Interference with work in fibromyalgia - effect of treatment with pregabalin and relation to pain response

BACKGROUND: Clinical trials in chronic pain often collect information about interference with work as answers to component questions of commonly used questionnaires but these data are not normally analysed separately. METHODS: We performed a meta-analysis of individual patient data from four large trials of pregabalin for fibromyalgia lasting 8-14 weeks. We analysed data on interference with work, inferred from answers to component questions of Fibromyalgia Impact Questionnaire (FIQ), Short Form 36 Health Survey, Sheehan Disability Scale, and Multidimensional Assessment of Fatigue, including "How many days in the past week did you miss work, including housework, because of fibromyalgia?" from FIQ. Analyses were performed according to randomised treatment group (pregabalin 150-600 mg daily or placebo), pain improvement (0-10 numerical pain rating scale scores at trial beginning vs. end), and end of trial pain state (100 mm visual analogue pain scale [VAS]). RESULTS: Comparing treatment group average outcomes revealed modest improvement over the duration of the trials, more so with active treatment than with placebo. For the 'work missed' question from FIQ the change for patients on placebo was from 2.2 (standard deviation [SD] 2.3) days of work lost per week at trial beginning to 1.9 (SD 2.1) days lost at trial end (p < 0.01). For patients on 600 mg pregabalin the change was from 2.1 (SD 2.2) days to 1.6 (SD 2.0) days (p < 0.001). However, the change in days of work lost was substantial in patients with a good pain response: from 2.0 (SD 2.2) days to 0.97 (SD 1.6) days (p < 0.0001) for those experiencing >/= 50% pain improvement and from 1.9 (SD 2.2) days to 0.73 (SD 1.4) days (p < 0.0001) for those achieving a low level of pain at trial end (<30 mm on the VAS). Patients achieving both >/= 50% pain improvement and a pain score <30 mm on the VAS had the largest improvement, from 2.0 (SD 2.2) days to 0.60 (SD 1.3) days (p < 0.0001). Analysing answers to the other questions yielded qualitatively similar results. CONCLUSIONS: Effective pain treatment goes along with benefit regarding work. A reduction in time off work >1 day per week can be achieved in patients with good pain responses

Exploring the Fundamental Dynamics of Error-Based Motor Learning Using a Stationary Predictive-Saccade Task

The maintenance of movement accuracy uses prior performance errors to correct future motor plans; this motor-learning process ensures that movements remain quick and accurate. The control of predictive saccades, in which anticipatory movements are made to future targets before visual stimulus information becomes available, serves as an ideal paradigm to analyze how the motor system utilizes prior errors to drive movements to a desired goal. Predictive saccades constitute a stationary process (the mean and to a rough approximation the variability of the data do not vary over time, unlike a typical motor adaptation paradigm). This enables us to study inter-trial correlations, both on a trial-by-trial basis and across long blocks of trials. Saccade errors are found to be corrected on a trial-by-trial basis in a direction-specific manner (the next saccade made in the same direction will reflect a correction for errors made on the current saccade). Additionally, there is evidence for a second, modulating process that exhibits long memory. That is, performance information, as measured via inter-trial correlations, is strongly retained across a large number of saccades (about 100 trials). Together, this evidence indicates that the dynamics of motor learning exhibit complexities that must be carefully considered, as they cannot be fully described with current state-space (ARMA) modeling efforts

Anxiety disorders in headache patients in a specialised clinic: prevalence and symptoms in comparison to patients in a general neurological clinic

Data from several studies indicate an association of headache with anxiety disorders. In this study, we assessed and differentiated anxiety disorders in 100 headache patients by using the PSWQ (Penn State Worry Questionnaire) screening tool for generalised anxiety disorder (GAD) and the ACQ (Agoraphobic Cognitions Questionnaire) and BSQ (Body Sensation Questionnaire) for panic disorder (PD). Control groups were constructed: (1) on the basis of epidemiological studies on PD and GAD in the general population and (2) by including neurological patients. 37.0% of headache patients had a GAD. 27% of headache patients met the score for PD in the BSQ, 4.0% in the ACQ. Significant results were obtained in comparison to the general population (p < 0.001) and with regard to GAD in comparison with a sample of neurological patients (p < 0.005). The BSQ significantly correlated with the number of medication days (p < 0.005). The results confirm the increased prevalence of GAD in headache patients. PD seems to increase the risk of medication overuse

Visual Exploration and Object Recognition by Lattice Deformation

Mechanisms of explicit object recognition are often difficult to investigate and require stimuli with controlled features whose expression can be manipulated in a precise quantitative fashion. Here, we developed a novel method (called “Dots”), for generating visual stimuli, which is based on the progressive deformation of a regular lattice of dots, driven by local contour information from images of objects. By applying progressively larger deformation to the lattice, the latter conveys progressively more information about the target object. Stimuli generated with the presented method enable a precise control of object-related information content while preserving low-level image statistics, globally, and affecting them only little, locally. We show that such stimuli are useful for investigating object recognition under a naturalistic setting – free visual exploration – enabling a clear dissociation between object detection and explicit recognition. Using the introduced stimuli, we show that top-down modulation induced by previous exposure to target objects can greatly influence perceptual decisions, lowering perceptual thresholds not only for object recognition but also for object detection (visual hysteresis). Visual hysteresis is target-specific, its expression and magnitude depending on the identity of individual objects. Relying on the particular features of dot stimuli and on eye-tracking measurements, we further demonstrate that top-down processes guide visual exploration, controlling how visual information is integrated by successive fixations. Prior knowledge about objects can guide saccades/fixations to sample locations that are supposed to be highly informative, even when the actual information is missing from those locations in the stimulus. The duration of individual fixations is modulated by the novelty and difficulty of the stimulus, likely reflecting cognitive demand

Neurotrophic gene polymorphisms and response to psychological therapy

Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR=0.60 (0.42–0.85), P=0.005). These effects remained even when other clinically relevant covariates were accounted for (OR=0.62 (0.41–0.92), P=0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions

Neuroanatomical Circuitry Associated with Exploratory Eye Movement in Schizophrenia: A Voxel-Based Morphometric Study

Schizophrenic patients present abnormalities in a variety of eye movement tasks. Exploratory eye movement (EEM) dysfunction appears to be particularly specific to schizophrenia. However, the underlying mechanisms of EEM dysfunction in schizophrenia are not clearly understood. To assess the potential neuroanatomical substrates of EEM, we recorded EEM performance and conducted a voxel-based morphometric analysis of gray matter in 33 schizophrenic patients and 29 well matched healthy controls. In schizophrenic patients, decreased responsive search score (RSS) and widespread gray matter density (GMD) reductions were observed. Moreover, the RSS was positively correlated with GMD in distributed brain regions in schizophrenic patients. Furthermore, in schizophrenic patients, some brain regions with neuroanatomical deficits overlapped with some ones associated with RSS. These brain regions constituted an occipito-tempro-frontal circuitry involved in visual information processing and eye movement control, including the left calcarine cortex [Brodmann area (BA) 17], the left cuneus (BA 18), the left superior occipital cortex (BA 18/19), the left superior frontal gyrus (BA 6), the left cerebellum, the right lingual cortex (BA 17/18), the right middle occipital cortex (BA19), the right inferior temporal cortex (BA 37), the right dorsolateral prefrontal cortex (BA 46) and bilateral precentral gyri (BA 6) extending to the frontal eye fields (FEF, BA 8). To our knowledge, we firstly reported empirical evidence that gray matter loss in the occipito-tempro-frontal neuroanatomical circuitry of visual processing system was associated with EEM performance in schizophrenia, which may be helpful for the future effort to reveal the underlying neural mechanisms for EEM disturbances in schizophrenia

Translational studies in the complex role of neurotransmitter systems in anxiety and anxiety disorders

Discovery of innovative anxiolytics is severely hampering. Existing anxiolytics are developed decades ago and are still the therapeutics of choice. Moreover, lack of new drug targets forecasts a severe jeopardy in the future treatment of the huge population of CNS-diseased patients. We simply lack the knowledge on what is wrong in brains of anxious people (normal and diseased). Translational research, based on interacting clinical and preclinical research, is extremely urgent. In this endeavor, genetic and genomic approaches are part of the spectrum of contributing factors. We focus on three druggable targets: serotonin transporter, 5-HT1A, and GABAA receptors. It is still uncertain whether and how these targets are involved in normal and diseased anxiety processes. For serotonergic anxiolytics, the slow onset of action points to indirect effects leading to plasticity changes in brain systems leading to reduced anxiety. For GABAA benzodiazepine drugs, acute anxiolytic effects are found indicating primary mechanisms directly influencing anxiety processes. Close translational collaboration between fundamental academic and discovery research will lead to badly needed breakthroughs in the search for new anxiolytics.</p

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p