Ocular surface information seen from the somatosensory thalamus and cortex.

Ocular Surface (OS) somatosensory innervation detects external stimuli producing perceptions, such as pain or dryness, the most relevant symptoms in many OS pathologies. Nevertheless, little is known about the central nervous system circuits involved in these perceptions, and how they integrate multimodal inputs in general. Here, we aim to describe the thalamic and cortical activity in response to OS stimulation of different modalities. Electrophysiological extracellular recordings in anaesthetized rats were used to record neural activity, while saline drops at different temperatures were applied to stimulate the OS. Neurons were recorded in the ophthalmic branch of the trigeminal ganglion (TG, 49 units), the thalamic VPM-POm nuclei representing the face (Th, 69 units) and the primary somatosensory cortex (S1, 101 units). The precise locations for Th and S1 neurons receiving OS information are reported here for the first time. Interestingly, all recorded nuclei encode modality both at the single neuron and population levels, with noxious stimulation producing a qualitatively different activity profile from other modalities. Moreover, neurons responding to new combinations of stimulus modalities not present in the peripheral TG subsequently appear in Th and S1, being organized in space through the formation of clusters. Besides, neurons that present higher multimodality display higher spontaneous activity. These results constitute the first anatomical and functional characterization of the thalamocortical representation of the OS. Furthermore, they provide insight into how information from different modalities gets integrated from the peripheral nervous system into the complex cortical networks of the brain. KEY POINTS: Anatomical location of thalamic and cortical ocular surface representation. Thalamic and cortical neuronal responses to multimodal stimulation of the ocular surface. Increasing functional complexity along trigeminal neuroaxis. Proposal of a new perspective on how peripheral activity shapes central nervous system function.

Blood flow effects of percutaneous peripheral nerve stimulation. A blinded, randomized clinical trial.

BACKGROUND: The vasculature function is mainly regulated by the autonomic nervous system. Importantly, the sensory-motor nervous system also innervates peripheral vessels and has the capacity to modulate vascular tone. Here we investigated the effects of electrical stimulation of a mixed nerve trunk on blood flow in deep arteries and muscle perfusion. Our hypothesis is that stimulation of a mixed nerve can modify blood flow. METHODS: Twenty-nine healthy participants were included into a randomized-crossover and blinded clinical trial. Each subject received a placebo and two percutaneous peripheral nerve stimulation (pPNS) protocols on the median nerve: Pain Threshold continuous Low Frequency (PT-cLF) and Sensory Threshold burst High Frequency (ST-bHF). Blood flow was then assessed bilaterally using Power Doppler Ultrasonography at the main arteries of the arm, and blood perfusion at the forearm muscles. Afterwards, blood flow was quantified using a semi-automatized software, freely shared here. RESULTS: Placebo, consisting in needle insertion, produced an immediate and generalized reduction on peak systolic velocity in all arteries. Although nerve stimulation produced mainly no effects, some significant differences were found: both protocols increased the relative perfusion area of the forearm muscles, the ST-bHF protocol prevented the reduction in peak systolic velocity and TAMEAN of the radial artery produced by the control protocol and PT-cLF produced a TAMEAN reduction of the ulnar artery. CONCLUSIONS: Therefore, the arterial blood flow in the arm is mainly impervious to the electrical stimulation of the median nerve, composed by autonomic and sensory-motor axons, although it produces mild modifications in the forearm muscles perfusion.

Nasal Obstruction: Overview of Pathophysiology and Presentation of a Clinically Relevant Preoperative Plan for Rhino(Septo)plasty.

Impairment of nasal breathing is a highly prevalent and bothersome symptom that affects daily functioning and/or sleep quality. Those surgeons dealing with patients seeking rhinoplasty need to carefully analyze the preoperative nasal breathing capacity and predict the positive or even negative impact of rhino(septo)plasty on nasal breathing. Given the lack of correlation between the subjective feeling of suboptimal nasal breathing and the objective measurements of nasal flow and nasal resistance, a critical and mainly clinical evaluation of all anatomical, mucosal, and sensory mechanisms involved in nasal obstruction is mandatory. Indeed, thermo-, mechano-, and chemosensory receptors on the nasal mucosa, airflow, and respiratory dynamics might all contribute to the overall perception of nasal breathing capacity. In this review, we provide an overview of the factors determining suboptimal nasal breathing including different diagnostic and experimental tests that can be performed to evaluate nasal flow and nasal resistance and current limitations in our understanding of the problem of nasal breathing in an individual patient. An algorithm for the preoperative or diagnostic workup for nasal obstruction is included that might be useful as a guide for clinicians dealing with patients seeking nose surgery.

The Contribution of TRPA1 to Corneal Thermosensitivity and Blink Regulation in Young and Aged Mice.

The role of TRPA1 in the thermosensitivity of the corneal cold thermoreceptor nerve endings was studied in young and aged mice. The contribution of the TRPA1-dependent activity to basal tearing and thermally-evoked blink was also explored. The corneal cold thermoreceptors' activity was recorded extracellularly in young (5-month-old) and aged (18-month-old) C57BL/6WT (WT) and TRPA1-/- knockout (TRPA1-KO) mice at basal temperature (34 °C) and during cooling (15 °C) and heating (45 °C) ramps. The blink response to cold and heat stimulation of the ocular surface and the basal tearing rate were also measured in young animals using orbicularis oculi muscle electromyography (OOemg) and phenol red threads, respectively. The background activity at 34 °C and the cooling- and heating-evoked responses of the cold thermoreceptors were similar in WT and TRPA1-KO animals, no matter the age. Similar to the aged WT mice, in the young and aged TRPA1-KO mice, most of the cold thermoreceptors presented low frequency background activity, a low cooling threshold, and a sluggish response to heating. The amplitude and duration of the OOemg signals correlated with the magnitude of the induced thermal change in the WT but not in the TRPA1-KO mice. The basal tearing was similar in the TRPA1-KO and WT mice. The electrophysiological data suggest that the TRPA1-dependent nerve activity, which declines with age, contributes to detecting the warming of the ocular surface and also to integrating the thermally-evoked reflex blink.

Epithelial and sensory mechanisms of nasal hyperreactivity.

"Nasal hyperreactivity" is a key feature in various phenotypes of upper airway diseases, whereby reactions of the nasal epithelium to diverse chemical and physical stimuli are exacerbated. In this review, we illustrate how nasal hyperreactivity can result from at least three types of mechanisms: (1) impaired barrier function, (2) hypersensitivity to external and endogenous stimuli, and (3) potentiation of efferent systems. We describe the known molecular basis of hyperreactivity related to the functional impairment of epithelial cells and somatosensory innervation, and indicate that the thermal, chemical, and mechanical sensors determining hyperreactivity in humans remain to be identified. We delineate research directions that may provide new insights into nasal hyperreactivity associated with rhinitis/rhinosinusitis pathophysiology and therapeutics. The elucidation of the molecular mechanisms underlying nasal hyperreactivity is essential for the treatment of rhinitis according to the precepts of precision medicine.

Static magnetic stimulation in the central nervous system: a systematic review.

OBJECTIVE: To systematically review the literature on the use of the transcranial static magnetic stimulation (tSMS) technique in humans and animals, its effects on different areas of the central nervous system (CNS), its influence on neural excitability and on the subject's behavior, and its biological effects and future possibilities. All static magnetic field applications that can be considered to have a physiologically similar effect have been reviewed. METHODS: We searched studies using key terms in NCBI PubMed, Scopus, PEDro, SciELO, Cochrane, and links to publications (inception to September 2019). Three reviewers independently selected the studies, extracted data, and assessed the methodological quality of the studies using the recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions, PRISMA guidelines. RESULTS: We analyzed 27 studies. The reviewed literature suggests that the use of these magnetic fields has an inhibitory effect on different areas of the CNS, such as motor, somatosensory, and visual cortex, cerebellum, and spinal cord. Regarding subject's behavior, the different effects of tSMS appear to be transient and dependent on the stimulated area, such as loss of visual discrimination or improvement of somatosensory perception. In addition, the technique has some therapeutic utility, specifically in pathologies with cortical hyperexcitability. CONCLUSIONS: These results suggest that tSMS may be a promising tool to modulate cerebral excitability in a safe and non-invasive way. Further investigations could give a better explanation of its precise mechanisms of action and applications.

Dynamical properties of heterogeneous nucleation of parallel hard squares.

We use the Dynamic Density-Functional Formalism and the Fundamental Measure Theory as applied to a fluid of parallel hard squares to study the dynamics of heterogeneous growth of non-uniform phases with columnar and crystalline symmetries. The hard squares are (i) confined between soft repulsive walls with a square symmetry, or (ii) exposed to external potentials that mimic the presence of obstacles with circular, square, rectangular or triangular symmetries. For the first case the final equilibrium profile of a well commensurated cavity consists of a crystal phase with highly localized particles in concentric square layers at the nodes of a slightly deformed square lattice. We characterize the growth dynamics of the crystal phase by quantifying the interlayer and intralayer fluxes and the non-monotonicity of the former, the saturation time, and other dynamical quantities. The interlayer fluxes are much more monotonic in time, and dominant for poorly commensurated cavities, while the opposite is true for well commensurated cells: although smaller, the time evolution of interlayer fluxes is much more complex, presenting strongly damped oscillations which dramatically increase the saturation time. We also study how the geometry of the obstacle affects the symmetry of the final equilibrium non-uniform phase (columnar vs. crystal). For obstacles with fourfold symmetry, (circular and square) the crystal is more stable, while the columnar phase is stabilized for obstacles without this symmetry (rectangular or triangular). We find that, in general, density waves of columnar symmetry grow from the obstacle. However, additional particle localization along the wavefronts gives rise to a crystalline structure which is conserved for circular and square obstacles, but destroyed for the other two obstacles where columnar symmetry is restored.

Ordering of hard rectangles in strong confinement.

Using transfer operator and fundamental measure theories, we examine the structural and thermodynamic properties of hard rectangles confined between two parallel hard walls. The side lengths of the rectangle (L and D, L>D) and the pore width (H) are chosen such that a maximum of two layers is allowed to form when the long sides of the rectangles are parallel to the wall, while only one layer is possible in case the rectangles are perpendicular to the wall. We observe three different structures: (i) at low density, the rectangles align mainly parallel to the wall, (ii) at intermediate or high density, two fluid layers form in which the rectangles are parallel to the wall, and (iii) a dense single fluid layer with rectangles aligned mainly perpendicular to the wall. The transition between these structures is smooth without any non-analytic behaviour in the thermodynamic quantities; however, the fraction of particles perpendicular (or parallel) to the wall can exhibit a relatively sudden change if L is close to H. In this case, interestingly, even three different structures can be observed with increasing density.

Biaxial nematic phase stability and demixing behaviour in monolayers of rod-plate mixtures.

We theoretically study the phase behaviour of monolayers of hard rod-plate mixtures using a fundamental-measure density functional in the restricted-orientation (Zwanzig) approximation. Particles can rotate in 3D but their centres of mass are constrained to be on a flat surface. In addition, we consider both species to be subject to an attractive potential proportional to the particle contact area on the surface and with adsorption strengths that depend on the species type. Particles have board-like shape, with sizes chosen using a symmetry criterion: same volume and same aspect ratio κ. Phase diagrams were calculated for κ = 10, 20 and 40 and different values of adsorption strengths. For small adsorption strengths the mixtures exhibit a second-order uniaxial nematic-biaxial nematic transition for molar fraction of rods 0 ≤x≲ 0.9. In the uniaxial nematic phase the particle axes of rods and plates are aligned perpendicular and parallel to the monolayer, respectively. At the transition, the orientational symmetry of the plate axes is broken, and they orient parallel to a director lying on the surface. For large and equal adsorption strengths the mixture demixes at low pressures into a uniaxial nematic phase, rich in plates, and a biaxial nematic phase, rich in rods. The demixing transition is located between two tricritical points. Also, at higher pressures and in the plate-rich part of the phase diagram, the system exhibits a strong first-order uniaxial nematic-biaxial nematic phase transition with a large density coexistence gap. When rod adsorption is considerably large while that of plates is small, the transition to the biaxial nematic phase is always of second order, and its region of stability in the phase diagram considerably widens. At very high pressures the mixture can effectively be identified as a two-dimensional mixture of squares and rectangles which again demixes above a certain critical point. We also studied the relative stability of uniform phases with respect to density modulations of smectic, columnar and crystalline symmetry.

Effect of orientational restriction on monolayers of hard ellipsoids.

The effect of out-of-plane orientational freedom on the orientational ordering properties of a monolayer of hard ellipsoids is studied using the Parsons-Lee scaling approach and replica exchange Monte Carlo computer simulation. Prolate and oblate ellipsoids exhibit very different ordering properties, namely, the axes of revolution of prolate particles tend to lean out, while those of oblate ones prefer to lean into the confining plane. The driving mechanism of this is that the particles try to maximize the available free area on the confining surface, which can be achieved by minimizing the cross section areas of the particles with the plane. In the lack of out-of-plane orientational freedom the monolayer of prolate particles is identical to a two-dimensional hard ellipse system, which undergoes an isotropic-nematic ordering transition with increasing density. With gradually switching on the out-of-plane orientational freedom the prolate particles lean out from the confining plane and destabilisation of the in-plane isotropic-nematic phase transition is observed. The system of oblate particles behaves oppositely to that of prolates. It corresponds to a two-dimensional system of hard disks in the lack of out-of-plane freedom, while it behaves similar to that of hard ellipses in the freely rotating case. Solid phases can be realised by lower surface coverage due to the out-of-plane orientation freedom for both oblate and prolate shapes.

Capillary and winding transitions in a confined cholesteric liquid crystal.

We consider a Lebwohl-Lasher model of chiral particles confined in a planar cell (slit pore) under different boundary conditions, and solve it using mean-field theory. The phase behaviour of the system with respect to temperature and pore width is studied. Two phenomena are observed: (i) an isotropic-cholesteric transition, which exhibits an oscillatory structure with respect to pore width, and (ii) an infinite set of winding transitions caused by commensuration effects between cholesteric pitch and pore width. The latter transitions have been predicted and analysed by other authors for cholesterics confined in a fixed pore and subjected to an external field promoting the uniaxial nematic phase; here we induce winding transitions solely from geometry by changing the pore width at zero external field (a setup recently explored in atomic-force microscopy experiments). In contrast with previous studies, we obtain the phase diagram in the temperature vs. pore width plane, including the isotropic-cholesteric transition, the winding transitions and their complex relationship. In particular, the structure of winding transitions terminates at the capillary isotropic-cholesteric transition via triple points where the confined isotropic phase coexists with two cholesterics with different helix indices. For symmetric and asymmetric monostable plate anchorings the phase diagrams are qualitatively similar.

Effect of shape biaxiality on the phase behavior of colloidal liquid-crystal monolayers.

We extend our previous work on monolayers of uniaxial particles [J. Chem. Phys., 2014, 140, 204906] to study the effect of particle biaxiality on the phase behavior of liquid-crystal monolayers. Particles are modelled as board-like hard bodies with three different edge lengths σ1 ≥ σ2 ≥ σ3, and the restricted-orientation approximation (Zwanzig model) is used. A density-functional formalism based on the fundamental-measure theory is used to calculate phase diagrams for a wide range of values with the largest aspect ratio κ1 = σ1/σ3 ∈ [1,100]. We find that particle biaxiality in general destabilizes the biaxial nematic phase already present in monolayers of uniaxial particles. While plate-like particles exhibit strong biaxial ordering, rod-like ones with κ1 > 21.34 exhibit reentrant uniaxial and biaxial phases. As particle geometry is changed from uniaxial- to increasingly biaxial-rod-like, the region of biaxiality is reduced, eventually ending in a critical-end point. For κ1 > 60, a density gap opens up in which the biaxial nematic phase is stable for any particle biaxiality. Regions of the phase diagram, where packing-fraction inversion occurs (i.e. packing fraction is a decreasing function of density), are found. Our results are compared with the recent experimental studies on nematic phases of magnetic nanorods.

Domain walls in two-dimensional nematics confined in a small circular cavity.

Using Monte Carlo simulation, we study a fluid of two-dimensional hard rods inside a small circular cavity bounded by a hard wall, from the dilute regime to the high-density, layering regime. Both planar and homeotropic anchoring of the nematic director can be induced at the walls through a free-energy penalty. The circular geometry creates frustration in the nematic phase and a polar-symmetry configuration with a distorted director field plus two +1/2 disclinations is created. At higher densities, a quasi-uniform structure is observed with a (minimal) director distortion which is relaxed via the formation of orientational domain walls. This novel structure is not predicted by elasticity theory and is similar to the step-like structures observed in three-dimensional hybrid slit pores. We speculate that the formation of domain walls is a general mechanism to relax elastic stresses under the conditions of strong surface anchoring and severe spatial confinement.

Interplay between columnar and smectic stability in suspensions of polydisperse colloidal platelets.

The phase behavior of a model suspension of colloidal polydisperse platelets is studied using density-functional theory. Platelets are modelled as parallel rectangular prisms of square section l(2) and height h, with length and height distributions given by different polydispersities δ(l) and δ(h). The model is intended to qualitatively represent experimental colloidal platelet suspensions at high densities with a high degree of orientational ordering. We obtain the phase behavior of the model, including nematic, smectic and columnar phases and its dependence on the two polydispersities δ(l) and δ(h). When δ(l) > δ(h) we observe that the smectic phase stabilises first with respect to the columnar. If δ(h) > δ(l) we observe the opposite behavior. Other more complicated cases occur, e.g. the smectic stabilises from the nematic first but then exists a first-order transition to the columnar phase. Our model assumes plate-rod symmetry, but the regions of stability of smectic and columnar phases are non-symmetric in the δ(l) - δ(h) plane due to the different dimensionality of ordering in the two phases. Microsegregation effects, i.e. different spatial distribution for different sizes within the periodic cell, take place in both phases and, in each case, is more apparent in the variable associated with ordering.

Phase behaviour of liquid-crystal monolayers of rod-like and plate-like particles.

Orientational and positional ordering properties of liquid crystal monolayers are examined by means of Fundamental-Measure Density Functional Theory. Particles forming the monolayer are modeled as hard parallelepipeds of square section of size σ and length L. Their shapes are controlled by the aspect ratio κ = L/σ (>1 for prolate and <1 for oblate shapes). The particle centers of mass are restricted to a flat surface and three possible and mutually perpendicular orientations (in-plane and along the layer normal) of their uniaxial axes are allowed. We find that the structure of the monolayer depends strongly on particle shape and density. In the case of rod-like shapes, particles align along the layer normal in order to achieve the lowest possible occupied area per particle. This phase is a uniaxial nematic even at very low densities. In contrast, for plate-like particles, the lowest occupied area can be achieved by random in-plane ordering in the monolayer, i.e., planar nematic ordering takes place even at vanishing densities. It is found that the random in-plane ordering is not favorable at higher densities and the system undergoes an in-plane ordering transition forming a biaxial nematic phase or crystallizes. For certain values of the aspect ratio, the uniaxial-biaxial nematic phase transition is observed for both rod-like and plate-like shapes. The stability region of the biaxial nematic phase enhances with decreasing aspect ratios for plate-like particles, while the rod-like particles exhibit a reentrant phenomenon, i.e., a sequence of uniaxial-biaxial-uniaxial nematic ordering with increasing density if the aspect ratio is larger than 21.34. In addition to this, packing fraction inversion is observed with increasing surface pressure due to the alignment along the layers normal. At very high densities the nematic phase destabilizes to a nonuniform phases (columnar, smectic, or crystalline phases) for both shapes.

Phase diagram of a square-well model in two dimensions.

The phase behavior of a two-dimensional square-well model of width 1.5σ, with emphasis on the low-temperature and/or high-density region, is studied using Monte Carlo simulation in the canonical and isothermal-isobaric ensembles, and discontinuous molecular-dynamics simulation in the canonical ensemble. Several properties, such as equations of state, Binder cumulant, order parameters, and correlation functions, were computed. Numerical evidence for vapor, liquid, hexatic, and triangular solid is given, and, in addition, a non-compact solid with square-lattice symmetry is obtained. The global phase diagram is traced out in detail (or sketched approximately whenever only inaccurate information could be obtained). The solid region of the phase diagram is explained using a simple mean-field model.

Temporal Dynamics of Adverse Effects across Five Sessions of Transcranial Direct Current Stimulation.

(1) Background: Transcranial direct current stimulation (tDCS) is a safe intervention, only producing mild and transient adverse effects (AEs). However, there is no detailed analysis of the pattern of adverse effects in an application transferable to the clinic. Therefore, our objective is to describe the AEs produced by tDCS and its temporal evolution. (2) Methods: A total of 33 young volunteers were randomized into a tDCS or sham group. Participants performed a hand dexterity task while receiving the tDCS or sham intervention (20 min and 1 mA), for five consecutive days. AEs were assessed daily after each intervention and classified as somatosensory, pain, or other effects. (3) Results: The number of AEs was generally increased by tDCS intervention. Specifically, tDCS led to more frequent somatosensory discomfort, characterized by sensations like itching and tingling, alongside painful sensations such as burning, compared to the sham intervention. Additionally, certain adverse events, including neck and arm pain, as well as dizziness and blurry vision, were exclusive to the tDCS group. Interestingly, tDCS produced similar AEs across the days; meanwhile, the somatosensory AEs in the sham group showed a trend to decrease. (4) Conclusions: tDCS produces mild and temporary somatosensory and pain AEs during and across sessions. The different evolution of the AEs between the tDCS and sham protocol could unmask the blinding protocol most used in tDCS studies. Potential solutions for improving blinding protocols for future studies are discussed.

Demographic Trends in Liver Transplant Survivors After 3 Decades of Program Implementation: The Impact of Cohort and Period Effects on Life Expectancy.

Background: Demographic analyses may reveal current patterns of change in the outcomes of rapidly developing medical procedures because they incorporate the period perspective. Methods: We analyzed the changes in size, age structure, and hospitalizations in the population of liver transplantation (LT) survivors in our center during the last 30 y (n = 1114 patients) and generated projections, including life expectancy (LE), considering cohort and period effects. Life tables were used to project the complete LE (overall 1990-2020 experience), the cohort LE (according to the decade of surgery: 1990-2000, 2000-2010, and 2010-2020), and the period LE (current 2015-2020 experience). Results: The population of LT recipients in follow-up continued to experience progressive growth and aging since 1990 (492 patients [41.9% >65 y] in 2020), and the magnitude of these phenomena may double in the next 30 y. However, the number of admissions and days of admission has been decreasing. The complete LE at LT was 12.4 y, whereas the period LE was 15.8 y. The cohort LE (limited to 10 y) was 5.3, 6.3, and 7.3 y for the 1990-2000, 2000-2010, and 2010-2020 cohorts, respectively. Conclusions: The target population of our medical care after LT is growing and aging. The prevalence of both of these phenomena is expected to increase in the coming years and is associated with a current improvement in LE. However, the hospitalization burden associated with LT survivors is declining. The period effect should be considered for generating up-to-date information on these current trends, which are crucial when designing health policies for LT survivors.

Is chronic pain caused by central sensitization? A review and critical point of view.

Chronic pain causes disability and loss of health worldwide. Yet, a mechanistic explanation for it is still missing. Frequently, neural phenomena, and among them, Central Sensitization (CS), is presented as causing chronic pain. This narrative review explores the evidence substantiating the relationship between CS and chronic pain: four expert researchers were divided in two independent teams that reviewed the available evidence. Three criteria were established for a study to demonstrate a causal relationship: (1) confirm presence of CS, (2) study chronic pain, and (3) test sufficiency or necessity of CS over chronic pain symptoms. No study met those criteria, failing to demonstrate that CS can cause chronic pain. Also, no evidence reporting the occurrence of CS in humans was found. Worryingly, pain assessments are often confounded with CS measures in the literature, omitting that the latter is a neurophysiological and not a perceptual phenomenon. Future research should avoid this misconception to directly interrogate what is the causal contribution of CS to chronic pain to better comprehend this problematic condition.

Prediction of the liquid-crystal phase behavior of hard right triangles from fourth-virial density-functional theories.

We have used an extended scaled-particle theory that incorporates four-body correlations through the fourth-order virial coefficient to analyze the orientational properties of a fluid of hard right isosceles triangles. This fluid has been analyzed by computer simulation studies, with clear indications of strong octatic correlations present in the liquid-crystal phase, although the more symmetric order tetratic phase would seem to be the most plausible candidate. Standard theories based on the second virial coefficient are unable to reproduce this behavior. Our extended theory predicts that octatic correlations, associated to a symmetry under global rotations of the oriented fluid by 45^{∘}, are highly enhanced, but not enough to give rise to a thermodynamically stable phase with strict octatic symmetry. We discuss different scenarios to improve the theoretical understanding of the elusive octatic phase in this intriguing fluid.