Virtual Endocrinology Care Emphasizing Data-Driven Insights and Continuous Engagement and Its Impact on Glycemic Outcomes in Patients With Uncontrolled Diabetes: A Real-world Retrospective Case Series.

BACKGROUND: Steady Health's novel virtual care model incorporates continuous glucose monitoring (CGM) and a multidisciplinary approach to timely person-centered diabetes care. OBJECTIVE: This real-world retrospective case series explores the early glycemic outcomes of its patients with uncontrolled diabetes. METHODS: All patients of Steady Health who had an initial time in range (TIR) below 70% from their first 4 weeks of available CGM data and who had completed onboarding by February 2021 were included in this analysis. We compared the change in TIR, time below range, and average blood glucose from their first 4 weeks with their latest 4 weeks of available CGM data. Hemoglobin A1c (HbA1c) values at baseline and at the end of the study were also compared. Patients completed a questionnaire assessing their satisfaction with Steady Health's intervention. RESULTS: A total of 53 patients (n=35, 66% with type 1 diabetes; n=44, 83% treated with insulin) were included in this analysis. This cohort had a median baseline TIR of 53.0% (IQR 40.9%, 61.7%) and saw a median change in TIR of +16.6% (IQR +6.0%, +27.9%; P<.001) over a median duration of care of 11 months, amounting to nearly 4 more hours spent between 70 to 180 mg/dL a day. Of the 27 patients who had both baseline and follow-up HbA1c results, their median baseline HbA1c was 8.6% (IQR 7.5%, 11.4%; 70 mmol/mol), while their median change in HbA1c was -1.2% (IQR -2.6%, -0.2%; P=.001). Importantly, these glycemic improvements were achieved with a median decrease in the time below range by -0.3% (IQR -1.1%, 0.0%; P<.001), regardless of whether patients were started on an automated insulin delivery system. A total of 40 (75.5%) patients improved TIR by ≥5%, and 27 (50.9%) achieved TIR≥70% by the end of the study. Glycemic improvements were greatest among patients with the lowest baseline TIR and those who collaborated most intensively with Steady Health's clinicians. A total of 25 of these patients responded to a questionnaire assessing levels of satisfaction with their care, and all of them agreed that Steady Health had a positive impact on their diabetes management. CONCLUSIONS: Our findings suggest that patients with uncontrolled diabetes can achieve significant glycemic improvements by working with a virtual multidisciplinary care team that uses CGM to provide continuous clinical feedback and support.

Leukocyte Telomere Length and Childhood Onset of Systemic Lupus Erythematosus in the Black Women's Experiences Living with Lupus Study.

OBJECTIVE: The study objective was to compare leukocyte telomere length (LTL) among patients with systemic lupus erythematosus (SLE) diagnosed in childhood versus adulthood. METHODS: Data are from the Black Women's Experiences Living with Lupus (BeWELL) study. Multivariable linear regression analyses that examined childhood diagnosis of SLE (diagnosed before 18 years of age), age, and their interaction in relationship to LTL were conducted, adjusting for a range of demographic, socioeconomic, and health-related covariates. RESULTS: The total analytic sample size was 415. Forty participants (9.6%) were diagnosed in childhood. There was no main effect of childhood diagnosis on LTL (b = 0.007; 95% confidence interval [CI]: -0.089 to 0.103). However, the interaction between age and childhood diagnosis was significant (b = -0.008; 95% CI: -0.016 to -0.001), indicating a steeper inverse association between age and LTL among those diagnosed in childhood compared with those diagnosed in adulthood. This interaction remained statistically significant (P = 0.024) after controlling for disease duration measured dichotomously (less than 10 years vs. 10 years or more); it was marginally significant (P = 0.083) when controlling for disease duration measured continuously. CONCLUSION: This cross-sectional analysis suggests that Black women with childhood-onset SLE may undergo accelerated LTL shortening compared with their adult-onset counterparts. This relationship persisted even after controlling for differences in SLE damage and disease duration. These findings inform research on immunosenescence mechanisms of SLE.

Olivocochlear projections contribute to superior intensity coding in cochlear nucleus small cells.

Understanding communication signals, especially in noisy environments, is crucial to social interactions. Yet, as we age, acoustic signals can be disrupted by cochlear damage and the subsequent auditory nerve fibre degeneration. The most vulnerable medium- and high-threshold-auditory nerve fibres innervate various cell types in the cochlear nucleus, among which the small cells are unique in receiving this input exclusively. Furthermore, small cells project to medial olivocochlear (MOC) neurons, which in turn send branched collaterals back into the small cell cap. Here, we use single-unit recordings to characterise small cell firing characteristics and demonstrate superior intensity coding in this cell class. We show converse effects when activating/blocking the MOC system, demonstrating that small-cell unique coding properties are facilitated by direct cholinergic input from the MOC system. Small cells also maintain tone-level coding in the presence of background noise. Finally, small cells precisely code low-frequency modulation more accurately than other ventral cochlear nucleus cell types, demonstrating accurate envelope coding that may be important for vocalisation processing. These results highlight the small cell olivocochlear circuit as a key player in signal processing in noisy environments, which may be selectively degraded in ageing or after noise insult. KEY POINTS: Cochlear nucleus small cells receive input from low/medium spontaneous rate auditory nerve fibres and medial olivocochlear neurons. Electrical stimulation of medial olivocochlear neurons in the ventral nucleus of the trapezoid body and blocking cholinergic input to small cells using atropine demonstrates an excitatory cholinergic input to small cells, which increases responses to suprathreshold sound. Unique inputs to small cells produce superior sound intensity coding. This coding of intensity is preserved in the presence of background noise, an effect exclusive to this cell type in the cochlear nucleus. These results suggest that small cells serve an essential function in the ascending auditory system, which may be relevant to disorders such as hidden hearing loss.

Audiotactile interactions in the mouse cochlear nucleus.

Multisensory integration of auditory and tactile information occurs already at the level of the cochlear nucleus. Rodents use their whiskers for tactile perception to guide them in their exploration of the world. As nocturnal animals with relatively poor vision, audiotactile interactions are of great importance for this species. Here, the influence of whisker deflections on sound-evoked spiking in the cochlear nucleus was investigated in vivo in anesthetized mice. Multichannel, silicon-probe electrophysiological recordings were obtained from both the dorsal and ventral cochlear nucleus. Whisker deflections evoked an increased spiking activity in fusiform cells of the dorsal cochlear nucleus and t-stellate cells in ventral cochlear nucleus, whereas bushy cells in the ventral cochlear nucleus showed a more variable response. The response to broadband noise stimulation increased in fusiform cells and primary-like bushy cells when the sound stimulation was preceded (~ 20 ms) by whisker stimulation. Multi-sensory integration of auditory and whisker input can thus occur already in this early brainstem nucleus, emphasizing the importance of early integration of auditory and somatosensory information.

Noise Exposure Alters Glutamatergic and GABAergic Synaptic Connectivity in the Hippocampus and Its Relevance to Tinnitus.

Accumulating evidence implicates a role for brain structures outside the ascending auditory pathway in tinnitus, the phantom perception of sound. In addition to other factors such as age-dependent hearing loss, high-level sound exposure is a prominent cause of tinnitus. Here, we examined how noise exposure altered the distribution of excitatory and inhibitory synaptic inputs in the guinea pig hippocampus and determined whether these changes were associated with tinnitus. In experiment one, guinea pigs were overexposed to unilateral narrow-band noise (98 dB SPL, 2 h). Two weeks later, the density of excitatory (VGLUT-1/2) and inhibitory (VGAT) synaptic terminals in CA1, CA3, and dentate gyrus hippocampal subregions was assessed by immunohistochemistry. Overall, VGLUT-1 density primarily increased, while VGAT density decreased significantly in many regions. Then, to assess whether the noise-induced alterations were persistent and related to tinnitus, experiment two utilized a noise-exposure paradigm shown to induce tinnitus and assessed tinnitus development which was assessed using gap-prepulse inhibition of the acoustic startle (GPIAS). Twelve weeks after sound overexposure, changes in excitatory synaptic terminal density had largely recovered regardless of tinnitus status, but the recovery of GABAergic terminal density was dramatically different in animals expressing tinnitus relative to animals resistant to tinnitus. In resistant animals, inhibitory synapse density recovered to preexposure levels, but in animals expressing tinnitus, inhibitory synapse density remained chronically diminished. Taken together, our results suggest that noise exposure induces striking changes in the balance of excitatory and inhibitory synaptic inputs throughout the hippocampus and reveal a potential role for rebounding inhibition in the hippocampus as a protective factor leading to tinnitus resilience.

Inhibitory interneurons in a brainstem circuit adjust their inhibitory motifs to process multimodal input.

KEY POINTS: Inhibitory-interneuron networks, consisting of multiple forms of circuit motifs including reciprocal (inhibitory interneurons inhibiting other interneurons) and feedforward (inhibitory interneurons inhibiting principal neurons) connections, are crucial in processing sensory information. The present study applies a statistical method to in vivo multichannel spike trains of dorsal cochlear nucleus neurons to disentangle reciprocal and feedforward-inhibitory motifs. After inducing input-specific plasticity, reciprocal and feedforward inhibition are found to be differentially regulated, and the combined effect synergistically modulates circuit output. The findings highlight the interplay among different circuit motifs as a key element in neural computation. ABSTRACT: Inhibitory interneurons play an essential role in neural computations by utilizing a combination of reciprocal (interneurons inhibiting each other) and feedforward (interneuron inhibiting the principal neuron) inhibition to process information. To disentangle the interplay between the two inhibitory-circuit motifs and understand their effects on the circuit output, in vivo recordings were made from the guinea pig dorsal cochlear nucleus, a cerebellar-like brainstem circuit. Spikes from inhibitory interneurons (cartwheel cell) and principal output neurons (fusiform cell) were compared before and after manipulating their common multimodal input. Using a statistical model based on the Cox method of modulated renewal process of spike train influence, reciprocal- and feedforward-inhibition motifs were quantified. In response to altered multimodal input, reciprocal inhibition was strengthened while feedforward inhibition was weakened, and the two motifs combined to modulate fusiform cell output and acoustic-driven responses. These findings reveal the cartwheel cell's role in auditory and multimodal processing, as well as illustrated the balance between different inhibitory-circuit motifs as a key element in neural computation.

Mechanisms of Noise-Induced Tinnitus: Insights from Cellular Studies.

Tinnitus, sound perception in the absence of physical stimuli, occurs in 15% of the population and is the top-reported disability for soldiers after combat. Noise overexposure is a major factor associated with tinnitus but does not always lead to tinnitus. Furthermore, people with normal audiograms can get tinnitus. In animal models, equivalent cochlear damage occurs in animals with and without behavioral evidence of tinnitus. But cochlear-nerve-recipient neurons in the brainstem demonstrate distinct, synchronized spontaneous firing patterns only in animals that develop tinnitus, driving activity in central brain regions and ultimately giving rise to phantom perception. Examining tinnitus-specific changes in single-cell populations enables us to begin to distinguish neural changes due to tinnitus from those that are due to hearing loss.

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs.

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus.

Tinnitus alters auditory-somatosensory plasticity in the cochlear nucleus (CN). Correspondingly, bimodal auditory-somatosensory stimulation treatment attenuates tinnitus, both in animals and humans (Marks et al., 2018). Therefore, we hypothesized that tinnitus is associated with altered somatosensory innervation of the CN. Here, we studied the expression of vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) in the CN, which reveals glutamatergic projections from the cochlea as well as somatosensory systems to this brainstem auditory center. Guinea pigs were unilaterally exposed to narrowband noise and behaviorally tested for tinnitus using gap-prepulse inhibition of the acoustic startle. Following physiological and behavioral measures, brain sections were immunohistochemically stained for VGLUT1 or VGLUT2. Puncta density was determined for each region of the ipsilateral and contralateral CN. Tinnitus was associated with an ipsilateral upregulation of VGLUT2 puncta density in the granule cell domain (GCD) and anteroventral CN (AVCN). Furthermore, there was a tinnitus-associated interaural asymmetry for VGLUT1 expression in the AVCN and deep layer of the dorsal CN (DCN3), due to contralateral downregulation of VGLUT1 expression. These tinnitus-related glutamatergic imbalances were reversed upon bimodal stimulation treatment. Tinnitus-associated ipsilateral upregulation of VGLUT2-positive projections likely derives from somatosensory projections to the GCD and AVCN. This upregulation may underlie the neurophysiological hallmarks of tinnitus in the CN. Reversing the increased ipsilateral glutamatergic innervation in the CN is likely a key mechanism in treating tinnitus.

Multisensory activation of ventral cochlear nucleus D-stellate cells modulates dorsal cochlear nucleus principal cell spatial coding.

KEY POINTS: Dorsal cochlear nucleus fusiform cells receive spectrally relevant auditory input for sound localization. Fusiform cells integrate auditory with other multisensory inputs. Here we elucidate how somatosensory and vestibular stimulation modify the fusiform cell spatial code through activation of an inhibitory interneuron: the ventral cochlear nucleus D-stellate cell. These results suggests that multisensory cues interact early in an ascending sensory pathway to serve an essential function. ABSTRACT: In the cochlear nucleus (CN), the first central site for coding sound location, numerous multisensory projections and their modulatory effects have been reported. However, multisensory influences on sound location processing in the CN remain unknown. The principal output neurons of the dorsal CN, fusiform cells, encode spatial information through frequency-selective responses to direction-dependent spectral features. Here, single-unit recordings from the guinea pig CN revealed transient alterations by somatosensory and vestibular stimulation in fusiform cell spatial coding. Changes in fusiform cell spectral sensitivity correlated with multisensory modulation of ventral CN D-stellate cell responses, which provide direct, wideband inhibition to fusiform cells. These results suggest that multisensory inputs contribute to spatial coding in DCN fusiform cells via an inhibitory interneuron, the D-stellate cell. This early multisensory integration circuit likely confers important consequences on perceptual organization downstream.

Multisensory Integration Enhances Temporal Coding in Ventral Cochlear Nucleus Bushy Cells.

Temporal coding of auditory stimuli is critical for understanding communication signals. The bushy cell, a major output neuron of the ventral cochlear nucleus, can "phase-lock" precisely to pure tones and the envelopes of complex stimuli. Bushy cells are also putative recipients of brainstem somatosensory projections and could therefore play a role in perception of communication signals because multisensory integration is required for such complex sound processing. Here, we examine the role of multisensory integration in temporal coding in bushy cells by activating the spinal trigeminal nucleus (Sp5) while recording responses from bushy cells. In normal-hearing guinea pigs of either sex, bushy cell single unit responses to amplitude-modulated (AM) broadband noise were compared with those in the presence of preceding Sp5 electrical stimulation (i.e., bimodal stimuli). Responses to the AM stimuli were also compared with those obtained 45 min after the bimodal stimulation. Bimodal auditory-Sp5 stimulation resulted in enhanced envelope coding for low modulation frequencies, which persisted for up to 45 min. AM detection thresholds were significantly improved 45 min after bimodal auditory-Sp5 stimulation, but not during bimodal auditory-Sp5 stimulation. Anterograde labeling of Sp5 projections was found within the dendritic fields of bushy cells and their inhibitory interneurons, D-stellate cells. Therefore, enhanced AM responses and improved AM sensitivity of bushy cells were likely facilitated by Sp5 neurons through monosynaptic excitatory projections and indirect inhibitory projections. These somatosensory projections may be involved in the improved perception of communication stimuli with multisensory stimulation, consistent with psychophysical studies in humans.SIGNIFICANCE STATEMENT Multisensory integration is crucial for sensory coding because it improves sensitivity to unimodal stimuli and enhances responses to external stimuli. Although multisensory integration has typically been described in the cerebral cortex, the cochlear nucleus in the brainstem is also innervated by multiple sensory systems, including the somatosensory and auditory systems. Here, we showed that convergence of these two sensory systems in the cochlear nucleus results in improved temporal coding in bushy cells, principal output neurons that send projections to higher auditory structures. The improved temporal coding instilled by bimodal auditory-Sp5 stimulation may be important in priming the neurons for coding biologically relevant sounds such as communication signals.

Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans.

The dorsal cochlear nucleus is the first site of multisensory convergence in mammalian auditory pathways. Principal output neurons, the fusiform cells, integrate auditory nerve inputs from the cochlea with somatosensory inputs from the head and neck. In previous work, we developed a guinea pig model of tinnitus induced by noise exposure and showed that the fusiform cells in these animals exhibited increased spontaneous activity and cross-unit synchrony, which are physiological correlates of tinnitus. We delivered repeated bimodal auditory-somatosensory stimulation to the dorsal cochlear nucleus of guinea pigs with tinnitus, choosing a stimulus interval known to induce long-term depression (LTD). Twenty minutes per day of LTD-inducing bimodal (but not unimodal) stimulation reduced physiological and behavioral evidence of tinnitus in the guinea pigs after 25 days. Next, we applied the same bimodal treatment to 20 human subjects with tinnitus using a double-blinded, sham-controlled, crossover study. Twenty-eight days of LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. Unimodal auditory stimulation did not deliver either benefit. Bimodal auditory-somatosensory stimulation that induces LTD in the dorsal cochlear nucleus may hold promise for suppressing chronic tinnitus, which reduces quality of life for millions of tinnitus sufferers worldwide.

Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group.

Background: Osteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density. Existing guidelines focus on treatment of the severe infantile forms with hematopoietic cell transplantation (HCT) but do not address the management of patients with less severe forms for whom HCT is not the standard of care. Therefore, our objective was to develop expert consensus guidelines for the management of these patients. Methods: A modified Delphi method was used to build consensus among participants of the Osteopetrosis Working Group, with responses to an anonymous online survey used to identify areas of agreement and conflict and develop a follow-up survey. The strength of recommendations and quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation system. Results: Consensus was found in the areas of diagnosis, monitoring, and treatment. We recommend relying on characteristic radiographic findings to make the diagnosis and found that genetic testing adds important information by identifying mutations associated with unique disease complications. We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease. We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile osteopetrosis has no effective treatment. Conclusions: Scarcity of published studies on osteopetrosis reduce the ability to develop evidence-based guidelines for the management of these patients. Expert opinion-based guidelines for this rare condition are nevertheless important to enable improved care.

Increased Synchrony and Bursting of Dorsal Cochlear Nucleus Fusiform Cells Correlate with Tinnitus.

Tinnitus, the perception of phantom sounds, is thought to arise from increased neural synchrony, which facilitates perceptual binding and creates salient sensory features in the absence of physical stimuli. In the auditory cortex, increased spontaneous cross-unit synchrony and single-unit bursting are de facto physiological correlates of tinnitus. However, it is unknown whether neurons in the dorsal cochlear nucleus (DCN), the putative tinnitus-induction site, exhibit increased synchrony. Using a temporary-threshold shift model and gap-prepulse inhibition of the acoustic startle to assess tinnitus, we recorded spontaneous activity from fusiform cells, the principle neurons of the DCN, in normal hearing, tinnitus, and non-tinnitus guinea pigs. Synchrony and bursting, as well as spontaneous firing rate (SFR), correlated with behavioral evidence of tinnitus, and increased synchrony and bursting were associated with SFR elevation. The presence of increased synchrony and bursting in DCN fusiform cells suggests that a neural code for phantom sounds emerges in this brainstem location and likely contributes to the formation of the tinnitus percept. SIGNIFICANCE STATEMENT: Tinnitus, a phantom auditory percept, is encoded by pathological changes in the neural synchrony code of perceptual processing. Increased cross-unit synchrony and bursting have been linked to tinnitus in several higher auditory stations but not in fusiform cells of the dorsal cochlear nucleus (DCN), key brainstem neurons in tinnitus generation. Here, we demonstrate increased synchrony and bursting of fusiform cell spontaneous firing, which correlate with frequency-specific behavioral measures of tinnitus. Thus, the neural representation of tinnitus emerges early in auditory processing and likely drives its pathophysiology in higher structures.

Tinnitus: Maladaptive auditory-somatosensory plasticity.

Tinnitus, the phantom perception of sound, is physiologically characterized by an increase in spontaneous neural activity in the central auditory system. However, as tinnitus is often associated with hearing impairment, it is unclear how a decrease of afferent drive can result in central hyperactivity. In this review, we first assess methods for tinnitus induction and objective measures of the tinnitus percept in animal models. From animal studies, we discuss evidence that tinnitus originates in the cochlear nucleus (CN), and hypothesize mechanisms whereby hyperactivity may develop in the CN after peripheral auditory nerve damage. We elaborate how this process is likely mediated by plasticity of auditory-somatosensory integration in the CN: the circuitry in normal circumstances maintains a balance of auditory and somatosensory activities, and loss of auditory inputs alters the balance of auditory somatosensory integration in a stimulus timing dependent manner, which propels the circuit towards hyperactivity. Understanding the mechanisms underlying tinnitus generation is essential for its prevention and treatment. This article is part of a Special Issue entitled .

Transcutaneous induction of stimulus-timing-dependent plasticity in dorsal cochlear nucleus.

The cochlear nucleus (CN) is the first site of multisensory integration in the ascending auditory pathway. The principal output neurons of the dorsal cochlear nucleus (DCN), fusiform cells, receive somatosensory information relayed by the CN granule cells from the trigeminal and dorsal column pathways. Integration of somatosensory and auditory inputs results in long-term enhancement or suppression in a stimulus-timing-dependent manner. Here, we demonstrate that stimulus-timing-dependent plasticity (STDP) can be induced in DCN fusiform cells using paired auditory and transcutaneous electrical stimulation of the face and neck to activate trigeminal and dorsal column pathways to the CN, respectively. Long-lasting changes in fusiform cell firing rates persisted for up to 2 h after this bimodal stimulation, and followed Hebbian or anti-Hebbian rules, depending on tone duration, but not somatosensory stimulation location: 50 ms paired tones evoked predominantly Hebbian, while 10 ms paired tones evoked predominantly anti-Hebbian plasticity. The tone-duration-dependent STDP was strongly correlated with first inter-spike intervals, implicating intrinsic cellular properties as determinants of STDP. This study demonstrates that transcutaneous stimulation with precise auditory-somatosensory timing parameters can non-invasively induce fusiform cell long-term modulation, which could be harnessed in the future to moderate tinnitus-related hyperactivity in DCN.

Listening to another sense: somatosensory integration in the auditory system.

Conventionally, sensory systems are viewed as separate entities, each with its own physiological process serving a different purpose. However, many functions require integrative inputs from multiple sensory systems and sensory intersection and convergence occur throughout the central nervous system. The neural processes for hearing perception undergo significant modulation by the two other major sensory systems, vision and somatosensation. This synthesis occurs at every level of the ascending auditory pathway: the cochlear nucleus, inferior colliculus, medial geniculate body and the auditory cortex. In this review, we explore the process of multisensory integration from (1) anatomical (inputs and connections), (2) physiological (cellular responses), (3) functional and (4) pathological aspects. We focus on the convergence between auditory and somatosensory inputs in each ascending auditory station. This review highlights the intricacy of sensory processing and offers a multisensory perspective regarding the understanding of sensory disorders.

Pharmacodynamics of potassium channel openers in cultured neuronal networks.

A novel class of drugs - potassium (K(+)) channel openers or activators - has recently been shown to cause anticonvulsive and neuroprotective effects by activating hyperpolarizing K(+) currents, and therefore, may show efficacy for treating tinnitus. This study presents measurements of the modulatory effects of four K(+) channel openers on the spontaneous activity and action potential waveforms of neuronal networks. The networks were derived from mouse embryonic auditory cortices and grown on microelectrode arrays. Pentylenetetrazol was used to create hyperactivity states in the neuronal networks as a first approximation for mimicking tinnitus or tinnitus-like activity. We then compared the pharmacodynamics of the four channel activators, retigabine and flupirtine (voltage-gated K(+) channel KV7 activators), NS1619 and isopimaric acid ("big potassium" BK channel activators). The EC50 of retigabine, flupirtine, NS1619, and isopimaric acid were 8.0, 4.0, 5.8, and 7.8µM, respectively. The reduction of hyperactivity compared to the reference activity was significant. The present results highlight the notion of re-purposing the K(+) channel activators for reducing hyperactivity of spontaneously active auditory networks, serving as a platform for these drugs to show efficacy toward target identification, prevention, as well as treatment of tinnitus.

Antioxidants L-carnitine and D-methionine modulate neuronal activity through GABAergic inhibition.

Antioxidants are well known for their neuroprotective properties against reactive oxygen species in cortical neurons and auditory cells. We recently identified L-carnitine and D-methionine to be among agents that provide such protection. Here, we investigated their neuronal modulatory actions. We used cultured neuronal networks grown on microelectrode arrays to assess the effects of L-carnitine and D-methionine on network function. Spike production and burst properties of neuronal networks were used as parameters to monitor pharmacological responses. L-Carnitine and D-methionine reduced spike activity with 100% efficacy with EC50 values of 0.22 (± 0.01) mM and 1.06 (± 0.05) mM, respectively. In the presence of 1.0-40 µM of the GABAA antagonist bicuculline, the sigmoidal concentration-response curves of both compounds exhibited stepwise shifts, without a change in efficacy. Under a maximal bicuculline concentration of 40 µM, the EC50 increased to 3.57 (± 0.26) mM for L-carnitine and to 10.52 (± 0.97) mM for D-methionine, more than a tenfold increase. The agonist-antagonist interactions with bicuculline were estimated by Lineweaver-Burk plot analyses to be competitive, corroborated by the computed dissociation constants of bicuculline. For both compounds, the effects on the network burst pattern, activity reversibility, and bicuculline antagonism resembled that elicited by the GABAA agonist muscimol. We showed that the antioxidants L-carnitine and D-methionine modulate cortical electrical spike activity primarily through GABAA receptor activation. Our findings suggest the involvement of GABAergic mechanisms that perhaps contribute to the protective actions of these compounds.