Teriflunomide, cognition and MRI: A longitudinal study.

BACKGROUND: As cognitive impairment in multiple sclerosis (MS) is a frequent and disabling symptom, it is particularly important to identify treatments that have proven efficacy in this aspect of the disease. Several disease-modifying therapies for MS have been evaluated and shown to have a potential effect on cognition and its neurobiological correlates, but to date there is very little data on Teriflunomide (TRF). The aim of this study is to explore the influence of TRF on comprehensive cognitive function and its MRI correlations (global and focal brain volume) in relapsing-remitting multiple sclerosis (RRMS) after two years of therapy. METHODS: Twenty-four patients with RRMS were evaluated at baseline and after two years of treatment with BCcogSEP, a French translation of the Brief Repeatable Battery (BRB-N) including 3 additional tests. We explored the performance evolution for each test and correlation with MRI data for all patients. We also differentiated MS patients with and without cognitive impairment. RESULTS: After two years of treatment, an improvement is observed at the Selective Reminding Test for mean number of words (p = 0.044), learning (p = 0.018), and delayed recall (p = 0.002) and at GoNoGo task (p = 0.022). At MRI, the corpus callosum volume variation correlates positively with SRT total recall test (p = 0,047). Intergoup analysis shows that the evolution of group performance differs only for the SRT total recall test. The comparison of patients with or without cognitive impairment showed a clear difference in white matter substance volume (p = 0,003) and in the Percentage Brain Volume Change (p = 0,016). CONCLUSION: Results suggest that TRF treatment in RRMS has a positive effect in cognitive function, and specifically on long term verbal memory and inhibition. Neuroimaging data suggest a link between cognition and global and focal white matter volume, particularly in the corpus callosum which is involved in anatomical disconnection syndrome and therefore brain plasticity capacities.

The multimodal connectivity of the hippocampal complex in auditory and visual hallucinations.

Hallucinations constitute one of the most representative and disabling symptoms of schizophrenia. Several Magnetic Resonance Imaging (MRI) findings support the hypothesis that distinct patterns of connectivity, particularly within networks involving the hippocampal complex (HC), could be associated with different hallucinatory modalities. The aim of this study was to investigate HC connectivity as a function of the hallucinatory modality, that is, auditory or visual. Two carefully selected subgroups of schizophrenia patients with only auditory hallucinations (AH) or with audio-visual hallucinations (A+VH) were compared using the following three complementary multimodal MRI methods: resting state functional MRI, diffusion MRI and structural MRI were used to analyze seed-based Functional Connectivity (sb-FC), Tract-Based Spatial Statistics (TBSS) and shape analysis, respectively. Sb-FC was significantly higher between the HC, the medial prefrontal cortex (mPFC) and the caudate nuclei in A+VH patients compared with the AH group. Conversely, AH patients exhibited a higher sb-FC between the HC and the thalamus in comparison with the A+VH group. In the A+VH group, TBSS showed specific higher white matter connectivity in the pathways connecting the HC with visual areas, such as the forceps major and the inferior-fronto-occipital fasciculus than in the AH group. Finally, shape analysis showed localized hippocampal hypertrophy in the A+VH group. Functional results support the fronto-limbic dysconnectivity hypothesis of schizophrenia, while specific structural findings indicate that plastic changes are associated with hallucinations. Together, these results suggest that there are distinct connectivity patterns in patients with schizophrenia that depend on the sensory-modality, with specific involvement of the HC in visual hallucinations.

Recruitment and derecruitment during acute respiratory failure: a clinical study.

In a model of acute lung injury, we showed that positive end-expiratory pressure (PEEP) and tidal volume (VT) are interactive variables that determine the extent of lung recruitment, that recruitment occurs across the entire range of total lung capacity, and that superimposed pressure is a key determinant of lung collapse. Aiming to verify if the same rules apply in a clinical setting, we randomly ventilated five ALI/ARDS patients with 10, 15, 20, 30, 35, and 45 cm H2O plateau pressure and 5, 10, 15, and 20 cm H2O of PEEP. For each PEEP-VT condition, we obtained computed tomography at end inspiration and end expiration. We found that recruitment occurred along the entire volume-pressure curve, independent of lower and upper inflection points, and that estimated threshold opening pressures were normally distributed (mode = 20 cm H2O). Recruitment occurred progressively from nondependent to dependent lung regions. Overstretching was not associated with hyperinflation. Derecruitment did not parallel deflation, and estimated threshold closing pressures were normally distributed (mode = 5 cm H2O). End-inspiratory and end-expiratory collapse were correlated, suggesting a plateau-PEEP interaction. When superimposed gravitational pressure exceeded PEEP, end-expiratory collapse increased. We concluded that the rules governing recruitment and derecruitment equally apply in an oleic acid model and in human ALI/ARDS.

Placental passage and uterine effects of fentanyl.

Using the chronic maternal-fetal sheep preparation, 27 pregnant ewes were studied to determine the effects of intravenous fentanyl on maternal and fetal physiology, with particular reference to its placental passage, and its effects on uterine blood flow and uterine tone. Three doses of fentanyl were studied--50, 75, and 100 micrograms. Maternal and fetal arterial blood was collected for determination of fentanyl levels. All blood levels, both maternal and fetal, were normalized to the 50-micrograms dose. The maternal normalized blood levels were found to fit a biexponential equation describing a two-compartment open model. The half-life of the maternal elimination phase was 42 +/- 7.0 min with an overall elimination constant (K) of 0.21 min-1. Maternal plasma fentanyl levels decreased very rapidly in the first 10 min after injection, at which time only 9% of the peak value remained. Fentanyl was detectable in fetal blood as early as 1 min and levels peaked at 5 min. Once equilibrium was established between maternal and fetal blood, the maternal levels remained 2.5 times those of the fetal level from 5 min to 60 min after drug injection. Both maternal and fetal drug levels declined in an approximately parallel fashion. No significant deleterious changes were seen in any maternal or fetal cardiovascular or acid-base parameters, and uterine blood flow and uterine tone were also unaffected (P greater than 0.05).

The maternal and fetal cardiovascular effects of epidural morphine in the sheep model.

Interest in the use of epidural narcotics for analgesia has been widespread since the demonstration of opiate receptors in the spinal cord in the mid nineteen-seventies. Recently, several studies have attempted to evaluate the effectiveness of epidural narcotics for the relief of pain in labor and after cesarean section. Using the chronically catheterized maternal-fetal sheep model, we injected 5 mg of preservative-free morphine into the epidural space. No statistically significant changes were observed, neither in maternal or fetal arterial pressure and acid-base status, nor in maternal central venous pressure, systemic and pulmonary vascular resistance, cardiac output, or intrauterine pressure (p greater than 0.05). There was a significant, although small, decrease in maternal heart rate (8%) and uterine blood flow (9%) at 120 minutes (p less than 0.05), and then a return to control values. The maternal levels of morphine peaked at 15 minutes (29 ng/ml) and the fetal levels of morphine peaked at 90 minutes (3 to 4 ng/ml). We conclude that the injection of 5 mg of morphine into the maternal epidural space has no adverse effect on mother or fetus in the sheep model.