A geometric network model of intrinsic grey-matter connectivity of the human brain

Network science provides a general framework for analysing the large-scale brain networks that naturally arise from modern neuroimaging studies, and a key goal in theoretical neuro- science is to understand the extent to which these neural architectures influence the dynamical processes they sustain. To date, brain network modelling has largely been conducted at the macroscale level (i.e. white-matter tracts), despite growing evidence of the role that local grey matter architecture plays in a variety of brain disorders. Here, we present a new model of intrinsic grey matter connectivity of the human connectome. Importantly, the new model incorporates detailed information on cortical geometry to construct ‘shortcuts’ through the thickness of the cortex, thus enabling spatially distant brain regions, as measured along the cortical surface, to communicate. Our study indicates that structures based on human brain surface information differ significantly, both in terms of their topological network characteristics and activity propagation properties, when compared against a variety of alternative geometries and generative algorithms. In particular, this might help explain histological patterns of grey matter connectivity, highlighting that observed connection distances may have arisen to maximise information processing ability, and that such gains are consistent with (and enhanced by) the presence of short-cut connections

A competitive strategy for atrial and aortic tract segmentation based on deformable models

Multiple strategies have previously been described for atrial region (i.e. atrial bodies and aortic tract) segmentation. Although these techniques have proven their accuracy, inadequate results in the mid atrial walls are common, restricting their application for specific cardiac interventions. In this work, we introduce a novel competitive strategy to perform atrial region segmentation with correct delineation of the thin mid walls, and integrated it into the B-spline Explicit Active Surfaces framework. A double stage segmentation process is used, which starts with a fast contour growing followed by a refinement stage with local descriptors. Independent functions are used to define each region, being afterward combined to compete for the optimal boundary. The competition locally constrains the surface evolution, prevents overlaps and allows refinement to the walls. Three different scenarios were used to demonstrate the advantages of the proposed approach, through the evaluation of its segmentation accuracy, and its performance for heterogeneous mid walls. Both computed tomography and magnetic resonance imaging datasets were used, presenting results similar to the state-of-the-art methods for both atria and aorta. The competitive strategy showed its superior performance with statistically significant differences against the traditional free-evolution approach in cases with bad image quality or missed atrial/aortic walls. Moreover, only the competitive approach was able to accurately segment the atrial/aortic wall. Overall, the proposed strategy showed to be suitable for atrial region segmentation with a correct segmentation of the mid thin walls, demonstrating its added value with respect to the traditional techniques.The authors acknowledge Fundacao para a Ciencia e a Tecnologia (FCT), in Portugal, and the European Social Found, European Union, for funding support through the "Programa Operacional Capital Humano" (POCH) in the scope of the PhD grants SFRH/BD/95438/2013 (P. Morais) and SFRH/BD/93443/2013 (S. Queiros).Authors gratefully acknowledge the funding of projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000022, co-financed by "Programa Operacional Regional do Norte" (NORTE2020), through "Fundo Europeu de Desenvolvimento Regional" (FEDER).info:eu-repo/semantics/publishedVersio

Introduction

La fonction de siège de la seigneurie donne la définition même du château et le distingue de toutes les autres formes d’habitat. S’il incarne le pouvoir militaire du seigneur depuis le Moyen Âge, le château subit une mutation importante lors de la pacification de la France au cours du xviie siècle. Bien que le seigneur demeure le représentant de l’ordre et des institutions monarchiques à l’échelle locale, la fin des guerres civiles entraîne la disparition de la dimension défensive du château...

Development and Evaluation of Two Potential 5-HT₇ Receptor PET Tracers:[¹⁸F]ENL09 and [¹⁸F]ENL10

The latest addition to the serotonin (5-HT) receptor family is the 5-HT7 receptor (5-HT7R). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HT7R available. But, the (arylpiperazinyl-butyl)­oxindole scaffold provides a promising lead structure for this purpose. Here, we synthesized 12 (arylpiperazinyl-butyl)­oxindole derivatives and in vitro affinity screening identified two structures with suitable affinity and selectivity to be radiolabeled and tested as 5-HT7R selective PET tracers. Next, the radiolabeled products [18F]­ENL09 and [18F]­ENL10 were evaluated as PET tracers in rats. Both tracers were found to be P-gp substrates, but after P-gp inhibition the brain uptake showed a regional distribution in line with the known 5-HT7R distribution.  The [18F]­ENL10 brain binding was displaceable with a 5-HT7R selective ligand, whereas [18F]­ENL09 was not. We find that [18F]­ENL10 is a promising 5-HT7R selective PET tracer candidate that should be investigated in higher species

Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats.

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [18F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [18F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity)

Blocking of efflux transporters in rats improves translational validation of brain radioligands

Background Positron emission tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp). Low brain uptake could, therefore, be species-specific and uptake in rodents not be predictive for that in humans. We hypothesized that a better prediction from rodent data could be achieved when a tracer is evaluated under P-gp inhibition. Consequently, we compared the performance of eight neuroreceptor tracers in rats with and without P-gp inhibition including a specific binding blockade. This data set was then used to predict the binding of these eight tracers in pigs. Methods PET tracers targeting serotonin 5-HT(2A)receptors ([F-18]MH.MZ, [F-18]Altanserin, [C-11]Cimbi-36, [C-11]Pimavanserin), serotonin 5-HT(7)receptors ([C-11]Cimbi-701, [C-11]Cimbi-717 and [C-11]BA-10) and dopamine D(2/3)receptors ([F-18]Fallypride) were used in the study. The brain uptake and target-specific binding of these PET radiotracers were evaluated in rats with and without inhibition of P-gp. Rat data were subsequently compared to the results obtained in pigs. Results Without P-gp inhibition, the amount of target-specific binding in the rat brain was sufficient to justify further translation for three out of eight evaluated tracers. With P-gp inhibition, results for five out of eight tracers justified further translation. The performance in pigs could correctly be predicted for six out of eight tracers when rat data obtained under P-gp inhibition were used, compared to four out of eight tracers without P-gp inhibition. Conclusions P-gp strongly affects the uptake of PET tracers in rodents, but false prediction outcomes can be reduced by evaluating a tracer under P-gp inhibition