Aging of the vestibular system and its relationship to dementia.

PURPOSE OF REVIEW: Since October 2022, substantial new information has been published on age-related effects on the vestibular system. Since much of this evidence relates to the risk of dementia, the purpose of this review will be to provide an overview of this new information and critically evaluate it. RECENT FINDINGS: This review will address studies published since October 2022 regarding age-related effects on the vestibular system and their relationship to cognition and dementia. There has been a particular increase in the last year in the number of studies relating aging of the vestibular system to Alzheimer's disease (AD), further supporting the view that vestibular dysfunction is associated with an increased risk of dementia. SUMMARY: The conclusion of these recent studies is that, consistent with previous studies, vestibular function declines with age, and that this age-related decline is associated with cognitive impairment and an increased risk of dementia. Efforts are being made to consider these implications for cognition in the treatment of vestibular disorders.

Targeting the Limbic System: Insights into Its Involvement in Tinnitus.

Tinnitus is originally derived from the Latin verb tinnire, which means "to ring". Tinnitus, a complex disorder, is a result of sentient cognizance of a sound in the absence of an external auditory stimulus. It is reported in children, adults, and older populations. Patients suffering from tinnitus often present with hearing loss, anxiety, depression, and sleep disruption in addition to a hissing and ringing in the ear. Surgical interventions and many other forms of treatment have been only partially effective due to heterogeneity in tinnitus patients and a lack of understanding of the mechanisms of tinnitus. Although researchers across the globe have made significant progress in understanding the underlying mechanisms of tinnitus over the past few decades, tinnitus is still deemed to be a scientific enigma. This review summarises the role of the limbic system in tinnitus development and provides insight into the development of potential target-specific tinnitus therapies.

Vanadium-Substituted Tunnel Structured Silver Hollandite (Ag1.2VxMn8-xO16): Impact on Morphology and Electrochemistry.

A series of tunnel structured V-substituted silver hollandite (Ag1.2VxMn8-xO16, x = 0-1.4) samples is prepared and characterized through a combination of synchrotron X-ray diffraction (XRD), synchrotron X-ray absorption spectroscopy (XAS), laboratory Raman spectroscopy, and electron microscopy measurements. The oxidation states of the individual transition metals are characterized using V and Mn K-edge XAS data indicating the vanadium centers exist as V5+, and the Mn oxidation state decreases with increased V substitution to balance the charge. Scanning transmission electron microscopy of reduced materials shows reduction-displacement of silver metal at high levels of lithiation. In lithium batteries, the V-substituted tunneled manganese oxide materials reveal previously unseen reversible nonaqueous Ag electrochemistry and exhibit up to 2.5× higher Li storage capacity relative to their unsubstituted counterparts. The highest capacity was observed for the Ag1.2(V0.8Mn7.2)O16·0.8H2O material with an intermediate level of V substitution, likely due to a combination of the atomic composition, the morphology of the particle, and the homogeneous distribution of the active material within the electrode structure where factors over multiple length scales contribute to the electrochemistry.

(De)lithiation of spinel ferrites Fe3O4, MgFe2O4, and ZnFe2O4: a combined spectroscopic, diffraction and theory study.

Iron based materials hold promise as next generation battery electrode materials for Li ion batteries due to their earth abundance, low cost, and low environmental impact. The iron oxide, magnetite Fe3O4, adopts the spinel (AB2O4) structure. Other 2+ cation transition metal centers can also occupy both tetrahedral and/or octahedral sites in the spinel structure including MgFe2O4, a partially inverse spinel, and ZnFe2O4, a normal spinel. Though structurally similar to Fe3O4 in the pristine state, previous studies suggest significant differences in structural evolution depending on the 2+ cation in the structure. This investigation involves X-ray absorption spectroscopy and X-ray diffraction affirmed by density functional theory (DFT) to elucidate the role of the 2+ cation on the structural evolution and phase transformations during (de)lithiation of the spinel ferrites Fe3O4, MgFe2O4, and ZnFe2O4. The cation in the inverse, normal and partially inverse spinel structures located in the tetrahedral (8a) site migrates to the previously unoccupied octahedral 16c site by 2 electron equivalents of lithiation, resulting in a disordered [A]16c[B2]16dO4 structure. DFT calculations support the experimental results, predicting full displacement of the 8a cation to the 16c site at 2 electron equivalents. Substitution of the 2+ cation results in segregation of oxidized phases in the charged state. This report provides significant structural insight into the (de)lithiation mechanisms for an intriguing class of iron oxide materials.

Vestibular impairment, cognitive decline and Alzheimer's disease: balancing the evidence.

The vestibular (inner ear balance) system senses head movement and orientation in space. Vestibular sensory input plays a critical role in spatial cognitive abilities such as spatial memory and spatial navigation. Vestibular function declines with age, and recent studies have shown that age-related vestibular impairment is associated with poorer spatial cognitive skills in healthy older adults. Moreover, vestibular impairment is disproportionately prevalent among individuals with mild cognitive impairment and Alzheimer's disease, and specifically in cognitively-impaired individuals who have spatial deficits such as disorientation and difficulty driving. Indeed, emerging evidence suggests that age-related vestibular impairment contributes to a 'spatial' subtype of Alzheimer's disease, characterized by highly morbid symptoms such as wandering and falls. Given that vestibular impairment can be treated through simple, physical-therapy based exercises, identifying and treating vestibular deficits in older adults with and without cognitive impairment may offer substantial benefit in preventing, mitigating and forestalling cognitive decline.

Sexual dimorphism in vestibular function and dysfunction.

It has been recognized for some time that females appear to be overrepresented in the incidence of many vestibular disorders, and recent epidemiological studies further support this idea. While it is possible that this is due to a reporting bias, another possibility is that there are actual differences in the incidence of vestibular dysfunction between males and females. If this is true, it could be due to a sexual dimorphism in vestibular function and therefore dysfunction, possibly related to the hormonal differences between females and males, although the higher incidence of vestibular dysfunction in females appears to last long after menopause. Many other neurochemical differences exist between males and females, however, that could be implicated in sexual dimorphism. This review critically explores the possibility of sexual dimorphism in vestibular function and dysfunction, and the implications it may have for the treatment of vestibular disorders.

Cannabinoid drugs: will they relieve or exacerbate tinnitus?

PURPOSE OF REVIEW: Recent enthusiasm for cannabinoid drugs for the treatment of chronic pain and some forms of epilepsy, raises the question of whether they could be useful for other disorders associated with abnormal neuronal activity in the brain, such as subjective tinnitus. Indeed, there is evidence to indicate that some tinnitus sufferers self-medicate using Cannabis. The aim of this review is to critically evaluate the available evidence relating to the effects of cannabinoids on tinnitus. RECENT FINDINGS: Despite the fact that cannabinoids have been shown to decrease neuronal hyperactivity in many parts of the brain, the current evidence suggests that in auditory brain regions such as the dorsal cochlear nucleus, they have the potential to facilitate neuronal hyperactivity and exacerbate tinnitus. All of the available experimental evidence from animal studies suggests that cannabinoid CB1 receptor agonists will either have no effect on tinnitus or will worsen it. SUMMARY: In our opinion, the use of the available cannabinoid drugs to alleviate tinnitus, based on their alleged efficacy for neuropathic pain conditions and some forms of epilepsy, is premature and not supported by the available evidence.

The modulation of hippocampal theta rhythm by the vestibular system.

The vestibular system is a sensory system that has evolved over millions of years to detect acceleration of the head, both rotational and translational, in three dimensions. One of its most important functions is to stabilize gaze during unexpected head movement; however, it is also important in the control of posture and autonomic reflexes. Theta rhythm is a 3- to 12-Hz oscillating EEG signal that is intimately linked to self-motion and is also known to be important in learning and memory. Many studies over the last two decades have shown that selective activation of the vestibular system, using either natural rotational or translational stimulation, or electrical stimulation of the peripheral vestibular system, can induce and modulate theta activity. Furthermore, inactivation of the vestibular system has been shown to significantly reduce theta in freely moving animals, which may be linked to its impairment of place cell function as well as spatial learning and memory. The pathways through which vestibular information modulate theta rhythm remain debatable. However, vestibular responses have been found in the pedunculopontine tegmental nucleus (PPTg) and activation of the vestibular system causes an increase in acetylcholine release into the hippocampus, probably from the medial septum. Therefore, a pathway from the vestibular nucleus complex and/or cerebellum to the PPTg, supramammillary nucleus, posterior hypothalamic nucleus, and septum to the hippocampus is likely. The modulation of theta by the vestibular system may have implications for vestibular effects on cognitive function and the contribution of vestibular impairment to the risk of dementia.

Holy Grails in Chemistry: Investigating and Understanding Fast Electron/Cation Coupled Transport within Inorganic Ionic Matrices.

Typically, power and energy are competing concepts in electrochemical energy storage, where one can be optimized only at the expense of the other. However, the specialized and diverse needs of new applications exceed the functional boundaries of existing battery chemistries, where both high power and high energy content are critical. The needed battery paradigms may not be realized by optimization of previous electrochemical energy storage technologies but rather require new basic science breakthroughs involving new materials chemistry. Here we propose that fundamental understanding of electron/cation coupled transport within inorganic ionic matrices is a holy grail that can potentially transform the energy storage landscape.

Vestibular-related eye movements in the rat following selective electrical stimulation of the vestibular sensors.

Rats are the most commonly used species in the neurosciences; however, little is known about the effects of selective electrical stimulation of individual vestibular sensors, on their eye movements. This limits their use to study the effects of vestibular stimulation on the brain, and their use in further exploring novel technologies such as artificial vestibular implants. We describe the effects of electrical stimulation of each vestibular sensor on vestibular-related eye movement in rats and compared the results to other species. We demonstrated that each sensor is responsible for specific bilateral eye movements. We found that the eye movements in rats differed from other species. Although the results were similar when stimulating the horizontal canal ampulla, differences appeared when stimulating the vertical canal sensors. During utricular stimulation, the ipsilateral eye moved dorsally in most cases, while the contralateral eye usually moved either caudally, or in extorsion. Saccular stimulation usually moved the ipsilateral eye dorsally or ventrally, while the contralateral eye usually moved ventrally or caudally. This study provides the first data on the application of selective electrical vestibular stimulation in the rat to the study of vestibular-related eye movements.

On the Application of Multivariate Statistical and Data Mining Analyses to Data in Neuroscience.

Research in neuroscience, whether at the level of genes, proteins, neurons or behavior, almost always involves the interaction of multiple variables, and yet many areas of neuroscience employ univariate statistical analyses almost exclusively. Since multiple variables often work together to produce a neuronal or behavioral effect, the use of univariate statistical procedures, analyzing one variable at a time, limits the ability of studies to reveal how interactions between different variables may determine a particular outcome. Multivariate statistical and data mining methods afford the opportunity to analyze many variables together, in order to understand how they function as a system, and how this system may change as a result of a disease or a drug. The aim of this review is to provide a succinct guide to methods such as linear discriminant analysis, support vector machines, principal component and factor analysis, cluster analysis, multiple linear regression, and random forest regression and classification, which have been used in circumscribed areas of neuroscience research, but which could be used more widely.

The vestibular system and cognition.

PURPOSE OF REVIEW: The last year has seen a great deal of new information published relating vestibular dysfunction to cognitive impairment in humans, especially in the elderly. The objective of this review is to summarize and critically evaluate this new evidence in the context of the previous literature. RECENT FINDINGS: This review will address the recent epidemiological/survey studies that link vestibular dysfunction with cognitive impairment in the elderly; recent clinical investigations into cognitive impairment in the context of vestibular dysfunction, both in the elderly and in the cases of otic capsule dehiscence and partial bilateral vestibulopathy; recent evidence that vestibular impairment is associated with hippocampal atrophy; and finally recent evidence relating to the hypothesis that vestibular dysfunction could be a risk factor for dementia. SUMMARY: The main implication of these recent studies is that vestibular dysfunction, possibly of any type, may result in cognitive impairment, and this could be especially so for the elderly. Such symptoms will need to be considered in the treatment of patients with vestibular disorders.

What vestibular tests to choose in symptomatic patients after a cochlear implant? A systematic review and meta-analysis.

Vestibular function after cochlear implantation is difficult to understand, as subjective vestibular symptoms seem uncorrelated with the results of objective tests. Consequently, clinicians may struggle to decide what assessments to perform for a symptomatic patient. We used a systematic review and meta-analysis approach to enlighten this point. After a study inclusion process, results were classified into four different groups for each test in each study: (1) 'true positive' if the test showed impairment from pre-operative to post-operative in symptomatic patients; (2) 'false positive' if the test showed impairment from pre-operative to post-operative in asymptomatic patients; (3) 'true negative' if the test showed no impairment in asymptomatic patients; and (4) 'false negative' if the test showed no impairment in symptomatic patients. From these groups, sensitivities and specificities of each test were calculated in a meta-analysis. After reviewing more than 3000 references, 16 studies were included, representing 957 patients. The meta-analysis revealed a sensitivity of 0.21 (CI 95 % 0.08-0.40) for the caloric tests, of 0.32 (CI 95 % 0.15-0.54) for the cervical vestibular evoked myogenic potentials (c-VEMP), and of 0.5 (CI 95 % 0.07-0.93) for the head impulse tests. The analysis of prevalence revealed that c-VEMPs were the most often impaired, and the HIT the most often conserved. Our review and meta-analysis revealed that no vestibular test is sensitive enough to be recommended as a single test. Ideally, all the five vestibular sensors should be tested. In clinical practice, we suggest a case-to-case strategy according to patient's symptoms and their suspected origin.

A Guerilla Guide to Common Problems in 'Neurostatistics': Essential Statistical Topics in Neuroscience.

Effective inferential statistical analysis is essential for high quality studies in neuroscience. However, recently, neuroscience has been criticised for the poor use of experimental design and statistical analysis. Many of the statistical issues confronting neuroscience are similar to other areas of biology; however, there are some that occur more regularly in neuroscience studies. This review attempts to provide a succinct overview of some of the major issues that arise commonly in the analyses of neuroscience data. These include: the non-normal distribution of the data; inequality of variance between groups; extensive correlation in data for repeated measurements across time or space; excessive multiple testing; inadequate statistical power due to small sample sizes; pseudo-replication; and an over-emphasis on binary conclusions about statistical significance as opposed to effect sizes. Statistical analysis should be viewed as just another neuroscience tool, which is critical to the final outcome of the study. Therefore, it needs to be done well and it is a good idea to be proactive and seek help early, preferably before the study even begins.

Hippocampal and striatal M1 -muscarinic acetylcholine receptors are down-regulated following bilateral vestibular loss in rats.

Permanent vestibular loss has detrimental effects on the hippocampus, resulting in a disruption to spatial learning and memory, hippocampal theta rhythm and place cell field spatial coherence. Little is known about the vestibular system-related hippocampal cholinergic transmission. Since the pharmacological blockade of muscarinic acetylcholine (ACh) receptors within the hippocampus produces deficits in learning and memory, we hypothesized that ACh receptors may at least partly support the integration of vestibular input. Consequently, we examined the expression of M1 muscarinic ACh receptors in the hippocampus at 7 and 30 days following bilateral vestibular lesions (BVL) in rats using autoradiography. Animals were divided into sham (n = 12) and BVL (n = 11) groups. BVL animals received intratympanic injections of sodium arsanilate (30 mg/0.1 ml) under isoflurane anesthesia and sham animals received the same volume of saline. Analysis of the brain tissue revealed a significant reduction in the number of M1 receptors throughout the hippocampus and striatum at 30 days (P ≤ 0.0001), but not at 7 days following BVL. This suggests that the changes in learning and memory seen following vestibular damage may be in part due to the loss of M1 muscarinic receptors in the hippocampus and striatum. © 2016 Wiley Periodicals, Inc.

Basal dendritic length is reduced in the rat hippocampus following bilateral vestibular deafferentation.

Some previous studies in humans have shown that bilateral loss of vestibular function is associated with a significant bilateral atrophy of the hippocampus, which correlated with the patients' spatial memory deficits. By contrast, studies in rats have failed to detect any changes in hippocampal volume following bilateral vestibular loss. Therefore, in this study we investigated whether bilateral vestibular deafferentation (BVD) might result in more subtle morphological changes in the rat hippocampus, involving alterations in dendritic intersections, using Golgi staining and Sholl analysis. We found that at 1month following BVD, there was a significant decrease in basal (P⩽0.0001) but not apical dendritic intersections in the CA1 region of the hippocampus compared to sham-operated animals and anaesthetic controls. However, dendritic branching was not significantly affected. These results suggest that the rat hippocampus does undergo subtle morphological changes following bilateral vestibular loss, and that they may be in the form of alterations in dendritic structure.

Water Oxidation by the [Co4O4(OAc)4(py)4](+) Cubium is Initiated by OH(-) Addition.

The cobalt cubium Co4O4(OAc)4(py)4(ClO4) (1A(+)) containing the mixed valence [Co4O4](5+) core is shown by multiple spectroscopic methods to react with hydroxide (OH(-)) but not with water molecules to produce O2. The yield of reaction products is stoichiometric (>99.5%): 41A(+) + 4OH(-) → O2 + 2H2O + 41A. By contrast, the structurally homologous cubium Co4O4(trans-OAc)2(bpy)4(ClO4)3, 1B(ClO4)3, produces no O2. EPR/NMR spectroscopies show clean conversion to cubane 1A during O2 evolution with no Co(2+) or Co3O4 side products. Mass spectrometry of the reaction between isotopically labeled µ-(16)O(bridging-oxo) 1A(+) and (18)O-bicarbonate/water shows (1) no exchange of (18)O into the bridging oxos of 1A(+), and (2) (36)O2 is the major product, thus requiring two OH(-) in the reactive intermediate. DFT calculations of solvated intermediates suggest that addition of two OH(-) to 1A(+) via OH(-) insertion into Co-OAc bonds is energetically favored, followed by outer-sphere oxidation to intermediate [1A(OH)2](0). The absence of O2 production by cubium 1B(3+) indicates the reactive intermediate derived from 1A(+) requires gem-1,1-dihydoxo stereochemistry to perform O-O bond formation. Outer-sphere oxidation of this intermediate by 2 equiv of 1A(+) accounts for the final stoichiometry. Collectively, these results and recent literature (Faraday Discuss., doi:10.1039/C5FD00076A and J. Am. Chem. Soc. 2015, 137, 12865-12872) validate the [Co4O4](4+/5+) cubane core as an intrinsic catalyst for oxidation of hydroxide by an inner-sphere mechanism.

Surface and Structural Investigation of a MnOx Birnessite-Type Water Oxidation Catalyst Formed under Photocatalytic Conditions.

Catalytically active MnOx species have been reported to form in situ from various Mn-complexes during electrocatalytic and solution-based water oxidation when employing cerium(IV) ammonium ammonium nitrate (CAN) oxidant as a sacrificial reagent. The full structural characterization of these oxides may be complicated by the presence of support material and lack of a pure bulk phase. For the first time, we show that highly active MnOx catalysts form without supports in situ under photocatalytic conditions. Our most active (4)MnOx catalyst (∼0.84 mmol O2 mol Mn(-1) s(-1)) forms from a Mn4O4 bearing a metal-organic framework. (4)MnOx is characterized by pair distribution function analysis (PDF), Raman spectroscopy, and HR-TEM as a disordered, layered Mn-oxide with high surface area (216 m(2) g(-1)) and small regions of crystallinity and layer flexibility. In contrast, the (S)MnOx formed from Mn(2+) salt gives an amorphous species of lower surface area (80 m(2) g(-1)) and lower activity (∼0.15 mmol O2 mol Mn(-1) s(-1)). We compare these catalysts to crystalline hexagonal birnessite, which activates under the same conditions. Full deconvolution of the XPS Mn2p3/2 core levels detects enriched Mn(3+) and Mn(2+) content on the surfaces, which indicates possible disproportionation/comproportionation surface equilibria.

Galvanic vestibular stimulation impairs cell proliferation and neurogenesis in the rat hippocampus but not spatial memory.

Galvanic vestibular stimulation (GVS) is a method of activating the peripheral vestibular system using direct current that is widely employed in clinical neurological testing. Since movement is recognized to stimulate hippocampal neurogenesis and movement is impossible without activation of the vestibular system, we speculated that activating the vestibular system in rats while minimizing movement, by delivering GVS under anesthesia, would affect hippocampal cell proliferation and neurogenesis, and spatial memory. Compared with the sham control group, the number of cells incorporating the DNA replication marker, bromodeoxyuridine (BrdU), was significantly reduced in the bilateral hippocampi in both the cathode left-anode right and cathode right-anode left stimulation groups (P ≤ 0.0001). The majority of the BrdU(+ve) cells co-expressed Ki-67, a marker for the S phase of the cell cycle, suggesting that these BrdU(+ve) cells were still in the cell cycle; however, there was no significant difference in the degree of co-labeling between the two stimulation groups. Single labeling for doublecortin (DCX), a marker of immature neurons, showed that while there was no significant difference between the different groups in the number of DCX(+ve) cells in the right dentate gryus, in the left dentate gyrus there was a significant decrease in the cathode left-anode right group compared with the sham controls (P ≤ 0.03). Nonetheless, when animals were tested in place recognition, object exploration and Morris water maze tasks, there were no significant differences between the GVS groups and the sham controls. These results suggest that GVS can have striking effects on cell proliferation and possibly neurogenesis in the hippocampus, without affecting spatial memory.

What determines catalyst functionality in molecular water oxidation? Dependence on ligands and metal nuclearity in cobalt clusters.

The metal-oxo M4O4 "cubane" topology is of special significance to the field of water oxidation as it represents the merging of bioinspired structural principles derived from natural photosynthesis with successful artificial catalysts known to date. Herein, we directly compare the rates of water oxidation/O2 evolution catalyzed by six cobalt-oxo clusters including the Co4O4 cubanes, Co4O4(OAc)4(py)4 and [Co4O4(OAc)2(bpy)4](2+), using the common Ru(bpy)3(2+)/S2O8(2-) photo-oxidant assay. At pH 8, the first-order rate constants for these cubanes differ by 2-fold, 0.030 and 0.015 s(-1), respectively, reflecting the number of labile carboxylate sites that allow substrate water binding in a pre-equilibrium step before O2 release. Kinetic results reveal a deprotonation step occurs on this pathway and that two electrons are removed before O2 evolution occurs. The Co4O4 cubane core is shown to be the smallest catalytic unit for the intramolecular water oxidation pathway, as neither "incomplete cubane" trimers [Co3O(OH)3(OAc)2(bpy)3](2+) and [Co3O(OH)2(OAc)3(py)5](2+) nor "half cubane" dimers [Co2(OH)2(OAc)3(bpy)2](+) and [Co2(OH)2(OAc)3(py)4](+) were found capable of evolving O2, despite having the same ligand sets as their cubane counterparts. Electrochemical studies reveal that oxidation of both cubanes to formally Co4(3III,IV) (0.7 V vs Ag/AgCl) occurs readily, while neither dimers nor trimers are oxidized below 1.5 V, pointing to appreciably greater charge delocalization in the [Co4O4](5+) core. The origin of catalytic activity by Co4O4 cubanes illustrates three key features for water oxidation: (1) four one-electron redox metals, (2) efficient charge delocalization of the first oxidation step across the Co4O4 cluster, allowing for stabilization of higher oxidizing equivalents, and (3) terminal coordination site for substrate aquo/oxo formation.