Mathematical Disease Progression Modeling in Type 2/3 Spinal Muscular Atrophy.

INTRODUCTION: We propose a mathematical model to empirically describe spinal muscular atrophy (SMA) progression assessed by the 3 domains of the motor function measure (MFM) scale. The model implements development and deterioration of muscle function. METHODS: Nonlinear mixed-effects modeling was applied to data from 2 observational studies and 1 prospective clinical efficacy study comprising 190 healthy participants and 277 patients with type 2/3 SMA. RESULTS: The model evidenced correlations between parameter estimates for different MFM domains. Slower development in MFM domain D1 (standing and transfers) was associated with faster deterioration for MFM domains D2 (proximal and axial motricity) and D3 (distal motor function). DISCUSSION: The model describes all individual data well, although sparseness and variability of observational data prevented numerically stable estimation of parameters. Treatment duration in clinical studies was too limited to determine a proper drug-effect model that could differentiate between symptomatic and disease modifying effects. Muscle Nerve 58: 528-535, 2018.

Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. METHODS: This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600. FINDINGS: The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and -1·82 for placebo (treatment difference 2·00 points, 96% CI -0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. INTERPRETATION: Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. FUNDING: AFM Téléthon and Trophos SA.

Common component classification: what can we learn from machine learning?

Machine learning methods have been applied to classifying fMRI scans by studying locations in the brain that exhibit temporal intensity variation between groups, frequently reporting classification accuracy of 90% or better. Although empirical results are quite favorable, one might doubt the ability of classification methods to withstand changes in task ordering and the reproducibility of activation patterns over runs, and question how much of the classification machines' power is due to artifactual noise versus genuine neurological signal. To examine the true strength and power of machine learning classifiers we create and then deconstruct a classifier to examine its sensitivity to physiological noise, task reordering, and across-scan classification ability. The models are trained and tested both within and across runs to assess stability and reproducibility across conditions. We demonstrate the use of independent components analysis for both feature extraction and artifact removal and show that removal of such artifacts can reduce predictive accuracy even when data has been cleaned in the preprocessing stages. We demonstrate how mistakes in the feature selection process can cause the cross-validation error seen in publication to be a biased estimate of the testing error seen in practice and measure this bias by purposefully making flawed models. We discuss other ways to introduce bias and the statistical assumptions lying behind the data and model themselves. Finally we discuss the complications in drawing inference from the smaller sample sizes typically seen in fMRI studies, the effects of small or unbalanced samples on the Type 1 and Type 2 error rates, and how publication bias can give a false confidence of the power of such methods. Collectively this work identifies challenges specific to fMRI classification and methods affecting the stability of models.

Brain networks underlying perceptual habituation to repeated aversive visceral stimuli in patients with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) show decreased discomfort and pain thresholds to visceral stimuli, as well hypervigilance to gastrointestinal sensations, symptoms, and the context in which these visceral sensations and symptoms occur. Previous research demonstrated normalization of visceral hypersensitivity following repeated exposure to experimental rectal stimuli over a 12-month period that was associated with reduction in cortical regions functionally associated with attention and arousal. Building upon these functional analyses, multivariate functional and effective connectivity analyses were applied to [(15)O] water positron emission tomography (PET) data from 12 IBS patients (male=4) participating in a PET study before and after 4 visceral sensory testing sessions involving rectal balloon distensions over a 1-year period. First, behavioral partial least squares was applied to test for networks related to reduced subjective ratings observed following repeated application of an aversive rectal stimulus. Next, path analysis within a structural equation modeling framework tested the hypothesis that perceptual habituation to the repeated visceral stimuli resulted in part from the reduced connectivity within a selective attention to threat network over time. Two independent, perception-related networks comprised of interoceptive, attentional and arousal regions were engaged differentially during expectation and distension. In addition, changes in the effective connectivity of an attentional network as well as modulatory amygdala influence suggested that perceptual habituation associated with repeated stimulus delivery results both in an increase in top-down modulation of attentional circuits, as well as in a reduction of amygdala-related interference with attentional mechanisms.

Does vivid emotional imagery depend on body signals?

The recall and re-experiencing of a personal emotional event (emotional imagery) are thought to evoke neural activity in the central nervous system that can affect the physiology of bodily states. It has been proposed that the more active the neural systems previously engaged in the emotional experience, and the more active the bodily state associated with that experience, the more vivid the emotional imagery is. The sympathetic nervous system (SNS) and the gastrointestinal system (GI) are engaged in emotional reactions. On this basis, we hypothesized that vivid emotional imagery would be accompanied by strong increases in gastrointestinal and sympathetic nervous system activity. To test this hypothesis, 17 healthy participants performed emotional imagery of strong autobiographical memories involving various emotional states (happy, fear, disgust, sadness, anger). SNS and GI changes, measured by skin conductance and electrogastrogram, respectively, correlated positively with subjective ratings of arousal during the imagery. However, the SNS changes did not correlate with ratings of emotional imagery vividness, and even more intriguingly, the GI changes correlated strongly and negatively with vividness ratings. To account for these findings, we propose that in highly vivid imagery experience, the central nervous system is simulating the whole emotional experience strongly, and bodily information plays a lesser role. In low vivid imagery experience, the central nervous system is not simulating very strongly the emotional experience, and information coming from the body (including the GI system) plays a greater role. This interpretation is set forth in the context of Damasio's [Damasio, A., (1999) The feeling of what happens: body and emotion in the making of consciousness, Orlando, Fl, Harcourt.] theoretical framework, which predicts such a dissociation between a "body loop" and an "as if body loop" for the experiencing and re-experiencing of emotions and feelings.

Neuroanatomical correlates of the Benton Facial Recognition Test and Judgment of Line Orientation Test.

Two of the most successful and widely used tests developed by Arthur Benton and colleagues are the Facial Recognition Test (FRT) and Judgment of Line Orientation Test (JLO), which probe visuoperceptual and visuospatial functions typically associated with right hemisphere structures, especially parietal, occipitoparietal, and occipitotemporal structures. Taking advantage of a large database of focal lesion patients (the Iowa Neurological Patient Registry), we used a new lesion-deficit mapping technique to investigate the neuroanatomical correlates of FRT and JLO performance. For the FRT, there were 201 patients with relevant data; of these, 38 were impaired on the FRT, and failure was most strongly associated with lesions in the right posterior-inferior parietal and right ventral occipitotemporal (fusiform gyrus) areas. For the JLO, there were 181 patients with relevant data; of these, 23 were impaired on the JLO, and failure was most strongly associated with lesions in the right posterior parietal region. These findings put new empirical teeth in the localizing value of the FRT and JLO tests, and they extend and sharpen previous work that had pointed to right posterior structures as being important for FRT and JLO performance

Does the Clock Drawing Test have focal neuroanatomical correlates?

The Clock Drawing Test (CDT) is widely used in clinical neuropsychological practice. The CDT has been used traditionally as a "parietal lobe" test (e.g., Kaplan, 1988), but most empirical work has focused on its sensitivity and specificity for detecting and differentiating subtypes of dementia. There are surprisingly few studies of its neuroanatomical correlates. The authors investigated the neuroanatomical correlates of the CDT, using 133 patients whose lesions provided effective coverage of most of both hemispheric convexities and underlying white matter. On the CDT, 30 subjects were impaired and 87 were unimpaired (16 were "borderline"). Impairments on the CDT were associated with damage to right parietal cortices (supramarginal gyrus) and left inferior frontal-parietal opercular cortices. Visuospatial errors were predominant in patients with right hemisphere damage, whereas time setting errors were predominant in patients with left hemisphere lesions. These findings provide new empirical evidence regarding the neuroanatomical correlates of the CDT, and together with previous work, support the use of this quick and easily administered test not only as a screening measure but also as a good index of focal brain dysfunction.

Increased feelings with increased body signals.

Since the beginning of psychology as a scientific endeavour, the question of whether the body plays a role in how a person experiences emotion has been the centre of emotion research. Patients with structural gastrointestinal disorders, such as Crohn's disease, provide an intriguing opportunity to study the influence of body signals on emotions and feelings. In the present study, emotionally salient films were presented to participants with Crohn's disease in either the active state (Crohn's-active, CA) or silent state (Crohn's-silent, CS), and to normal comparison (NC) participants. We hypothesized that CA participants would have increased feelings, compared with CS and NC participants, when viewing emotional films designed to elicit happiness, disgust, sadness and fear. Gastric myoelectrical activity (electrogastrogram, or EGG) was measured during the films, and after each film was presented, participants rated emotion intensity (arousal) and pleasantness (valence). All groups labelled the emotions similarly. In support of the hypothesis, CA participants showed an increase in subjective arousal for negative emotions compared with CS and NC participants. The CA participants also showed increased EGG during emotional film viewing, as well as a strong positive correlation of EGG with arousal ratings. Together, these findings can be taken as evidence that aberrant feedback from the gastrointestinal system up-regulates the intensity of feelings of negative emotions.

Modulation of seizures and synaptic plasticity by adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats.

PURPOSE: Adenosine is a major negative neuromodulator of synaptic activity in the central nervous system and can exert anticonvulsant and neuroprotective effects in many experimental models of epilepsy. Extracellular adenosine can be formed by a membrane-anchored enzyme ecto-5'-nucleotidase. The purposes of this study were to characterize the role of adenosine receptors in modulating status epilepticus (SE) induced by pilocarpine and evaluate its neuroprotective action. Ecto-5'-nucleotidase activity was studied during the different phases of pilocarpine-induced epilepsy in rats. METHODS: Adult rats were pretreated with different adenosinergic agents to evaluate the latency and incidence of SE induced by pilocarpine in rats. The neuroprotective effect also was evaluated. RESULTS: A proconvulsant effect was observed with DPCPX and DMPX that reduced the latency of SE in almost all rats. Pretreatment with the MRS 1220 did not alter the incidence of SE but reduced the latency to develop SE. An anticonvulsant and neuroprotective effect was detected with R-PIA. Rats pretreated with R-PIA had a decreased number of apoptotic cells in the hippocampus, whereas pretreatment with DPCPX did not modify the hippocampal damage. An intensification of neuronal death was observed in the dentate gyrus and CA3 when rats were pretreated with DMPX. MRS-1220 did not modify the number of apoptotic cells in the hippocampus. An increase in the ecto-5 -nucleotidase staining was detected in the hippocampus during silent and chronic phases. CONCLUSIONS: The present data show that adenosine released during pilocarpine-induced SE via A1-receptor stimulation can exhibit neuroprotective and anticonvulsant roles. Similar effects could also be inferred with A2a and A3 adenosinergic agents, but further experiments are necessary to confirm their roles. Ecto-5 -nucleotidase activity during silent and chronic phases might have a role in blocking spontaneous seizures by production of inhibitory neuromodulator adenosine, besides taking part in the mechanism that controls sprouting.

Anestesia em paciente com distrofia muscular de Duchenne: relato de caso / Anesthesia in DuchenneÆs Muscular Dystrophy patient: case report

JUSTIFICATIVA E OBJETIVOS: A distrofia muscular de Duchenne é uma afecçäo recessiva ligada ao cromossomo X, geralmente diagnosticada na infância, acentuando-se progressivamente até agravar a funçäo respiratória. O objetivo deste relato é apresentar um caso de um paciente com distrofia muscular de Duchenne diagnosticada há 2 anos, submetido à postectomia, sob anestesia geral com cetamina S. RELATO DO CASO: Paciente com 9 anos de idade com Distrofia Muscular de Duchenne diagnosticada há 2 anos, submetido à anestesia geral com levo-cetamina (1,5 mg.kg-1), por via venosa, sob ventilaçäo espontânea assistida manualmente por sistema de Baraka (Mapleson A) e bloqueio peniano com bupivacaína a 0,5 por cento (25 mg). Foram usados monitores de pressäo arterial näo invasiva, oximetria de pulso, cardioscopia e temperatura esofagiana. No decorrer da cirurgia, o caso evoluiu sem intercorrências, sendo que no período pós-operatório o paciente apresentou alguns episódios de vômitos sem outras alterações significativas. Permaneceu internado por 24 horas, tendo alta hospitalar assintomático. CONCLUSÕES: A avaliaçäo pré-anestésica cuidadosa, o uso de monitorizaçäo adequada e medicações que näo predisponham o aparecimento de complicações tornam seguro o procedimento em pacientes portadores de Distrofia Muscular de Duchenne e seu pós-operatório

[Anesthesia in Duchennes Muscular Dystrophy patient: case report]. / Anestesia em paciente com Distrofia Muscular de Duchenne: relato de caso.

BACKGROUND AND OBJECTIVES: Duchennes Muscular Dystrophy is an X-linked recessive disorder, generally diagnosed in childhood, which progressively worsens to degenerate respiratory function. This report aimed at presenting the case of a patient with Duchennes Muscular Dystrophy diagnosed 2 years before, submitted to postectomy under general anesthesia with ketamine S. CASE REPORT: Male patient, 9 years old, with Duchennes Muscular Dystrophy diagnosed 2 years before, submitted to general anesthesia with intravenous levo-ketamine (1.5 mg.kg-1), under spontaneous ventilation manually assisted by Mapleson A Baraka system and penile block with 25 mg of 0.5% bupivacaine. Monitoring consisted of non invasive blood pressure, pulse oximetry, cardioscopy and esophageal temperature. There were no incidents during surgery, and after surgery patient had a few vomiting episodes, without other significant complications. Patient remained in hospital for 24 hours and was discharged asymptomatic. CONCLUSIONS: Very careful pre-anesthetic evaluation, adequate monitoring and drugs not predisposing to complications make surgery and postoperative period safe for Duchennes Muscular Dystrophy patients.

Serial clinical, colpo-cytological and endocrinological evaluations of Cerdocyon thous bitches from the Rio de Janeiro zoo

Serial clinical, colpo-cytological and endocrinological examinations of two five-year-old females of the crab-eating dog (Cerdocyon thous), from the RIOZOO Foundation in the State of Rio de Janeiro - Brazil, were carried out over a 10-month period. Clinically healthy animals were kept in sand substratum enclosures, located 500m apart from each other. They were each housed with two males. The colpo-cytological technique employed for Cerdocyon thous used methods similar to those developed for domestic bitches. Unlike domestic dogs, blood cells were absent in all phases of the estrus cycle, including the pro-estrus phase. Differentiation of each type of vaginal cells during the estrus cycle phases in this species follows the same patterns shown by domestic bitches. The estradiol and progesterone levels were similar to those occurring in domestic bitches. The progesterone levels reach their maximum (46 ng/ml) around the 10th day of pregnancy. The estradiol analysis demonstrated that, although levels of this hormone could be high at various times throughout the year, mating actually occurs in late winter and in spring. It was impossible to evaluate whether males and females kept in close proximity throughout the entire year would stimulate the production of estradiol, resulting in what would be considered a captivity artifice