Biomedical subjects

Richard J Salvi

Publications and source records attributed to Richard J Salvi.

At least 19 recordsLinked to original sources

PubMed2005

Mapping the 40-Hz auditory steady-state response using current density reconstructions.

We mapped the 40-Hz aSSR from nine normal subjects using PET-independent low-resolution electroencephalographic tomography (LORETA) as well as PET-weighted LORETA and minimum norm (MinNorm) current density reconstructions. In grand mean data, PET-independent LORETA identified seven sites with peaks in current density in right temporal lobe, right brainstem/cerebellum, right parietal lobe, left cerebellum/temporal lobe, and right frontal lobe. PET-weighted LORETA found six of the same sites as the PET-independent LORETA: the right brainstem source was eliminated and two right-frontal sources were added. Both LORETA analyses revealed considerable phase dispersion across identified sources. In both LORETA analyses, the relative time course of activation measured from an arbitrary starting phase progressed from right temporal lobe to right mid-frontal lobe to right parietal-frontal to right inferior parietal and finally to left cerebellum and left temporal lobe. MinNorm analysis incorporating PET information identified sources in the same locations as specified in the PET data. These sources were synchronized, with their amplitudes peaking almost simultaneously. Both PET-independent and PET-weighted LORETA results suggest that the aSSR is: (1) the result of a reverberating network with two or more groups of sources that recurrently excite each other or (2) the result of sequential auditory processing through various levels of a hierarchical network. In contrast, the PET-weighted MinNorm results suggest that the 40-Hz response represents simultaneous activation over widely spaced areas of the brain, perhaps due to synchronization of gamma-band activity to a common neural clock.

Acoustic Stimulation↗

PubMed2005

Amino acid concentrations in chinchilla cochlear nucleus at different times after carboplatin treatment.

Amino acid concentrations were measured in the cochlear nucleus for a group of 20 chinchillas: four each of control and 4, 8, 29, and 85 days after treatment with the ototoxic anti-tumor drug carboplatin (100 mg/kg, i.p.). The treated chinchillas showed various extents of inner hair cell loss, generally more complete at longer survival times, but little loss of outer hair cells. Aspartate concentration in rostral anteroventral cochlear nucleus (AVCN) showed a decline to 28% less than the control value at 29 and 85 days after treatment, whereas glutamate concentration showed little change through 29 days, then dropped by 22% at 85 days after treatment. In caudal posteroventral cochlear nucleus (PVCN), the aspartate concentration decreased by 32% at 29 days, in animals with significant inner hair cell loss, and 48% at 85 days after treatment, while the glutamate concentration showed no decrease through 29 days and 40% decrease at 85 days. The concentration of gamma-aminobutyrate (GABA) was about 18% lower than control in caudal PVCN at all survival times. Significant correlations were found between the proportion of inner hair cells remaining and glutamate and aspartate concentrations in PVCN and AVCN, but not GABA or other amino acids.

Amino Acids↗

PubMed2005

Voltage-sensitive and ligand-gated channels in differentiating neural stem-like cells derived from the nonhematopoietic fraction of human umbilical cord blood.

Fetal cells with the characteristics of neural stem cells (NSCs) can be derived from the nonhematopoietic fraction of human umbilical cord blood (HUCB), expanded as a nonimmortalized cell line (HUCB-NSC), and further differentiated into neuron-like cells (HUCB-NSCD); however, the functional and neuronal properties of these cells are poorly understood. To address this issue, we used whole-cell patch-clamp recordings, gene microarrays, and immunocytochemistry to identify voltage-gated channels and ligand-gated receptors on HUCB-NSCs and HUCB-NSCDs. Gene microarray analysis identified genes for voltage-dependent potassium and sodium channels and the neurotransmitter receptors acetylcholine (ACh), gamma-aminobutyric acid (GABA), glutamate, glycine, 5-hydroxytryptamine (5-HT), and dopamine (DA). Several of these genes (GABA-A, glycine and glutamate receptors, voltage-gated potassium channels, and voltage-gated sodium type XII alpha channels) were not expressed in the HUCB mono-nuclear fraction (HUCB-MC), which served as a starting cell population for HUCB-NSC. HUCB-NSCD acquired neuronal phenotypes and displayed an inward rectifying potassium current (Kir) and an outward rectifying potassium current (I(K+)). Kir was present on most HUCB-NSCs and HUCB-NSCDs, whereas I(K+) was present only on HUCB-NSCDs. Many HUCB-NSCDs were immunopositive for glutamate, glycine, nicotinic ACh, DA, 5-HT, and GABA receptors. Kainic acid (KA), a non-N-methyl-D-asparate (NMDA) glutamate-receptor agonist, induced an inward current in some HUCB-NSCDs. KA, glycine, DA, ACh, GABA, and 5-HT partially blocked Kir through their respective receptors. These results suggest that HUCB-NSCs differentiate toward neuron-like cells, with functional voltage- and ligand-gated channels identified in other neuronal systems.

Antigens, CD34↗

PubMed2004

Changes in NMDA receptor expression in auditory cortex after learning.

Extensive practice on auditory learning tasks dramatically alters the functional organization and response properties of neurons in the auditory cortex. The cellular mechanisms responsible for this auditory learning-induced cortical plasticity are unclear; however, changes in synaptic function involving NMDA receptors have been strongly implicated. To test this hypothesis, we measured the change in gene expression of NMDA receptors and associated proteins in the auditory cortex of adult rats trained to perform an auditory identification task. NMDA receptor 2A and 2B gene expression in auditory cortex decreased significantly as auditory discrimination improved whereas expression of Arc, an immediate early gene involved in memory stabilization, increased. These results suggest that changes in NMDA receptors 2A and 2B and Arc enhance synaptic plasticity, thereby facilitating experience-dependent cortical remodeling and auditory learning.

Adaptation, Physiological↗

PubMed2004

Substance P inhibits potassium and calcium currents in inner ear spiral ganglion neurons.

Substance P (SP), a member of the tachykinin family of neurotransmitters and neuromodulators, has been identified on spiral ganglion neurons (SGNs) in the inner ear; however, its high affinity receptor, neurokinin-1 (NK1), has not been identified and the physiological effects of SP on SGNs are not well understood. To address these issues, immunolabeling, RT-PCR, Western blots and whole-cell patch-clamp recordings were made from SGNs in P0-P5 mouse cochlear organotypic cultures. The NK1 receptor was detected on SGNs by immunocytochemistry, the protein was detected in cochlear tissues by Western blots, and the mRNA for the NK1 receptor was also found in cochlear tissues of postnatal mice (P2) by RT-PCR. Application of SP (1 to 25 microM) significantly increased the latency of SGN action potentials (APs) (mean increase 7.8 +/- 4 ms; 25 microM of SP), prolonged the duration of the action potential and made the resting potential (RP) more positive (mean 9.0 +/- 7 mV) relative to normal values (-54 +/- 6 mV). SP (1 to 25 microM) also suppressed voltage-activated potassium currents (IK+) and calcium currents (ICa2+). Puffing 25 microM of SP onto SGNs suppressed IK+ by 43 +/- 9% (n = 7) and ICa2+ by 40.6 +/- 5.6% (n = 7); both currents recovered when SP was washed out. A SP antagonist blocked the SP-induced suppression of IK+ and ICa2+. These results indicate that SP acting through NK1 receptors can have direct neuromodulatory effects on SGNs.

Action Potentials↗

PubMed2004

Time course of efferent fiber and spiral ganglion cell degeneration following complete hair cell loss in the chinchilla.

Ethacrynic acid (EA) is known to interact with aminoglycoside antibiotics such as gentamicin (GM). In the chinchilla, co-administration of GM and EA can produce hair cell lesions ranging from a small loss of outer hair cells (OHCs) in the base of the cochlea to complete destruction of all hair cells, depending on dosing parameters. Although hair cell loss has been characterized, little is known about the fate of efferent fibers or spiral ganglion neurons (SGNs) in this model. To study the time course of efferent fiber and SGN loss, chinchillas were injected with GM (125 mg/kg IM) followed immediately by EA (40 mg/kg IV). Estimates of efferent fiber loss and density changes were made after 3 days or 1, 2, 3, or 4 weeks of survival. Estimates of SGN loss and density changes were made after 15 days or 1, 2, 4, or 6 months of survival. Cochlear function was rapidly abolished and all cochlear hair cells were missing within 24 h after treatment. Inner hair cells (IHCs) in the middle turn of the cochlea died earlier than cells in the apex or base, and OHCs in Rows 1 and 2 died earlier than OHCs in Row 3. Degeneration of efferent nerve fibers began 3-7 days post-injection, versus 15-30 days for SGNs, and the loss of efferent fibers was essentially complete within 1 month, versus 2-4 months for SGNs. The rapid time course of efferent fiber and SGN loss in the chinchilla may make it a practical model for studying mechanisms of neural loss and survival in the mammalian inner ear.

Acetylcholinesterase↗

PubMed2004

PET imaging of the 40 Hz auditory steady state response.

The auditory steady state response (aSSR) is an oscillatory electrical potential recorded from the scalp induced by amplitude-modulated (AM) or click/tone burst stimuli. Its clinical utility has been limited by uncertainty regarding the specific areas of the brain involved in its generation. To identify the generators of the aSSR, 15O-water PET imaging was used to locate the regions of the brain activated by a steady 1 kHz pure tone, the same tone amplitude modulated (AM) at 40 Hz and the specific regions of the brain responsive to the AM component of the stimulus relative to the continuous tone. The continuous tone produced four clusters of activation. The boundaries of these activated clusters extended to include regions in left primary auditory cortex, right non-primary auditory cortex, left thalamus, and left cingulate. The AM tone produced three clusters of activation. The boundaries of these activated clusters extended to include primary auditory cortex bilaterally, left medial geniculate and right middle frontal gyrus. Two regions were specifically responsive to the AM component of the stimulus. These activated clusters extended to include the right anterior cingulate near frontal cortex and right auditory cortex. We conclude that cortical sites, including areas outside primary auditory cortex, are involved in generating the aSSR. There was an unexpected difference between morning and afternoon session scans that may reflect a pre- versus post-prandial state. These results support the hypothesis that a distributed resonating circuit mediates the generation of the aSSR.

Adult↗

PubMed2004

Neuronal gene expression and function in the growth-stimulated R28 retinal precursor cell line.

PURPOSE: Proliferative retinal progenitor cells that express neuronal characteristics are potentially useful for developmental studies and as experimental graft material. The continuously-growing R28 retinal cell line has been distributed to over 60 laboratories for a variety of studies, yet has not been fully characterized. In this study, we tested the hypothesis that the proliferative R28 retinal cell line contains subpopulations of cells that express neuronal mRNAs and proteins characteristic of CNS neurons. METHODS: To this end, we sought to determine the potential retinal, neuronal, and growth-related characteristics of this retinal cell line through gene expression profiling, coupled with confirmatory immunocytochemistry and electrophysiology. RESULTS: Despite expression of growth-stimulatory oncogenes and growth-promoting factors, subpopulations of R28 cells express abundant retinal and neuronal markers, as well as the functional capacity to respond to specific neurotransmitters such as dopamine, acetylcholine, serotonin, and glycine. CONCLUSION: Proliferative R28 cells retain functional neuronal properties that may prove useful in future studies of neuronal differentiation and development.

Animals↗

PubMed2003

M40403, a superoxide dismutase mimetic, protects cochlear hair cells from gentamicin, but not cisplatin toxicity.

Gentamicin, an aminoglycoside antibiotic, and cisplatin, a platinum-based anticancer drug, are two commonly used clinical drugs with ototoxic side effects. The ototoxicity of gentamicin and cisplatin has been linked to the production of reactive oxygen species (ROS), although the specific ROS pathways have not been identified. One ROS that might play a role in ototoxicity is the superoxide radical, which is enzymatically dismutated to molecular oxygen and hydrogen peroxide by endogenous superoxide dismutase (SOD) enzymes. M40403, a manganese-based nonpeptidyl molecule that mimics the activity of SOD, was tested for its ability to protect against gentamicin and cisplatin toxicity in cochlear organotypic cultures from neonatal C57BL/10J mice. Cultures were treated with gentamicin or cisplatin alone or in combination with M40403. M40403 alone had no effect on outer hair cell (OHC) or inner hair cell (IHC) survival at doses of 1, 5, and 10 microM, but a high dose of 30 microM reduced hair cell numbers by approximately 30%. Gentamicin alone and cisplatin alone killed OHCs and IHCs in a dose-dependent manner. The addition of M40403 to gentamicin-treated cultures significantly increased OHC and IHC survival in a dose-dependent manner, whereas M40403 failed to protect hair cells in cisplatin-treated cultures at any dose. The results suggest that the toxicity of gentamicin and cisplatin to cochlear hair cells are mediated by different pathways. Clinically, increased levels of SOD or SOD mimetics might provide significant protection against aminoglycoside ototoxicity.

Animals↗

PubMed2003

Carboplatin-induced early cochlear lesion in chinchillas.

Carboplatin preferentially damages inner hair cells (IHC) and type I spiral ganglion neurons (SGNs) in the chinchilla; however, the temporal sequence of events leading to the destruction of these structures is poorly understood. To better understand the mechanisms leading up to the destruction of IHCs and type I SGNs, we measured the activity in single auditory nerve fibers for the first 8 h following carboplatin treatment and also monitored the development of histopathologies in SGNs and IHCs using a dose of carboplatin that killed approximately 50% of the IHCs. The spontaneous discharge rate (SDR) showed a slight increase around 3 h post carboplatin followed by a significant decline at 4-5 h. The saturation driven discharge rate (DDR) showed a significant increase 1-5 h post carboplatin. These physiological changes were associated with the formation of small vacuoles in type I afferent terminals and proximal nerve fibers 1-6 h post carboplatin; signs of IHC damage were first observed around 24-48 h. Thus, the neurotoxic effects of carboplatin occur approximately a day before the IHCs are damaged. The large fluctuations in SDR and DDR that occur several hours after carboplatin treatment are most likely due to the neurotoxic effects of carboplatin.

Animals↗

PubMed2003

Late dosing with ethacrynic acid can reduce gentamicin concentration in perilymph and protect cochlear hair cells.

A key factor in the well-known interaction between ethacrynic acid (EA) and aminoglycoside antibiotics (AABs) is disruption of the blood-labyrinth barrier (BLB), leading to rapid entry of EA and AABs into the cochlear fluids. The idea that the blood-labyrinthine fluid concentration gradient might be utilized in a protective manner was tested in the current experiment. We hypothesized that administering EA when gentamicin (GM) levels are higher in the cochlea than in the blood might actually reduce cochlear damage by permitting efflux of GM from the cochlear fluids into the bloodstream, down a concentration gradient and across a temporarily disrupted BLB. Guinea pigs received 1, 11, 14 or 20 injections of GM (125 mg/kg i.m.). Approximately half of the animals also received a single injection of EA (40 mg/kg i.v.) either concurrently or 12-18 h after the last GM injection. Concurrent injection of EA significantly increased GM concentration in serum and perilymph at all time points sampled (2.5, 5-8, and 12 h post injection). Compared to animals that received GM only, animals that received a delayed injection of EA had a significantly lower GM concentration in perilymph, lower thresholds of the compound action potential, and less outer hair cell loss. Collectively, the evidence suggests that EA can reduce GM ototoxicity if it is administered 12-18 h after GM, but the mechanism remains to be elucidated. The results may have implications for the clinical management of aminoglycoside ototoxicity in humans, as well as for understanding the mechanisms underlying AAB/EA interactions.

Action Potentials↗

PubMed2002

Retinal precursor cells express functional ionotropic glutamate and GABA receptors.

R28 retinal progenitor cells offer the potential to replace damaged neurons; however, their ability to differentiate into the appropriate phenotype may depend on whether they express glutamatergic and GABAergic receptors. Whole-cell recordings and immunocytochemistry were used to identify glutamatergic and GABAergic receptors on proliferating R28 cells. R28 cells lacked voltage-gated channels; however, they produced inward currents when non-NMDA, NMDA, GABAa and GABAb receptor agonists were perfused onto the cells. R28 cells were immunoreactive to GluR1, 2 and 3, NMDA and GABAa receptors consistent with electrophysiological results. These results indicate that R28 progenitor cells express glutamatergic and GABAergic receptors capable of influencing their fate and function when grafted into retina or elsewhere in the nervous system.

Animals↗

PubMed2002

Tinnitus.

Explore the source record for details and available documents.

Algorithms↗

PubMed2002

Calpain immunoreactivity and morphological damage in chinchilla inner ears after carboplatin.

Carboplatin produces an unusual pattern of damage in the chinchilla inner ear, characterized by early destruction of type I afferent fibers and preferential loss of type I hair cells in the vestibular end organs and inner hair cells (IHCs) in the cochlea. In the present study, we investigated a potential role of calpains, a family of calcium-activated proteases, in carboplatin ototoxicity. Chinchillas received carboplatin (100 mg/kg IP) and were sacrificed 12, 24, 48, or 72 h later for morphological evaluation or immunocytochemistry. Nerve fibers and myelin were the initial sites of increased calpain immunoreactivity (IR) and morphological damage. At 12 h, granular immunoreactive puncta were present within nerve fibers and their myelin sheaths in the spiral ganglion. In the habenula perforata, dense reaction product was present in large vacuoles in the myelin surrounding the nerve fibers. At 24 h, nerve fibers and myelin were destroyed in the habenula, and those in the spiral ganglion showed increased calpain IR and morphological damage. At 72 h, nerve fibers and myelin were completely destroyed. Calpain IR was not a prominent feature of IHCs, type I vestibular hair cells, or ganglion cells at any time after carboplatin. The results show a correlation between calpain IR and carboplatin-induced axon and myelin degeneration. We propose that calpain-induced axonopathy and myelinopathy are primary features of carboplatin ototoxicity in chinchilla.

Animals↗

PubMed2002

Leupeptin protects cochlear and vestibular hair cells from gentamicin ototoxicity.

Calpains, a family of calcium-activated proteases that breakdown proteins, kinases, phosphatases and transcription factors, can promote cell death. Since leupeptin, a calpain inhibitor, protected against hair cell loss from acoustic overstimulation, we hypothesized that it might protect cochlear and vestibular hair cells against gentamicin (GM) ototoxicity. To test this hypothesis, mouse organotypic cultures from the cochlea, maculae of the utricle and the crista of the semicircular canal (P1-P3) were treated with different doses of GM (0.1-3 mM) alone or in the presence of leupeptin (0.1-3 mM). The percentage of outer hair cells (OHCs) and inner hair cells (IHCs) decreased with increasing doses of GM between 0.1 and 3 mM. The addition of 1 mM of leupeptin significantly reduced GM-induced damage to IHCs and OHCs; this protective effect was dose-dependent. GM also significantly reduced hair cell density in the crista and utricle in a dose-dependent manner between 0.1 and 3 mM. The addition of 1 mM of leupeptin significantly reduced hair cell loss in the crista and utricle for GM concentrations between 0.1 and 3 mM. These results suggest that one of the early steps in GM ototoxicity may involve calcium-activated proteases that lead to the demise of cochlear and vestibular hair cells.

Animals↗

PubMed2002

Brain imaging of the effects of lidocaine on tinnitus.

Using a single-blind placebo-controlled design, we mapped lidocaine related changes in neural activity, measured by regional cerebral blood flow (rCBF) with (15)O-H(2)O positron emission tomography. Intravenous lidocaine produced both increases and decreases in the loudness of tinnitus. The change in tinnitus loudness was associated with a statistically significant change in neural activity in the right temporal lobe in auditory association cortex. Decreases in tinnitus loudness resulted in larger changes in rCBF than increases. The unilateral activation pattern associated with tinnitus, in contrast with the bilateral activation produced by a real sound, suggests that tinnitus originates in the central auditory system rather than the cochlea. In addition, generalized lidocaine effects were found in the basal ganglia, thalamus, and a region spanning the Rolandic fissure.

Acoustic Stimulation↗

PubMed2002

Functional reorganization in chinchilla inferior colliculus associated with chronic and acute cochlear damage.

This paper describes some of the unexpected functional changes that occur in the inferior colliculus (IC) following noise- and drug-induced cochlear pathology. A striking example of this is the compensation that is seen in IC responsiveness after drug-induced selective inner hair cell (IHC) loss. Despite a massive reduction in the compound action potential (CAP) caused by partial IHC loss, the evoked potential amplitude from the IC shows little or no reduction. Acoustic trauma, which impairs cochlear sensitivity and tuning, also reduces the CAP amplitude. Despite this reduced neural input, IC amplitude sometimes increases at a faster than normal rate and the response amplitude is enhanced at frequencies below the hearing loss. Single unit recordings suggest the IC enhancement phenomenon may be due to the loss of lateral inhibition. After an acute traumatizing exposure to a tone located above the characteristic frequency (CF), approximately 50% of IC neurons show a significant increase in their spike rate, a significant expansion of the low frequency tail of the tuning curve and a significant improvement in sensitivity in the tail of the tuning curve. These changes suggest that IC neurons receive inhibition from a high frequency side band and that this inhibition is diminished by acoustic trauma above CF. To determine if side band inhibition was locally mediated, specific antagonist(s) to inhibitory neurotransmitters were applied and found to produce effects similar to acoustic trauma. The results suggest that lesioned-induced central auditory plasticity could contribute to several symptoms associated with sensorineural hearing loss such as loudness recruitment, tinnitus and poor speech discrimination in noise.

Action Potentials↗

PubMed2002

Ethacrynic acid rapidly and selectively abolishes blood flow in vessels supplying the lateral wall of the cochlea.

The mechanisms underlying the ototoxicity of ethacrynic acid (EA) are not fully understood. Previous studies have focused on morphologic and enzymatic changes in the stria vascularis. The current experiment shows that one of the earliest effects of EA is ischemia, resulting from impaired blood flow in vessels supplying the lateral wall of the cochlea. Inner ear microcirculation, endocochlear potentials, compound action potentials (CAP), cochlear microphonics (CM) and summating potentials (SP) were monitored over time in chinchillas following a single injection of EA (40 mg/kg i.v.). At all times after EA injection, blood vessels supplying the spiral lamina, modiolus, and vestibular end organs appeared normal. In contrast, lateral wall (spiral ligament and stria vascularis) vessels were poorly stained with eosin 2 min after EA injection, and devoid of red blood cells at 30 min post EA. Decline, but not recovery, of CAP, CM and SP followed the microcirculation changes in the lateral wall. Reperfusion was delayed in stria vascularis arterioles relative to other lateral wall vessels. The ischemia-reperfusion caused by EA would be expected to generate large quantities of free radicals, which may trigger or contribute to the cellular, enzymatic, and functional pathologies that have been described in detail previously.

Action Potentials↗