long-term exposure to stress is a significant risk factor for the onset and maintenance of depression. Rats exposed to repeated treatment with the stress hormone corticosterone (CORT), a well-established rodent model of depression, begin to display depression-like symptoms. The development of depression-like symptoms with prolonged exposure to CORT is accompanied by reductions in the number and maturation rate of immature dentate granule cells within the hippocampus. Furthermore, these changes are paralleled by gradual decreases in reelin-expressing cells in the dentate subgranular zone of the hippocampus. Reelin is a large extracellular matrix protein that has been implicated in a number of neuropsychiatric disorders, including szchiphrenia, bipolar disorder, autism, as well as major depression. It holds important roles in learning and memory, cell migration and integration, synaptic contact formation, and adult neurogenesis. Mice deficient in reelin are more susceptible to CORT-induced impairments in hippocampal neurogenesis and the development of a depressive phenotype. Previous work has shown that intra-hippocampal infusions of reelin into the hippocampus reverse CORT-induced increases in depression-like behavior in rats, while restoring accompanying impairments in hippocampal neurogenesis. Reelin is also expressed in peripheral organs and tissues, though its roles here are not well understood. However, reelin-deficient mice show peripheral alterations in the clustering pattern of the serotonin transporter (SERT) in membranes of blood lymphocytes. The serotonin transporter is one of the main targets of antidepressant action, and importantly, this altered pattern of SERT clustering in reelin-deficient mice is mirrored both in patients with depression and in rats exposed to prolonged CORT treatment. Based on the previous findings, we were motivated to examine whether peripheral injections of reelin could restore CORT-induced increases in depression-like behavior. To investigate possible mechanisms, we examined (i) the SERT clustering pattern in peripheral lymphocyte membranes, and (ii) the maturation rate of immature hippocampal neurons. 40mg/kg of CORT was administered subcutaneously once per day for 21 consecutive days. In conjunction, we utilized a novel reelin injection paradigm, where reelin was delivered via the lateral tail vein at either 3μg/ml or 5μg/ml every 5 or 10 days during the period of CORT injections. Depression-like behavior was measured using the forced swim test the day following the last CORT injection. The open field test was included as a measure of locomotive and anxiety-like behavior. Importantly, peripheral reelin at all dosages administered restored CORT-induced increases in depression-like behavior in the forced swim test, normalizing both immobility and swimming behaviors. Neither CORT nor reelin impacted open field behavior. As expected, CORT-treated rats displayed alterations in SERT membrane protein clustering, and importantly this was restored by all doses of reelin administered. Peripheral reelin did not significantly reverse the CORT-induced deficits in immature neuron maturation rate. These novel findings demonstrate that reelin has antidepressant-like actions when given peripherally and provide evidence for the regulation of serotonin transporter clustering in lymphocyte membranes as a mechanism for the antidepressant action of reelin

A control systems engineering approach for adaptive behavioral interventions: illustration with a fibromyalgia intervention

abstract: The term adaptive intervention has been used in behavioral medicine to describe operationalized and individually tailored strategies for prevention and treatment of chronic, relapsing disorders. Control systems engineering offers an attractive means for designing and implementing adaptive behavioral interventions that feature intensive measurement and frequent decision-making over time. This is illustrated in this paper for the case of a low-dose naltrexone treatment intervention for fibromyalgia. System identification methods from engineering are used to estimate dynamical models from daily diary reports completed by participants. These dynamical models then form part of a model predictive control algorithm which systematically decides on treatment dosages based on measurements obtained under real-life conditions involving noise, disturbances, and uncertainty. The effectiveness and implications of this approach for behavioral interventions (in general) and pain treatment (in particular) are demonstrated using informative simulations

Persuasive Health:Back to the Future

With individual behaviour and lifestyle determining 30-50% of people’s health, research and supportive technology for affecting behaviour alteration remain urgently needed. Most existing persuasive systems are designed to persuade a user to change a finite set of behaviours to achieve a specific goal. However, if the user’s situation or goal changes, such systems cannot adapt to the changes. A much more robust type of persuasive systems is needed today to enable adequate health navigation and to empower people to face and change their own realities in terms of a large variety of health behaviours and lifestyles. In this paper, we provide a perspective on the impressive body of work contributed over the past 15 years, to better look into the future of persuasive health and to the opportunities a broader theoretical framework and practical methodologies may bring about. We present a taxonomy that attempts to explain the contributions in this field including health behaviour theory, cybernetic action behaviour models, social cognitive theory, and control theory. We identify potentially promising approaches to advance persuasive health’s efficacy in empowering individuals to improve their own health outcomes

Rare coding variants in ten genes confer substantial risk for schizophrenia

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, PPeer reviewe

Shaping cash transfer impacts through “soft-conditions”: evidence from Lesotho

Cash transfer programmes have been shown to have positive effects on a variety of outcomes. While much of the literature focuses on the role of conditionality in achieving desired impact, this paper focuses on the role of ‘soft conditionality’ implemented through both ‘labelling’ and ‘messaging’ in evaluating the impact of the Child Grants Program in Lesotho, an unconditional cash transfer programme targeting poor households with orphans and vulnerable children. Beneficiary households received a clear message that the transfer should be spent on the interest and needs of children. Our findings suggest that ‘soft conditionality’ does play a role in increasing expenditure for children, especially on education, clothing and footwear. Results indicate in fact that transfer income is spent differently from general income as it exerts both an income and a substitution effect. This behavioural change is confirmed by comparing the ex-ante expected behaviours with the ex-post actual response to the programme. We find that for expenditure categories linked to the well-being of children the expost response was much higher than the ex-ante expected behaviour

Rare coding variants in ten genes confer substantial risk for schizophrenia

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach

Annual Reviews in Control

There is growing interest in the use of control theory for interdisciplinary applications, where data may be sparse or missing, be non-uniformly sampled, have greater uncertainty, and where there is no opportunity to collect repeat measurements. In such applications, problems posed by observational data and the issue of missing or irregular data need to be considered. We present a review on dealing with observational, missing and irregular data for control applications. This considers the following issues: (i) how to identify a system model from observational data subject to missing measurements, (ii) how to determine control inputs when output data includes missing measurements, and (iii) how to ensure stability when future update times may be missed. Dealing with observational data and missing measurements is a key problem within the statistics literature, so we introduce statistical methods for dealing with this type of data. We aim to enable the integration of well-developed statistical methods of dealing with missing data into control theory. An example problem of using anticoagulants to control the blood clotting speed of patients is used throughout the paper