The neural correlates of anesthetic-induced unconsciousness have yet to be fully elucidated. Sedative and anesthetic states induced by propofol have been studied extensively, consistently revealing a ...decrease of frontoparietal and thalamocortical connectivity. There is, however, less understanding of the effects of halogenated ethers on functional brain networks.
The authors recorded simultaneous resting-state functional magnetic resonance imaging and electroencephalography in 16 artificially ventilated volunteers during sevoflurane anesthesia at burst suppression and 3 and 2 vol% steady-state concentrations for 700 s each to assess functional connectivity changes compared to wakefulness. Electroencephalographic data were analyzed using symbolic transfer entropy (surrogate of information transfer) and permutation entropy (surrogate of cortical information processing). Functional magnetic resonance imaging data were analyzed by an independent component analysis and a region-of-interest-based analysis.
Electroencephalographic analysis showed a significant reduction of anterior-to-posterior symbolic transfer entropy and global permutation entropy. At 2 vol% sevoflurane concentrations, frontal and thalamic networks identified by independent component analysis showed significantly reduced within-network connectivity. Primary sensory networks did not show a significant change. At burst suppression, all cortical networks showed significantly reduced functional connectivity. Region-of-interest-based thalamic connectivity at 2 vol% was significantly reduced to frontoparietal and posterior cingulate cortices but not to sensory areas.
Sevoflurane decreased frontal and thalamocortical connectivity. The changes in blood oxygenation level dependent connectivity were consistent with reduced anterior-to-posterior directed connectivity and reduced cortical information processing. These data advance the understanding of sevoflurane-induced unconsciousness and contribute to a neural basis of electroencephalographic measures that hold promise for intraoperative anesthesia monitoring.
Multiple system atrophy is a progressive neurodegenerative disease characterized by the association of autonomic failure and a movement disorder that consist of either a hypokinetic movement disorder ...or a cerebellar syndrome or both. In addition to these core characteristics other movement disorders (e.g. dystonia, myoclonus, spasticity), and neuropsychiatric symptoms (e.g. depression, cognitive dysfunction) may occur in the course of the disease and can severely impair patients' quality of live. To date no causal therapy is available and therefore symptomatic treatment plays a pivotal role in patient care. In this article we provide an overview of frequent clinical symptoms and their symptomatic treatment options.
Progressive supranuclear palsy (PSP) is a neurodegenerative movement disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells of the brain. These ...deposits are a key neuropathological finding, allowing a diagnosis of "definite PSP," which is usually established post mortem. To date criteria for clinical diagnosis of PSP
do not include biomarkers of tau pathology. For intervention trials, it is increasingly important to (i) establish biomarkers for an early diagnosis and (ii) to develop biomarkers that correlate with disease progression of PSP.
F-THK5351 is a novel PET-ligand that may afford
visualization and quantification of tau-related alterations. We investigated binding characteristics of
F-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. Eleven patients (68.4 ± 7.4 year;
= 6 female) with probable PSP according to current clinical criteria and nine healthy controls (71.7 ± 7.2 year;
= 4 female) underwent
F-THK5351 PET scanning. Voxel-wise statistical parametric comparison and volume-of-interest based quantification of standardized-uptake-values (SUV) were conducted using the cerebellar cortex as reference region. We correlated disease severity as measured with the help of the PSP Rating Scale (PSPRS) as well as several other clinical parameters with the individual PET findings. By voxel-wise mapping of
F-THK5351 uptake in the patient group we delineated typical distribution patterns that fit to known tau topology for PSP post mortem. Quantitative analysis indicated the strongest discrimination between PSP patients and healthy controls based on tracer uptake in the midbrain (+35%;
= 3.01E-7; Cohen's d: 4.0), followed by the globus pallidus, frontal cortex, and medulla oblongata. Midbrain
F-THK5351 uptake correlated well with clinical severity as measured by PSPRS (
= 0.66;
= 0.026). OCT and MRI delineated PSP patients from healthy controls by use of established discrimination thresholds but only OCT did as well correlate with clinical severity (
= 0.79;
= 0.024). Regional
F-THK5351 binding patterns correlated well with the established post mortem distribution of lesions in PSP and with clinical severity. The contribution of possible MAO-B binding to the
F-THK5351 signal needs to be further evaluated, but nevertheless
F-THK5351 PET may still serve as valuable biomarker for diagnosis of PSP.
Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e. aggregates of ...α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to MAO-B has been observed across first generation ligands. Nonetheless, astrogliosis related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of 18F-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. 18F-THK5351 PET was performed in 34 patients: six with Parkinson’s disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C) and 13 with progressive supranuclear palsy (PSP) Richardson’s syndrome. Volume-of-interest based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated 18F-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with 18F-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.
AIM： To investigate the clinical presentations associated with bile acid synthesis defects and to describe identification of individual disorders and diagnostic pitfalls. METHODS： We describe ...semiquantitative determination of 16 urinary bile acid metabolites by electrospray ionization-tandem mass spectrometry. Sample preparation was performed by solid-phase extraction. The total analysis time was 2 min per sample. We determined bile acid metabolites in 363 patients with suspected defects in bile acid metabolism. RESULTS： Abnormal bile acid metabolites were found in 36 patients. Two patients had bile acid synthesis defects but presented with atypical presentations. In 2 other patients who were later shown to be affected by biliary atresia and cystic fibrosis the profile of bile acid metabolites was initially suggestive of a bile acid synthesis defect. Three adult patients suffered from cerebrotendinous xanthomatosis. Nineteen patients had peroxisomal disorders, and 10 patients had cholestatic hepatopathy of other cause. CONCLUSION： Screening for urinary cholanoids should be done in every infant with cholestatic hepatopathy as well as in children with progressive neurological disease to provide specific therapy.
Introduction
Changes in neural activity induce changes in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) signal. Commonly, increases in BOLD signal are ascribed to ...cellular excitation.
Objective
The relationship between electrical activity and BOLD signal in the human brain was probed on the basis of burst suppression EEG. This condition includes two distinct states of high and low electrical activity.
Methods
Resting‐state simultaneous EEG and BOLD measurements were acquired during deep sevoflurane anesthesia with burst suppression EEG in nineteen healthy volunteers. Afterwards, fMRI volumes were assigned to one of the two states (burst or suppression) as defined by the EEG.
Results
In the frontal, parietal and temporal lobes as well as in the basal ganglia, BOLD signal increased after burst onset in the EEG and decreased after onset of EEG suppression. In contrast, BOLD signal in the occipital lobe was anticorrelated to electrical activity. This finding was obtained consistently in a general linear model and in raw data.
Conclusions
In human brains exhibiting burst suppression EEG induced by sevoflurane, the positive correlation between BOLD signal and electrical brain activity could be confirmed in most gray matter. The exceptional behavior of the occipital lobe with an anticorrelation of BOLD signal and electrical activity might be due to specific neurovascular coupling mechanisms that are pronounced in the deeply anesthetized brain.
In human brains exhibiting burst suppression EEG induced by sevoflurane, the positive correlation between BOLD signal and electrical brain activity could be confirmed in most gray matter. The exceptional behavior of the occipital lobe with an anticorrelation of BOLD signal and electrical activity might be due to specific neurovascular coupling mechanisms that are pronounced in the deeply anesthetized brain.
This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, ...studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic dermatitis (AD) pathology. Four randomized clinical studies (Phase 1 and 2) investigated the safety, ...tolerability, efficacy, and pharmacokinetic profile of the anti-IL-17C monoclonal antibody MOR106 for up to 12 weeks (NCT03568071:
= 207 adults with moderate-severe AD; NCT03689829 Part 1:
= 32 healthy males; NCT03689829 Part 2:
= 44 adults with moderate-severe AD; and NCT03864627:
= 76 adults with moderate-severe AD). In these studies, MOR106 was either administered intravenously (i.v.) every 2 or 4 weeks at doses between 1-10 mg/kg, or subcutaneously (s.c.), either as a single dose or doses every 2 weeks at 320 mg. Overall, MOR106 was well-tolerated, and the safety profile was consistent with monoclonal antibodies approved for AD. Bioavailability following s.c. dosing was 55%, and steady-state drug levels were reached at 2-4 weeks. Ongoing studies were terminated following a futility analysis of the Phase 2 placebo-controlled dose-finding study (NCT03568071) due to a low probability for achieving the primary efficacy endpoint. Cumulatively, MOR106 demonstrated ineffectiveness for the treatment of AD, but its safety and pharmacokinetic characteristics warrant further drug development in other indications. Funding: sponsored by Galapagos NV; funded by Novartis AG.
Sympathetic neurons are generated through a succession of differentiation steps that initially lead to noradrenergic neurons innervating different peripheral target tissues. Specific targets, like ...sweat glands in rodent footpads, induce a change from noradrenergic to cholinergic transmitter phenotype. Here, we show that cytokines acting through the gp 130 receptor are present in sweat glands. Selective elimination of the gp 130 receptor in sympathetic neurons prevents the acquisition of cholinergic and peptidergic features (VAChT, ChT1, VIP) without affecting other properties of sweat gland innervation. The vast majority of cholinergic neurons in the stellate ganglion, generated postnatally, are absent in gp 130-deficient mice. These results demonstrate an essential role of gp 130-signaling in the target-dependent specification of the cholinergic neurotransmitter phenotype.
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