Characterization of Large Scale Functional Brain Networks During Ketamine-Medetomidine Anesthetic Induction

Several experiments evidence that specialized brain regions functionally interact and reveal that the brain processes and integrates information in a specific and structured manner. Networks can be used to model brain functional activities constituting a way to characterize and quantify this structured form of organization. Reports state that different physiological states or even diseases that affect the central nervous system may be associated to alterations on those networks, that might reflect in graphs of different architectures. However, the relation of their structure to different states or conditions of the organism is not well comprehended. Thus, experiments that involve the estimation of functional neural networks of subjects exposed to different controlled conditions are of great relevance. Within this context, this research has sought to model large scale functional brain networks during an anesthetic induction process. The experiment was based on intra-cranial recordings of neural activities of an old world macaque of the species Macaca fuscata. Neural activity was recorded during a Ketamine-Medetomidine anesthetic induction process. Networks were serially estimated in time intervals of five seconds. Changes were observed in various networks properties within about one and a half minutes after the administration of the anesthetics. These changes reveal the occurrence of a transition on the networks architecture. During general anesthesia a reduction in the functional connectivity and network integration capabilities were verified in both local and global levels. It was also observed that the brain shifted to a highly specific and dynamic state. The results bring empirical evidence and report the relation of the induced state of anesthesia to properties of functional networks, thus, they contribute for the elucidation of some new aspects of neural correlates of consciousness.Comment: 28 pages , 9 figures, 7 tables; - English errors were corrected; Figures 1,3,4,5,6,8 and 9 were replaced by (exact the same)figures of higher resolution; Three(3) references were added on the introduction sectio

Characterization of the Community Structure of Large Scale Functional Brain Networks During Ketamine-Medetomidine Anesthetic Induction

One of the central questions in neuroscience is to understand the way communication is organized in the brain, trying to comprehend how cognitive capacities or physiological states of the organism are potentially related to brain activities involving interactions of several brain areas. One important characteristic of the functional brain networks is that they are modularly structured, being this modular architecture regarded to account for a series of properties and functional dynamics. In the neurobiological context, communities may indicate brain regions that are involved in one same activity, representing neural segregated processes. Several studies have demonstrated the modular character of organization of brain activities. However, empirical evidences regarding to its dynamics and relation to different levels of consciousness have not been reported yet. Within this context, this research sought to characterize the community structure of functional brain networks during an anesthetic induction process. The experiment was based on intra-cranial recordings of neural activities of an old world macaque of the species Macaca fuscata during a Ketamine-Medetomidine anesthetic induction process. Networks were serially estimated in time intervals of five seconds. Changes were observed within about one and a half minutes after the administration of the anesthetics, revealing the occurrence of a transition on the community structure. The awake state was characterized by the presence of large clusters involving frontal and parietal regions, while the anesthetized state by the presence of communities in the primary visual and motor cortices, being the areas of the secondary associative cortex most affected. The results report the influence of general anesthesia on the structure of functional clusters, contributing for understanding some new aspects of neural correlates of consciousness.Comment: 24 pages, 8 figures. arXiv admin note: text overlap with arXiv:1604.0000

Structure and Dynamics of Brain Lobes Functional Networks at the Onset of Anesthesia Induced Loss of Consciousness

Anesthetic agents are neurotropic drugs able to induce dramatic alterations in the thalamo-cortical system, promoting a drastic reduction in awareness and level of consciousness. There is experimental evidence that general anesthesia impacts large scale functional networks leading to alterations in the brain state. However, the way anesthetics affect the structure assumed by functional connectivity in different brain regions have not been reported yet. Within this context, the present study has sought to characterize the functional brain networks respective to the frontal, parietal, temporal and occipital lobes. In this experiment, electro-physiological neural activity was recorded through the use of a dense ECoG-electrode array positioned directly over the cortical surface of an old world monkey of the species Macaca fuscata. Networks were serially estimated over time at each five seconds, while the animal model was under controlled experimental conditions of an anesthetic induction process. In each one of the four cortical brain lobes, prominent alterations on distinct properties of the networks evidenced a transition in the networks architecture, which occurred within about one and a half minutes after the administration of the anesthetics. The characterization of functional brain networks performed in this study represents important experimental evidence and brings new knowledge towards the understanding of neural correlates of consciousness in terms of the structure and properties of the functional brain networks.Comment: 41 pages; 30 figures; 30 tables. arXiv admin note: substantial text overlap with arXiv:1604.0000

Macaque's Cortical Functional Connectivity Dynamics at the Onset of Propofol-Induced Anesthesia

Propofol, when administered for general anesthesia, induces oscillatory dynamic brain states that are thought to underlie the drug's pharmacological effects. Despite the elucidation of propofol's mechanisms of action at the molecular level, its effects on neural circuits and overall cortical functioning, which eventually lead to unconsciousness, are still unclear. To identify possible mechanisms, the spatial-temporal patterns of functional connectivity established among specialized cortical areas in anesthetized subjects need to be described. Within this context, the present research involved the analysis of dense sub-dural ECoG electrode array recordings from macaques under propofol anesthetic induction. Granger causality methodology was used to infer functional connectivity interactions in five physiological frequency bands serially over time, every five seconds throughout the experiment. The time-resolved networks obtained permitted us to observe the unfolding of the anesthetic induction and compare the networks obtained under different experimental conditions. About one minute after administering propofol, functional connectivity started to increase for 4-5 minutes, then decreased until the LOC was achieved. A predominant Granger causality flow from the occipital and temporal areas towards the frontal and parietal regions was also evidenced during the transition. During general anesthesia, the local connectivity of the occipital lobe increased, as did the interactions between the occipital and temporal lobes. Conversely, the functional connectivity from the frontal and parietal lobes toward the temporal and occipital regions was mainly impaired. The research is one of the first studies to describe the dynamics of the functional connectivity during the transitional state that precedes the LOC.Comment: 20 pages, 5 figure

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Percutaneous nephrolithotomy in patients with solitary kidney: a critical outcome analysis

<title>ABSTRACT</title><sec><title>Purpose:</title><p>To describe our experience with percutaneous nephrolithotomy (PCNL) in patients with solitary kidneys and analyze factors that can impact on intra-operative bleeding and postoperative complications.</p></sec><sec><title>Materials and Methods:</title><p>We reviewed our stone database searching for patients with solitary kidney who underwent PCNL from Jan-05 through Oct-13. Demographic data, stone characteristics, and intra- and postoperative outcomes were recorded. Spearman correlation was performed to assess which variables could impact on bleeding and surgical complications. Linear and logistic regressions were also performed.</p></sec><sec><title>Results:</title><p>Twenty-seven patients were enrolled in this study. The mean age and BMI were 45.6 years and 28.8Kg/m², respectively; 45% of cases were classified as Guys 3 (partial staghorn or multiple stones) or 4 (complete staghorn) – complex cases. Stone-free rate was 67%. Eight (29.6%) patients had postoperative complications (five of them were Clavien 2 and three were Clavien 3). On univariate analysis only number of tracts was associated with increased bleeding (p=0.033) and only operative time was associated with a higher complication rate (p=0.044). Linear regression confirmed number of access tracts as significantly related to bleeding (6.3, 95%CI 2.2-10.4; p=0.005), whereas logistic regression showed no correlation between variables in study and complications.</p></sec><sec><title>Conclusions:</title><p>PCNL in solitary kidneys provides a good stone-free rate with a low rate of significant complications. Multiple access tracts are associated with increased bleeding.</p></sec