Time-dependent effects of acoustic trauma and tinnitus on extracellular levels of amino acids in the inferior colliculus of rats.

Chronic tinnitus is a debilitating condition with very few management options. Acoustic trauma that causes tinnitus has been shown to induce neuronal hyperactivity in multiple brain areas in the auditory pathway, including the inferior colliculus. This neuronal hyperactivity could be attributed to an imbalance between excitatory and inhibitory neurotransmission. However, it is not clear how the levels of neurotransmitters, especially neurotransmitters in the extracellular space, change over time following acoustic trauma and the development of tinnitus. In the present study, a range of amino acids were measured in the inferior colliculus of rats during acoustic trauma as well as at 1 week and 5 months post-trauma using in vivo microdialysis and high-performance liquid chromatography. Amino acid levels in response to sound stimulation were also measured at 1 week and 5 months post-trauma. It was found that unilateral exposure to a 16 kHz pure tone at 115 dB SPL for 1 h caused immediate hearing loss in all the animals and chronic tinnitus in 58 % of the animals. Comparing to the sham condition, extracellular levels of GABA were significantly increased at both the acute and 1 week time points after acoustic trauma. However, there was no significant difference in any of the amino acid levels measured between sham, tinnitus positive and tinnitus negative animals at 5 months post-trauma. There was also no clear pattern in the relationship between neurochemical changes and sound frequency/acoustic trauma/tinnitus status, which might be due to the relatively poorer temporal resolution of the microdialysis compared to electrophysiological responses.

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.

Interpreting the meaning of changes in hippocampal volume associated with vestibular loss.

Many studies have documented cognitive deficits, especially spatial cognitive deficits, in patients with some form of vestibular loss. Almost 20 years ago, hippocampal (HPC) atrophy was reported to be correlated with spatial memory deficits in such patients and the idea has gradually emerged that HPC atrophy may be causally responsible for the cognitive deficits. However, the results of studies of HPC volume following vestibular loss have not always been consistent, and a number of studies have reported no evidence of HPC atrophy. This paper argues that HPC atrophy, if it does occur following vestibular loss, may not be directly, causally responsible for the cognitive deficits, and that it is more likely that rapid functional changes in the HPC are responsible, due to the interruption of the transmission of vestibular information to the HPC. The argument presented here rests on 3 tranches of evidence: (1) Cognitive deficits have been observed in humans even in the absence of HPC atrophy; (2) HPC atrophy has not been reported in animal studies following vestibular loss, despite cognitive deficits; and (3) Animal studies have shown that the interruption of the transmission of vestibular information to the HPC has immediate consequences for HPC place cells, far too quickly to be explained by HPC atrophy. It is possible that HPC atrophy, when it does occur, is related to the longer-term consquences of living with vestibular loss, which are likely to increase circulating cortisol.

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.

Scoping out noisy galvanic vestibular stimulation: a review of the parameters used to improve postural control.

Objective: Noisy galvanic vestibular stimulation (nGVS) has been used to facilitate vestibular function and improve gait and balance in people with poor postural control. The aim of this scoping review is to collate, summarize and report on the nGVS parameters that have been used to augment postural control. Method: A systematic scoping review was conducted up to December 2022. Data were extracted and synthesized from 31 eligible studies. Key nGVS parameters were identified, and the importance of these parameters and their influence on postural control evaluated. Results: A range of nGVS parameters have been used to augment postural control, including; noise waveform, amplitude, frequency band, duration of stimulation, method of amplitude optimization, size and composition of electrodes and the electrode skin interface. Conclusion: Systematic evaluation of the individual parameters that can be manipulated in the nGVS waveform identified that a broad array of settings have been utilized in each parameter across the studies. Choices made around the electrode and electrode-skin interface, as well as the amplitude, frequency band, duration and timing of the waveform are likely to influence the efficacy of nGVS. The ability to draw robust conclusions about the selection of optimal nGVS parameters to improve postural control, is hindered by a lack of studies that directly compare parameter settings or consider the variability in individuals' response to nGVS. We propose a guideline for the accurate reporting of nGVS parameters, as a first step toward establishing standardized stimulation protocols.

Vestibular modulation of the tail of the rat striatum.

Fragmented and piecemeal evidence from animal and human studies suggests that vestibular information is transmitted to the striatum, a part of the basal ganglia that degenerates in Parkinson's Disease. Nonetheless, surprisingly little is known about the precise effects of activation of the vestibular system on the striatum. Electrophysiological studies have yielded inconsistent results, with many studies reporting only sparse responses to vestibular stimulation in the dorsomedial striatum. In this study, we sought to elucidate the effects of electrical stimulation of the peripheral vestibular system on electrophysiological responses in the tail of the rat striatum, a newly discovered region for sensory input. Rats were anaesthetised with urethane and a bipolar stimulating electrode was placed in the round window in order to activate the peripheral vestibular system. A recording electrode was positioned in the tail of the striatum. Local field potentials (LFPs) were recorded ipsilaterally and contralaterally to the stimulation using a range of current parameters. In order to confirm that the vestibular system was activated, video-oculography was used to monitor vestibular nystagmus. At current amplitudes that evoked vestibular nystagmus, clear triphasic LFPs were evoked in the bilateral tail of the striatum, with the first phase of the waveform exhibiting latencies of less than 22 ms. The LFP amplitude increased with increasing current amplitude (P ≤ 0.0001). In order to exclude the possibility that the LFPs were evoked by the activation of the auditory system, the cochlea was surgically lesioned in some animals. In these animals the LFPs persisted despite the cochlear lesions, which were verified histologically. Overall, the results obtained suggest that there are vestibular projections to the tail of the striatum, which could possibly arise from projections via the vestibular nucleus or cerebellum and the parafasicular nucleus of the thalamus.

Exploring the Mechanism and Suggesting Combination Therapies for HDAC Inhibitors in Androgen Receptor-Null Prostate Cancer Using Multivariate Statistical Analysis and Data Mining Techniques.

Previously, we showed that novel histone deacetylase (HDAC) inhibitors, N1-hydroxy-N 8-(4-(pyridine-2-carbothioamido)phenyl)octanediamide (Jazz90) and [chlorido(η5-pentamethylcyclopentadienyl)(N1-hydroxy-N8-(4-(pyridine-2-carbothioamido-κ2 N, S)phenyl)octanediamide)rhodium(III)] chloride (Jazz167), have cytostatic and anti-angiogenic effects in androgen receptor-negative prostate cancer cells and are also non-toxic in BALB/c mice. However, only univariate statistical analysis was carried out to determine the role of individual proteins. In this study, multivariate statistical analyses (MVAs) and data mining procedures were carried out with the objective of determining the molecular networks that explain the growth inhibitory potential of Jazz90 and Jazz167 in PC3 cells and to determine potential inhibitors that can be used in combination with these HDAC inhibitors. Lasso regression revealed that angiogenic factors, vascular endothelial growth factor-A (VEGF-A), and vascular endothelial growth factor receptor-2 (VEGFR-2), alongside HDAC inhibition, predicted the reduction in cell number with an adjusted R 2 value of 0.99 following Jazz90 treatment, whereas VEGFR-2, acetylation of histone-3, and HDAC inhibition predicted cell number with an adjusted R 2 value of 0.84 following Jazz167 treatment. These results were further followed up with ridge regression, hierarchical cluster analysis, random forest classification (RFC), and support vector machines. RFC and support vector machines also predicted the treatment groups with a 100% accuracy. MVAs also revealed that Jazz90 should be examined in combination with epithelial to mesenchymal transitioning inhibitors, such as simvastatin and olaparib, whereas Jazz167 should be examined with venetoclax or navitoclax. Future studies should also address the roles of VEGF-A and VEGFR-2 in cellular proliferation, whereas p27 function should be examined for its role in PC3 cell migration.

Efficacy of nGVS to improve postural stability in people with bilateral vestibulopathy: A systematic review and meta-analysis.

Objective: Noisy galvanic vestibular stimulation (nGVS) has been used to boost vestibular afferent information to the central nervous system. This has the potential to improve postural control for people for whom vestibular signals are weak, such as in bilateral vestibulopathy (BVP). The aim of this systematic review and meta-analysis is to investigate the evidence for nGVS as a modality to improve postural control in people with BVP. Methods: A comprehensive systematic search was conducted of five databases up to July 2022 to find studies applying nGVS to people with BVP, with the aim of improving postural control. Two independent reviewers screened and identified eligible studies, completed a risk of bias evaluation (Cochrane) and extracted relevant data. The standardized mean difference (SMD) based on Hedges' g was calculated as a measure of effect size for the primary outcome measure that best identified postural control, and a forest plot generated. Results: Seven studies met the eligibility criteria, with five being suitable for meta-analysis. Meta-analysis revealed a moderate effect in favor of nGVS improving postural control during standing and walking [pooled SMD = 0.47 95% CI (0.25, 0.7)]. nGVS-mediated improvements in postural control were most evident in observations of reduced sway velocity when standing on a firm surface with eyes closed, and in the reduced variability of gait parameters, particularly those measuring lateral stability. Conclusions: Coincident nGVS in people with BVP improves postural control during standing and walking. This improvement appears to be context specific, in that vestibular augmentation is most effective in situations where visual inputs are limited, and where reliable context specific proprioceptive cues are available. Further research is warranted investigating additional circumstances in which nGVS improves postural control, including investigating the residual, and sustained effects of nGVS. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=342147, identifier: 342147.

Recent developments in the understanding of the interactions between the vestibular system, memory, the hippocampus, and the striatum.

Over the last two decades, evidence has accumulated to demonstrate that the vestibular system has extensive connections with areas of the brain related to spatial memory, such as the hippocampus, and also that it has significant interactions with areas associated with voluntary motor control, such as the striatum in the basal ganglia. In fact, these functions are far from separate and it is believed that interactions between the striatum and hippocampus are important for memory processing. The data relating to vestibular-hippocampal-striatal interactions have considerable implications for the understanding and treatment of Alzheimer's Disease and Parkinson's Disease, in addition to other neurological disorders. However, evidence is accumulating rapidly, and it is difficult to keep up with the latest developments in these and related areas. The aim of this review is to summarize and critically evaluate the relevant evidence that has been published over the last 2 years (i.e., since 2021), in order to identify emerging themes in this research area.

Why Should Constant Stimulation of Saccular Afferents Modify the Posture and Gait of Patients with Bilateral Vestibular Dysfunction? The Saccular Substitution Hypothesis.

An ongoing EU Horizon 2020 Project called BionicVEST is investigating the effect of constant electrical stimulation (ES) of the inferior vestibular nerve in patients with bilateral vestibular dysfunction (BVD). The evidence is that constant ES results in improved postural stability and gait performance, and so the question of central importance concerns how constant ES of mainly saccular afferents in these BVD patients could cause this improved performance. We suggest that the constant ES substitutes for the absent saccular neural input to the vestibular nuclei and the cerebellum in these BVD patients and indirectly via these structures to other structures, which have been of great recent interest in motor control. One target area, the anterior midline cerebellum (the uvula), has recently been targeted as a location for deep-brain stimulation in human patients to improve postural stability and gait. There are projections from midline cerebellum to basal ganglia, including the striatum, which are structures involved in the initiation of gait. It may be that the effect of this activation of peripheral saccular afferent neurons is analogous to the effect of deep-brain stimulation (DBS) by electrodes in basal ganglia acting to help alleviate the symptoms of patients with Parkinson's disease.

Hearing loss versus vestibular loss as contributors to cognitive dysfunction.

In the last 5 years, there has been a surge in evidence that hearing loss (HL) may be a risk factor for cognitive dysfunction, including dementia. At the same time, there has been an increase in the number of studies implicating vestibular loss in cognitive dysfunction. Due to the fact that vestibular disorders often present with HL and other auditory disorders such as tinnitus, it has been suggested that, in many cases, what appears to be vestibular-related cognitive dysfunction may be due to HL (e.g., Dobbels et al. Front Neurol 11:710, 2020). This review analyses the studies of vestibular-related cognitive dysfunction which have controlled HL. It is suggested that despite the fact that many studies in the area have not controlled HL, many other studies have (~ 19/44 studies or 43%). Therefore, although there is certainly a need for further studies controlling HL, there is evidence to suggest that vestibular loss is associated with cognitive dysfunction, especially related to spatial memory. This is consistent with the overwhelming evidence from animal studies that the vestibular system transmits specific types of information about self-motion to structures such as the hippocampus.

Frequency-Specific Effects of Galvanic Vestibular Stimulation on Response-Time Performance in Parkinson's Disease.

Background: Galvanic vestibular stimulation (GVS) is being increasingly explored as a non-invasive brain stimulation technique to treat symptoms in Parkinson's disease (PD). To date, behavioral GVS effects in PD have been explored with only two stimulus types, direct current and random noise (RN). The interaction between GVS effects and anti-parkinsonian medication is unknown. In the present study, we designed multisine (ms) stimuli and investigated the effects of ms and RN GVS on motor response time. In comparison to the RN stimulus, the ms stimuli contained sinusoidal components only at a set of desired frequencies and the phases were optimized to improve participants' comfort. We hypothesized GVS motor effects were a function of stimulation frequency, and specifically, that band-limited ms-GVS would result in better motor performance than conventionally used broadband RN-GVS. Materials and Methods: Eighteen PD patients (PDMOFF/PDMON: off-/on-levodopa medication) and 20 healthy controls (HC) performed a simple reaction time task while receiving sub-threshold GVS. Each participant underwent nine stimulation conditions: off-stimulation, RN (4-200 Hz), ms-θ (4-8 Hz), ms-α (8-13 Hz), ms-ß (13-30 Hz), ms-γ (30-50 Hz), ms-h1 (50-100 Hz), ms-h2 (100-150 Hz), and ms-h3 (150-200 Hz). Results: The ms-γ resulted in shorter response time (RPT) in both PDMOFF and HC groups compared with the RN. In addition, the RPT of the PDMOFF group decreased during the ms-ß while the RPT of the HC group decreased during the ms-α, ms-h1, ms-h2, and ms-h3. There was considerable inter-subject variability in the optimum stimulus type, although the frequency range tended to fall within 8-100 Hz. Levodopa medication significantly reduced the baseline RPT of the PD patients. In contrast to the off-medication state, GVS did not significantly change RPT of the PD patients in the on-medication state. Conclusions: Using band-limited ms-GVS, we demonstrated that the GVS frequency for the best RPT varied considerably across participants and was >30 Hz for half of the PDMOFF patients. Moreover, dopaminergic medication was found to influence GVS effects in PD patients. Our results indicate the common "one-size-fits-all" RN approach is suboptimal for PD, and therefore personalized stimuli aiming to address this variability is warranted to improve GVS effects.

Noisy Galvanic Vestibular Stimulation Combined With a Multisensory Balance Program in Older Adults With Moderate to High Fall Risk: Protocol for a Feasibility Study for a Randomized Controlled Trial.

BACKGROUND: Reduced mobility and falls are common among older adults. Balance retraining programs are effective in reducing falls and in improving balance and mobility. Noisy galvanic vestibular stimulation is a low-level electrical stimulation used to reduce the threshold for the firing of vestibular neurons via a mechanism of stochastic resonance. OBJECTIVE: This study aims to determine the feasibility of using noisy galvanic vestibular stimulation to augment a balance training program for older adults at risk of falls. We hypothesize that noisy galvanic vestibular stimulation will enhance the effects of balance retraining in older adults at risk of falls. METHODS: In this 3-armed randomized controlled trial, community dwelling older adults at risk of falling will be randomly assigned to a noisy galvanic vestibular stimulation plus balance program (noisy galvanic vestibular stimulation group), sham plus balance program (sham group), or a no treatment group (control). Participants will attend the exercise group twice a week for 8 weeks with assessment of balance and gait pretreatment, posttreatment, and at 3 months postintervention. Primary outcome measures include postural sway, measured by center of pressure velocity, area and root mean square, and gait parameters such as speed, step width, step variability, and double support time. Spatial memory will also be measured using the triangle completion task and the 4 Mountains Test. RESULTS: Recruitment began in November 2020. Data collection and analysis are expected to be completed by December 2022. CONCLUSIONS: This study will evaluate the feasibility of using noisy galvanic vestibular stimulation alongside balance retraining in older adults at risk of falls and will inform the design of a fully powered randomized controlled trial. TRIAL REGISTRATION: New Zealand Clinical Trials Registry (ACTRN12620001172998); https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379944. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32085.

Metabolic changes in the brain and blood of rats following acoustic trauma, tinnitus and hyperacusis.

It has been increasingly recognized that tinnitus is likely to be generated by complex network changes. Acoustic trauma that causes tinnitus induces significant changes in multiple metabolic pathways in the brain. However, it is not clear whether those metabolic changes in the brain could also be reflected in blood samples and whether metabolic changes could discriminate acoustic trauma, hyperacusis and tinnitus. We analyzed brain and serum metabolic changes in rats following acoustic trauma or a sham procedure using metabolomics. Hearing levels were recorded before and after acoustic trauma and behavioral measures to quantify tinnitus and hyperacusis were conducted at 4 weeks following acoustic trauma. Tissues from 11 different brain regions and serum samples were collected at about 3 months following acoustic trauma. Among the acoustic trauma animals, eight exhibited hyperacusis-like behavior and three exhibited tinnitus-like behavior. Using Gas chromatography-mass spectrometry and multivariate statistical analysis, significant metabolic changes were found in acoustic trauma animals in both the brain and serum samples with a number of metabolic pathways significantly perturbated. Furthermore, metabolic changes in the serum were able to differentiate sham from acoustic trauma animals, as well as sham from hyperacusis animals, with high accuracy. Our results suggest that serum metabolic profiling in combination with machine learning analysis may be a promising approach for identifying biomarkers for acoustic trauma, hyperacusis and potentially, tinnitus.

Applications of Multivariate Statistical and Data Mining Analyses to the Search for Biomarkers of Sensorineural Hearing Loss, Tinnitus, and Vestibular Dysfunction.

Disorders of sensory systems, as with most disorders of the nervous system, usually involve the interaction of multiple variables to cause some change, and yet often basic sensory neuroscience data are analyzed using univariate statistical analyses only. The exclusive use of univariate statistical procedures, analyzing one variable at a time, may limit the potential of studies to determine how interactions between variables may, as a network, determine a particular result. The use of multivariate statistical and data mining methods provides the opportunity to analyse many variables together, in order to appreciate how they may function as a system of interacting variables, and how this system or network may change as a result of sensory disorders such as sensorineural hearing loss, tinnitus or different types of vestibular dysfunction. Here we provide an overview of the potential applications of multivariate statistical and data mining techniques, such as principal component and factor analysis, cluster analysis, multiple linear regression, random forest regression, linear discriminant analysis, support vector machines, random forest classification, Bayesian classification, and orthogonal partial least squares discriminant analysis, to the study of auditory and vestibular dysfunction, with an emphasis on classification analytic methods that may be used in the search for biomarkers of disease.

Emerging Topics in the Behavioral Neuroscience of Tinnitus.

This volume has highlighted the many recent advances in tinnitus theory, models, diagnostics, therapies, and therapeutics. But tinnitus knowledge is far from complete. In this chapter, contributors to the Behavioral Neuroscience of Tinnitus consider emerging topics and areas of research needed in light of recent findings. New research avenues and methods to explore are discussed. Issues pertaining to current assessment, treatment, and research methods are outlined, along with recommendations on new avenues to explore with research.

Pharmacological Evaluation of Drugs in Animal Models of Tinnitus.

Despite the pressing need for effective drug treatments for tinnitus, currently, there is no single drug that is approved by the FDA for this purpose. Instead, a wide range of unproven over-the-counter tinnitus remedies are available on the market with little or no benefit for tinnitus but with potential harm and adverse effects. Animal models of tinnitus have played a critical role in exploring the pathophysiology of tinnitus, identifying therapeutic targets and evaluating novel and existing drugs for tinnitus treatment. This review summarises and compares the studies on pharmacological evaluation of tinnitus treatment in different animal models based on the pharmacological properties of the drug and provides insights into future directions for tinnitus drug discovery.

Stratification of hippocampal electrophysiological activation evoked by selective electrical stimulation of different angular and linear acceleration sensors in the rat peripheral vestibular system.

It has become well established that vestibular information is important for hippocampal function and spatial memory. However, as yet, relatively little is known about how different kinds of vestibular information are 'represented' in different parts of the hippocampus. This study used selective electrical stimulation of each of the 5 vestibular sensors (the horizontal (HC), anterior (AC) and posterior (PC) semi-circular canals, and the utricle and saccule) in the rat and recorded local field potentials (LFPs) across the hippocampus, using a 16 electrode microarray. We found that stimulation of any vestibular sensor in the left labyrinth evoked triphasic LFPs in both hippocampi, although it was clear that, in general, the amplitudes were greater for the right, contralateral side. This was particularly true for Phase 1 for the HC, AC, utricle and saccule, Phase 2 for the HC, PC, utricle and saccule, and Phase 3 for the AC, PC and saccule. Overall, our results suggest that vestibular input to the hippocampus is bilateral, preferentially contralateral, but highly stratified in that stimulation of the same vestibular sensor results in activation of different specific areas of the hippocampus, with different LFP amplitudes and latencies. This suggests the possibility that different regions of the hippocampus use different kinds of vestibular information for different purposes and that there may be a high degree of redundancy in the representation of vestibular input, perhaps ensuring that the hippocampus is more robust to the partial loss of vestibular information.

Mental Health and Benzodiazepine Use Among Patients on Chronic Opioid Therapy.

INTRODUCTION: Higher daily doses of opioids as well as co-prescription of benzodiazepines have been associated with risk of overdose. The current study characterizes prescribing patterns in a family medicine practice with regard to patient mental health diagnoses, benzodiazepine prescriptions, morphine milligram equivalent opioid dose, and patient demographics. METHODS: Patients on chronic opioid therapy were studied in 2018 and 2019. Mental health diagnoses, opioid dose, benzodiazepine prescriptions and demographic characteristics were extracted from the electronic health record. Data were compared between years and logistic regression was used to determine which patient characteristics were associated with likelihood of decreased opioid dose. RESULTS: A total of 387 patients were prescribed chronic opioid therapy in 2018, and 231 in 2019. In 2018, 49.9% of patients prescribed chronic opioids had mental health diagnoses. In 2019, this proportion rose to 92.2%. In 2019, 205 of the original 387 patients were still with the practice but were not prescribed chronic opioids. Among the factors studied, psychiatric diagnosis and higher opioid dose were associated with a significantly lower likelihood of tapering doses. DISCUSSION: As practices taper or de-prescribe opioids, or implement harm reduction methods such as de-prescribing benzodiazepines, it is important to understand patient characteristics and their relationship to success with tapering. This study adds to the evidence that odds of successfully tapering opioids may be significantly impacted by patients' mental health diagnosis and opioid dose.

Reduction of silver ions in molybdates: elucidation of framework acidity as the factor controlling charge balance mechanisms in aqueous zinc-ion electrolyte.

A percolating network of high electrical conductivity needed to operate electrodes at a fast rate can be formed by in situ reduction of Ag+ originating from mixed metal oxide lattices, but few studies have elucidated trends in this mechanism as a function of Ag+ concentration and structure. Candidates compared for the first time here are spinel Ag2MoO4, monoclinic and triclinic Ag2Mo2O7, and Ag2Mo3O10·2H2O, which have reduction potentials for Ag+ and Mo6+ strongly decoupled by up to ∼600 mV in aqueous zinc-ion electrolyte. Under these conditions, Ag0 is the first reduction product and a decrease of charge transfer resistance by ∼100× is observed within 2.5% consumption of total Ag+ independent of initial structure. However, resistance metrics alone poorly describe materials which are robust to reducing silver with high energy at faster rates. Instead, after accounting for crystallinity and morphology differences, we find that the acidity of the molybdate framework is responsible for a switch in charge balance mechanism from the bulk formation of a mixed ZnMoO x to pseudocapacitive Zn2+ precipitation, and that this mechanism switch is associated with minimized losses to rate, voltage and capacity yields as carbon/binder free electrodes relative to composites. The location of this acidity cutoff near the pH of the ZnSO4 electrolyte may suggest a design principle for future low-carbon electrodes beyond molybdate framework structures.