What you need to know: Disease-modifying therapies (DMTs) early in the course of active relapsing multiple sclerosis can prevent relapses, new brain and spinal cord lesions, and worsening ...neurological disability; Some DMTs are associated with potentially serious adverse reactions, and careful monitoring is required, usually through a specialist multiple sclerosis clinic; Newer DMTs have better short term outcomes than older DMTs, but there are insufficient data about their long term effectiveness and harms. A 32 year old woman with multiple sclerosis presented to her general practitioner with a five day history of numbness and weakness in the right leg. She felt well in herself and did not describe any symptoms to suggest an intercurrent infection. She had been taking weekly intramuscular injections of interferon beta-1a for the previous 18 months and reported flu-like symptoms that could last for up to 24 hours after each dose. She asked if there was a need to change her treatment and what alternatives were available.
Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with ...white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include
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, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.
► Resistance to extinction depends on the strengthening effects of reinforcement as well as the disruptive effects of nonreinforcement. ► Behavioral momentum theory can explain extinction in multiple ...schedules, including the PREE in discrete trials. ► The relation between resistance to extinction and rate of intermittent reinforcement differs for multiple and single schedules. ► The number of reinforcers omitted to a 50% extinction criterion is an increasing function of reinforcer rate in all data reviewed here.
In the metaphor of behavioral momentum, reinforcement is assumed to strengthen discriminated operant behavior in the sense of increasing its resistance to disruption, and extinction is viewed as disruption by contingency termination and reinforcer omission. In multiple schedules of intermittent reinforcement, resistance to extinction is an increasing function of reinforcer rate, consistent with a model based on the momentum metaphor. The partial-reinforcement extinction effect, which opposes the effects of reinforcer rate, can be explained by the large disruptive effect of terminating continuous reinforcement despite its strengthening effect during training. Inclusion of a term for the context of reinforcement during training allows the model to account for a wide range of multiple-schedule extinction data and makes contact with other formulations. The relation between resistance to extinction and reinforcer rate on single schedules of intermittent reinforcement is exactly opposite to that for multiple schedules over the same range of reinforcer rates; however, the momentum model can give an account of resistance to extinction in single as well as multiple schedules. An alternative analysis based on the number of reinforcers omitted to an extinction criterion supports the conclusion that response strength is an increasing function of reinforcer rate during training.
Behavioral momentum theory provides a quantitative account of how reinforcers experienced within a discriminative stimulus context govern the persistence of behavior that occurs in that context. The ...theory suggests that all reinforcers obtained in the presence of a discriminative stimulus increase resistance to change, regardless of whether those reinforcers are contingent on the target behavior, are noncontingent, or are even contingent on an alternative behavior. In this paper, we describe the equations that constitute the theory and address their application to issues of particular importance in applied settings. The theory provides a framework within which to consider the effects of interventions such as extinction, noncontingent reinforcement, differential reinforcement of alternative behavior, and other phenomena (e.g., resurgence). Finally, the theory predicts some counterintuitive and potentially counterproductive effects of alternative reinforcement, and can serve as an integrative guide for intervention when its terms are identified with the relevant conditions of applied settings.
Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three ...neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.
We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25–65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0–6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.
Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% 95% CI −0·4 to 0·5; p=0·99; fluoxetine vs placebo −0·1% –0·5 to 0·3; p=0·86; riluzole vs placebo −0·1% –0·6 to 0·3; p=0·77). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten 9% patients in the amiloride group, seven 6% in the fluoxetine group, 12 11% in the riluzole group, and 13 12% in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.
The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.
Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
•Resistance to extinction depends on the strengthening effects of reinforcement as well as the disruptive effects of nonreinforcement.•Behavioral momentum theory can explain extinction in multiple ...schedules, including the PREE in discrete trials.•The relation between resistance to extinction and rate of intermittent reinforcement differs for multiple and single schedules.•The number of reinforcers omitted to a 50% extinction criterion is an increasing function of reinforcer rate in all data reviewed here.
We review quantitative accounts of behavioral momentum theory (BMT), its application to clinical treatment, and its extension to post-intervention relapse of target behavior. We suggest that its extension can account for relapse using reinstatement and renewal models, but that its application to resurgence is flawed both conceptually and in its failure to account for recent data. We propose that the enhanced persistence of target behavior engendered by alternative reinforcers is limited to their concurrent availability within a distinctive stimulus context. However, a failure to find effects of stimulus-correlated reinforcer rates in a Pavlovian-to-Instrumental Transfer (PIT) paradigm challenges even a straightforward Pavlovian account of alternative reinforcer effects. BMT has been valuable in understanding basic research findings and in guiding clinical applications and accounting for their data, but alternatives are needed that can account more effectively for resurgence while encompassing basic data on resistance to change as well as other forms of relapse.
It is often asserted that hearing the voice of the customer (VOC) can generate meaningful product and process innovation. Minimal empirical attention has, however, been devoted to evaluating this ...claim. The paucity of academic research exists, in part, due to the lack of an underlying conceptual foundation for the VOC concept. An opportunity thereby exists to impart theory, and evaluate whether hearing the VOC can indeed lead to favorable consequences. This research construes customer focus as a market‐sensing capability which manifests itself in the key organizational processes (i.e., intelligence generation and continual performance assessment) and values (i.e., a customer orientation serves as the guiding principle) that allow the VOC to be heard throughout the organization. Those manifestations are hypothesized to impact positions (i.e., relative task‐related performance) and outcomes (i.e., customer loyalty). The results based on data obtained from a cross‐sectional survey research design fielded in a supplier‐business customer context provide empirical support for the favorable consequences of being customer‐focused, and support the need to consider moderating variables. This paper advances theory by (1) answering the call to examine the capabilities that underlie a customer‐focused organization; (2) establishing empirical support for the (a) linkage between hearing the VOC and acting on that information, (b) elusive relationship between acting on the VOC and future buyer intentions, and (c) sources→positions→outcomes model as a path to achieving competitive advantage; (3) demonstrating that being customer‐focused does not have a direct effect on customer loyalty, thereby revealing a result different than that obtained in the consumer empowerment literature; and (4) demonstrating the importance of key moderators, namely (a) that relative (operational) performance has a strong positive effect on loyalty in relationships characterized by lower switching costs, and (b) that the effect of customer focus may lessen over time, implying that core capabilities may evolve into core rigidities. Additionally, this research contributes to business practice by providing managers with an understanding of how to hear the VOC throughout the firm (i.e., how to become a customer‐focused organization), and offering guidance on how to manage buyer–seller relationships.
Background
1H‐magnetic resonance spectroscopy (1H‐MRS) may provide a direct index for the testing of medicines for neuroprotection and drug mechanisms in multiple sclerosis (MS) through measures of ...total N‐acetyl‐aspartate (tNAA), total creatine (tCr), myo‐inositol (mIns), total‐choline (tCho), and glutamate + glutamine (Glx). Neurometabolites may be associated with clinical disability with evidence that baseline neuroaxonal integrity is associated with upper limb function and processing speed in secondary progressive MS (SPMS).
Purpose
To assess the effect on neurometabolites from three candidate drugs after 96‐weeks as seen by 1H‐MRS and their association with clinical disability in SPMS.
Study‐Type
Longitudinal.
Population
108 participants with SPMS randomized to receive neuroprotective drugs amiloride mean age 55.4 (SD 7.4), 61% female, fluoxetine 55.6 (6.6), 71%, riluzole 54.6 (6.3), 68%, or placebo 54.8 (7.9), 67%.
Field Strength/Sequence
3‐Tesla. Chemical‐shift‐imaging 2D‐point‐resolved‐spectroscopy (PRESS), 3DT1.
Assessment
Brain metabolites in normal appearing white matter (NAWM) and gray matter (GM), brain volume, lesion load, nine‐hole peg test (9HPT), and paced auditory serial addition test were measured at baseline and at 96‐weeks.
Statistical Tests
Paired t‐test was used to analyze metabolite changes in the placebo arm over 96‐weeks. Metabolite differences between treatment arms and placebo; and associations between baseline metabolites and upper limb function/information processing speed at 96‐weeks assessed using multiple linear regression models. P‐value<0.05 was considered statistically significant.
Results
In the placebo arm, tCho increased in GM (mean difference = −0.32 IU) but decreased in NAWM (mean difference = 0.13 IU). Compared to placebo, in the fluoxetine arm, mIns/tCr was lower (β = −0.21); in the riluzole arm, GM Glx (β = −0.25) and Glx/tCr (β = −0.29) were reduced. Baseline tNAA(β = 0.22) and tNAA/tCr (β = 0.23) in NAWM were associated with 9HPT scores at 96‐weeks.
Data Conclusion
1H‐MRS demonstrated altered membrane turnover over 96‐weeks in the placebo group. It also distinguished changes in neuro‐metabolites related to gliosis and glutaminergic transmission, due to fluoxetine and riluzole, respectively. Data show tNAA is a potential marker for upper limb function.
Level of Evidence
1
Technical Efficacy
Stage 4
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