The clinical use of deep brain stimulation (DBS) is among the most important advances in the clinical neurosciences in the past two decades. As a surgical tool, DBS can directly measure pathological ...brain activity and can deliver adjustable stimulation for therapeutic effect in neurological and psychiatric disorders correlated with dysfunctional circuitry. The development of DBS has opened new opportunities to access and interrogate malfunctioning brain circuits and to test the therapeutic potential of regulating the output of these circuits in a broad range of disorders. Despite the success and rapid adoption of DBS, crucial questions remain, including which brain areas should be targeted and in which patients. This Review considers how DBS has facilitated advances in our understanding of how circuit malfunction can lead to brain disorders and outlines the key unmet challenges and future directions in the DBS field. Determining the next steps in DBS science will help to define the future role of this technology in the development of novel therapeutics for the most challenging disorders affecting the human brain.
Food allergy can result in considerable morbidity, impairment of quality of life, and healthcare expenditure. There is therefore interest in novel strategies for its treatment, particularly food ...allergen immunotherapy (FA‐AIT) through the oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. This Guideline, prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE‐mediated Food Allergy, aims to provide evidence‐based recommendations for active treatment of IgE‐mediated food allergy with FA‐AIT. Immunotherapy relies on the delivery of gradually increasing doses of specific allergen to increase the threshold of reaction while on therapy (also known as desensitization) and ultimately to achieve post‐discontinuation effectiveness (also known as tolerance or sustained unresponsiveness). Oral FA‐AIT has most frequently been assessed: here, the allergen is either immediately swallowed (OIT) or held under the tongue for a period of time (SLIT). Overall, trials have found substantial benefit for patients undergoing either OIT or SLIT with respect to efficacy during treatment, particularly for cow's milk, hen's egg, and peanut allergies. A benefit post‐discontinuation is also suggested, but not confirmed. Adverse events during FA‐AIT have been frequently reported, but few subjects discontinue FA‐AIT as a result of these. Taking into account the current evidence, FA‐AIT should only be performed in research centers or in clinical centers with an extensive experience in FA‐AIT. Patients and their families should be provided with information about the use of FA‐AIT for IgE‐mediated food allergy to allow them to make an informed decision about the therapy.
This study attempts to improve the understanding of how factors related to the board of directors in emerging countries from America determine a firm's sustainability performance. This paper examines ...the effect of board cultural diversity and the mediating effect of the existence of a corporate social responsibility (CSR) committee. To test our objectives, we carried out a sample analysis on data gathered between 2012 and 2018 from a group of firms located in Argentina, Brazil, Chile and Mexico. The results suggest that board cultural diversity promotes a firm's commitment toward sustainability issues and leads to higher social and environmental performance. Moreover, the results show the mediating effect of the existence of a CSR committee, where a positive impact on sustainability performance appears to be linked to board cultural diversity.
Fornical Closed-Loop Stimulation for Alzheimer’s Disease Senova, Suhan; Chaillet, Antoine; Lozano, Andres M.
Trends in neurosciences (Regular ed.),
July 2018, 2018-07-00, 20180701, 2018-07, Letnik:
41, Številka:
7
Journal Article
Recenzirano
Pharmacological neuromodulation strategies have shown limited efficacy in treating memory deficits related to Alzheimer’s disease (AD). Despite encouraging results from a few preclinical studies, ...clinical trials investigating open-loop deep brain stimulation (DBS) for AD have not been successful. Recent refinements in understanding the various phases of memory processes, animal studies investigating phase-specific modulation of hippocampal activity during memorization, and clinical studies using closed-loop DBS strategies to treat patients with movement disorders, all point to the need to investigate closed-loop fornical DBS strategies to better understand memory dynamics and potentially treat memory deficits in AD preclinical models.
Dysfunction of synapses and brain oscillations within the Papez circuit may be crucial in AD.
Open-loop DBS of the fornix activates robustly the Papez circuit, but does not translate into significant alleviation of memory deficits in patients with AD.
The timing and rhythmicity of neuromodulation by DBS may be crucial for a more physiologically relevant functional activation of memory circuits and better clinical outcomes.
There is an emerging need for noninvasive neuromodulation techniques to improve patient outcomes while minimizing adverse events and morbidity. Low-intensity focused ultrasound (LIFUS) is gaining ...traction as a non-surgical experimental approach of modulating brain activity. Several LIFUS sonication parameters have been found to potentiate neural firing, suppress cortical and epileptic discharges, and alter behavior when delivered to cortical and subcortical mammalian brain regions.
This review introduces the elements of an effective sonication protocol and summarizes key preclinical studies on LIFUS as a neuromodulation modality. The state of the art in human ultrasound neuromodulation is then comprehensively summarized, and current hypotheses regarding the underlying mechanism of action on neural activity are presented.
Peer-reviewed literature on human ultrasound neuromodulation was obtained by searching several electronic databases. The abstracts of all reports were read and publications which examined low-intensity transcranial ultrasound applied to human subjects were selected for review.
LIFUS can noninvasively influence human brain activity by suppressing cortical evoked potentials, influencing cortical oscillatory dynamics, and altering outcomes of sensory/motor tasks compared to sham sonication. Proposed mechanisms include cavitation, direct effects on neural ion channels, and plasma membrane deformation.
Though optimal sonication paradigms and transcranial delivery methods are still being established, future applications may include non-invasive human brain mapping experiments, and nonsurgical treatments for functional neurological disorders.
•Low-intensity ultrasound can noninvasively modulate mammalian brain activity.•Pulsing parameters and intensity determine excitatory or inhibitory neural effects.•Human US neuromodulation has been achieved in cortical and deep structures.•Ultrasound holds promise as a precise, nonsurgical and safe brain stimulation tool.
Context.
The existence of a maximum correlation angle (
θ
max
≳ 60°) in the two-point angular temperature correlations of cosmic microwave background (CMB) radiation, measured by WMAP and
Planck
, ...stands in sharp contrast to the prediction of standard inflationary cosmology, in which the correlations should extend across the full sky (i.e., 180°). The introduction of a hard lower cutoff (
k
min
) in the primordial power spectrum, however, leads naturally to the existence of
θ
max
. Among other cosmological anomalies detected in these data, an apparent dominance of odd-over-even parity multipoles has been seen in the angular power spectrum of the CMB. This feature, however, may simply be due to observational contamination in certain regions of the sky.
Aims.
In attempting to provide a more detailed assessment of whether this odd-over-even asymmetry is intrinsic to the CMB, we therefore proceed in this paper, first, to examine whether this odd-even parity imbalance also manifests itself in the angular correlation function and, second, to examine in detail the interplay between the presence of
θ
max
and this observed anomaly.
Methods.
We employed several parity statistics and recalculated the angular correlation function for different values of the cutoff
k
min
in order to optimize the fit to the different
Planck
2018 data.
Results.
We find a phenomenological connection between these features in the data, concluding that both must be considered together in order to optimize the theoretical fit to the
Planck
2018 data.
Conclusions.
This outcome is independent of whether the parity imbalance is intrinsic to the CMB, but if it is, the odd-over-even asymmetry would clearly point to the emergence of new physics.
Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our ...preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.
The extragalactic background light (EBL) is of fundamental importance both for understanding the entire process of galaxy evolution and for γ-ray astronomy, but the overall spectrum of the EBL ...between 0.1 and 1000 μm has never been determined directly from galaxy spectral energy distribution (SED) observations over a wide redshift range. The evolving, overall spectrum of the EBL is derived here utilizing a novel method based on observations only. This is achieved from the observed evolution of the rest-frame K-band galaxy luminosity function up to redshift 4, combined with a determination of galaxy-SED-type fractions. These are based on fitting Spitzer Wide-Area Infrared Extragalactic Survey (SWIRE) templates to a multiwavelength sample of about 6000 galaxies in the redshift range from 0.2 to 1 from the All-wavelength Extended Groth Strip International Survey (AEGIS). The changing fractions of quiescent galaxies, star-forming galaxies, starburst galaxies and active galactic nucleus (AGN) galaxies in that redshift range are estimated, and two alternative extrapolations of SED types to higher redshifts are considered. This allows calculation of the evolution of the luminosity densities from the ultraviolet (UV) to the infrared (IR), the evolving star formation rate density of the Universe, the evolving contribution to the bolometric EBL from the different galaxy populations including AGN galaxies and the buildup of the EBL. Our EBL calculations are compared with those from a semi-analytic model, another observationally based model and observational data. The EBL uncertainties in our modelling based directly on the data are quantified, and their consequences for attenuation of very-high-energy γ-rays due to pair production on the EBL are discussed. It is concluded that the EBL is well constrained from the UV to the mid-IR, but independent efforts from IR and γ-ray astronomy are needed in order to reduce the uncertainties in the far-IR.
Nanometric biocompatible Metal-Organic Frameworks (nanoMOFs) are promising candidates for drug delivery. Up to now, most studies have targeted the intravenous route, related to pain and severe ...complications; whereas nanoMOFs for oral administration, a commonly used non-invasive and simpler route, remains however unexplored. We propose here the biofriendly preparation of a suitable oral nanocarrier based on the benchmarked biocompatible mesoporous iron(III) trimesate nanoparticles coated with the bioadhesive polysaccharide chitosan (CS). This method does not hamper the textural/structural properties and the sorption/release abilities of the nanoMOFs upon surface engineering. The interaction between the CS and the nanoparticles has been characterized through a combination of high resolution soft X-ray absorption and computing simulation, while the positive impact of the coating on the colloidal and chemical stability under oral simulated conditions is here demonstrated. Finally, the intestinal barrier bypass capability and biocompatibility of CS-coated nanoMOF have been assessed in vitro, leading to an increased intestinal permeability with respect to the non-coated material, maintaining an optimal biocompatibility. In conclusion, the preservation of the interesting physicochemical features of the CS-coated nanoMOF and their adapted colloidal stability and progressive biodegradation, together with their improved intestinal barrier bypass, make these nanoparticles a promising oral nanocarrier.
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