Neuronal circuitry is often considered a clean slate that can be dynamically and arbitrarily molded by experience. However, when we investigated synaptic connectivity in groups of pyramidal neurons ...in the neocortex, we found that both connectivity and synaptic weights were surprisingly predictable. Synaptic weights follow very closely the number of connections in a group of neurons, saturating after only 20% of possible connections are formed between neurons in a group. When we examined the network topology of connectivity between neurons, we found that the neurons cluster into small world networks that are not scale-free, with less than 2 degrees of separation. We found a simple clustering rule where connectivity is directly proportional to the number of common neighbors, which accounts for these small world networks and accurately predicts the connection probability between any two neurons. This pyramidal neuron network clusters into multiple groups of a few dozen neurons each. The neurons composing each group are surprisingly distributed, typically more than 100 μm apart, allowing for multiple groups to be interlaced in the same space. In summary, we discovered a synaptic organizing principle that groups neurons in a manner that is common across animals and hence, independent of individual experiences. We speculate that these elementary neuronal groups are prescribed Lego-like building blocks of perception and that acquired memory relies more on combining these elementary assemblies into higher-order constructs.
D1 and D2 receptor expressing striatal medium spiny neurons (MSNs) are ascribed to striatonigral ("direct") and striatopallidal ("indirect") pathways, respectively, that are believed to function ...antagonistically in motor control. Glutamatergic synaptic transmission onto the two types is differentially affected by Dopamine (DA), however, less is known about the effects on MSN intrinsic electrical properties. Using patch clamp recordings, we comprehensively characterized the two pathways in rats and mice, and investigated their DA modulation. We identified the direct pathway by retrograde labeling in rats, and in mice we used transgenic animals in which EGFP is expressed in D1 MSNs. MSNs were subjected to a series of current injections to pinpoint differences between the populations, and in mice also following bath application of DA. In both animal models, most electrical properties were similar, however, membrane excitability as measured by step and ramp current injections consistently differed, with direct pathway MSNs being less excitable than their counterparts. DA had opposite effects on excitability of D1 and D2 MSNs, counteracting the initial differences. Pronounced changes in AP shape were seen in D2 MSNs. In direct pathway MSNs, excitability increased across experimental conditions and parameters, and also when applying DA or the D1 agonist SKF-81297 in presence of blockers of cholinergic, GABAergic, and glutamatergic receptors. Thus, DA induced changes in excitability were D1 R mediated and intrinsic to direct pathway MSNs, and not a secondary network effect of altered synaptic transmission. DAergic modulation of intrinsic properties therefore acts in a synergistic manner with previously reported effects of DA on afferent synaptic transmission and dendritic processing, supporting the antagonistic model for direct vs. indirect striatal pathway function.
Enteric viruses encounter diverse environments as they migrate through the gastrointestinal tract to infect their hosts. The interaction of eukaryotic viruses with members of the host microbiota can ...greatly impact various aspects of virus biology, including the efficiency with which viruses can infect their hosts. Mammalian orthoreovirus, a human enteric virus that infects most humans during childhood, is negatively affected by antibiotic treatment prior to infection. However, it is not known how components of the host microbiota affect reovirus infectivity. In this study, we show that reovirus virions directly interact with Gram positive and Gram negative bacteria. Reovirus interaction with bacterial cells conveys enhanced virion thermostability that translates into enhanced attachment and infection of cells following an environmental insult. Enhanced virion thermostability was also conveyed by bacterial envelope components lipopolysaccharide (LPS) and peptidoglycan (PG). Lipoteichoic acid and N-acetylglucosamine-containing polysaccharides enhanced virion stability in a serotype-dependent manner. LPS and PG also enhanced the thermostability of an intermediate reovirus particle (ISVP) that is associated with primary infection in the gut. Although LPS and PG alter reovirus thermostability, these bacterial envelope components did not affect reovirus utilization of its proteinaceous cellular receptor junctional adhesion molecule-A or cell entry kinetics. LPS and PG also did not affect the overall number of reovirus capsid proteins σ1 and σ3, suggesting their effect on virion thermostability is not mediated through altering the overall number of major capsid proteins on the virus. Incubation of reovirus with LPS and PG did not significantly affect the neutralizing efficiency of reovirus-specific antibodies. These data suggest that bacteria enhance reovirus infection of the intestinal tract by enhancing the thermal stability of the reovirus particle at a variety of temperatures through interactions between the viral particle and bacterial envelope components.
To determine the occurrence of neuropsychiatric symptomatology and the relation to future development of Alzheimer disease (AD) in persons with and without mild cognitive impairment (MCI).
We ...followed 185 persons with no cognitive impairment and 47 with MCI (amnestic and multidomain), ages 75 to 95, from the population-based Kungsholmen Project, Stockholm, Sweden, for 3 years. Three types of neuropsychiatric symptoms were assessed at baseline: mood-related depressive symptoms, motivation-related depressive symptoms, and anxiety-related symptomatology. AD at 3-year follow-up was diagnosed according to Diagnostic and Statistical Manual for Mental Disorders-III-R criteria.
Psychiatric symptoms occurred more frequently in persons with MCI (36.2% mood, 36.2% motivation, and 46.8% anxiety symptoms) than in cognitively intact elderly individuals (18.4% mood, 13.0% motivation, and 24.9% anxiety). Of persons with both MCI and anxiety symptoms, 83.3% developed AD over follow-up vs 6.1% of cognitively intact persons and 40.9% persons who had MCI without anxiety. Among persons with MCI, the 3-year risk of progressing to AD almost doubled with each anxiety symptom (relative risk RR = 1.8 1.2 to 2.7 per symptom). Conversely, among cognitively intact subjects, only symptoms of depressive mood were related to AD development (RR = 1.9 1.0 to 3.6 per symptom).
The predictive validity of mild cognitive impairment (MCI) for identifying future Alzheimer disease (AD) cases is improved in the presence of anxiety symptoms. Mood-related depressive symptoms (dysphoria, suicidal ideation, etc.) in preclinical AD might be related to the neuropathologic mechanism, as they appear preclinically in persons both with and without MCI.
Multimorbidity, defined as the coexistence of 2 or more chronic diseases, is a common phenomenon especially in older people. Numerous efforts to establish a standardized instrument to assess the ...level of multimorbidity have failed until now, and indices are primarily characterized by their high heterogeneity. Thus, the objective is to provide a comprehensive overview on existing instruments on the basis of a systematic literature review.
The review was performed in MedLine. All articles published between January 1, 1960 and August 31, 2009 in German or English language, with the primary focus either on the development of a weighted index or on the effect of multimorbidity on different outcomes, were identified.
A total of 39 articles met the inclusion criteria. In the majority of studies (59.0%), the list of included diseases was presented without any selection criteria. Only the high prevalence of diseases (17.9%), their impact on mortality, function, and health status served as a point of reference. Information on the prevalence of chronic conditions mostly rely on self-reports. On average, the 39 indices included 18.5 diseases, ranging between 4 and 102 different conditions. Most frequently mentioned diseases were diabetes mellitus (in 97.5% of indices), followed by stroke (89.7%), hypertension, and cancer (each 84.6%). Overall, three different weighting methods could be distinguished.
The systematic literature further emphasis the heterogeneity of existing multimorbidity indices. However, one important similarity is that the focus is on diseases with a high prevalence and a severe impact on affected individuals.
In order to increase the reach of the astrophysical searches, various sources of instrumental and environmental noise must be identified and ameliorated. Here we discuss efforts to understand the ...origin of noise manifested as short-duration bursts (glitches) and/or range-impacting features at LIGO Hanford. Several examples found at LIGO Hanford Observatory in O1 and O2 were identified including glitches due to an air compressor, ringing phone, airplanes, and an incorrect servo setting, and a decrease in detector sensitivity due to truck traffic.
Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with ...multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies.
For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry.
We obtained 10 133 blood samples from 5390 people (median samples per patient 1 IQR 1–2 in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 IQR 3·0–8·0). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry.
The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials.
Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche.
Cognitive dysfunction is a frequent complication after cardiac surgery and has been found to be associated with decreases in cerebral oxygen saturation ScO2 measured with near-infrared spectroscopy. ...Sevoflurane has neuroprotective properties in vitro and in animal models. This study was designed to determine cognitive and clinical outcomes after sevoflurane- compared with propofol-based anaesthesia for on-pump cardiac surgery and the impact of decreases in ScO2 under different anaesthesia regimens.
One hundred and twenty-eight patients were randomly assigned to either i.v. anaesthesia with propofol- (PROP) or sevoflurane-based anaesthesia (SEVO). An intraoperative ScO2 <50% was defined as desaturation. The Abbreviated Mental Test, Stroop Test, Trail-Making Test, Word Lists, and mood-assessment tests were performed before, 2, 4, and 6 days after cardiac surgery. Markers of general outcome were obtained.
The analysis groups had differences in baseline cognitive performance. Analysis of variance for repeated measures (incorporating covariance of baseline scores) showed that in three of four cognitive tests, patients with cerebral desaturation showed worse results than patients without desaturation. Patients assigned to sevoflurane-based anaesthesia showed better results in all cognitive tests than patients after propofol. Interactions between the anaesthetic regimen and desaturation were found in all four cognitive tests. There were no differences in markers of organ dysfunction or general clinical outcome.
Patients with impaired cognitive performance before operation may be at particular risk for intraoperative cerebral insult. A sevoflurane-based anaesthesia was associated with better short-term postoperative cognitive performance than propofol.
Background and purpose
In contrast to anterior circulation stroke (ACS), there is no evidence from randomized trials that mechanical thrombectomy (MT) with modern stent retrievers or ...thromboaspiration is safe and effective in posterior circulation stroke (PCS).
Methods
The present analysis was based on the prospective multicentre Registry on Revascularization in Ischemic Stroke Patients (REVASK) in Germany. Demographic data, periprocedural times and complications, recanalization rates, and functional outcome at discharge and after 3 months were compared between 139 consecutive patients with PCS (84.9% basilar artery, 16.5% vertebral artery and 4.3% posterior cerebral artery occlusion) and 961 patients with ACS treated with MT.
Results
Compared to ACS, PCS patients were significantly younger (65 vs. 69 years, P = 0.021) and had a lower median National Institutes of Health Stroke Scale (NIHSS) score at baseline (12 vs. 15, P = 0.024). Patients with PCS had a significantly longer time delay between symptom onset and both start and end of the MT procedure. Successful recanalization and thrombectomy passes did not significantly differ between the two groups. No symptomatic intracranial haemorrhage occurred in PCS compared to 3% in ACS (P = 0.010). The median NIHSS score at discharge was 3 in PCS and 4 in ACS. Favourable functional outcome at 3 months (modified Rankin Scale 0–2 38.0% vs. 42.6%, P = 0.392) and mortality (33.7% vs. 30.8%, P = 0.539) did not differ significantly between PCS and ACS.
Conclusions
The study suggests that MT in PCS shows a lower risk of symptomatic intracranial haemorrhage and similar effectiveness compared to ACS. PCS patients also seem to benefit from MT started beyond 6 h after symptom onset.
Background
The aim of this study was to evaluate the effect of smoking on taste and smell impairment in a large population- based study.
Study design
Cross-sectional survey in Dortmund, Germany.
...Methods
The population sample was randomly drawn from the city’s central registration office. Following a standardized interview, validated taste and smell tests were performed. Descriptive statistics and logistic regression was used in the analysis.
Results
Among the 1312 study participants, 3.6 % were functionally anosmic, and 18 % had olfactory dysfunction. Approximately 20 % recognized only three or less of the four tastes when presented at suprathreshold concentrations, indicating signs of taste impairment. Current smoking in general increased the risk for impairment of olfactory function (odds ratio 1.71, 95 % CI 1.19–2.47), but not the risk for taste impairment. Heavy smokers of 20 or more cigarettes/day had significant increased risks for impairment in both senses.
Conclusions
Our results reveal that both olfactory and gustatory function are compromised in a significant proportion of the general population. Smoking increases significantly the risk of impairment of olfactory function. Our findings add an important detail to the large body of evidence that describes adverse health effects of smoking.
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