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1.  A Novel Behavioral Assay for the Assessment of Acute Tinnitus in Rats Optimized for Simultaneous Recording of Oscillatory Neural Activity 
Journal of neuroscience methods  2013;219(2):224-232.
Background
Human magneto/electrophysiology studies suggest that the phantom sound of tinnitus arises from spontaneous oscillatory neural activity in auditory cortex; however, in animal models, behavioral techniques suitable for testing this hypothesis in combination with electrophysiology recordings have yet to be evaluated. While electrophysiological studies of tinnitus have been reported in passive, awake animals, these studies fail to control for attentional mechanisms likely to play a role in the perception of tinnitus.
New Method
A novel appetitive operant conditioning, two-alternative identification task was developed for detecting acute tinnitus in rats. The procedure optimizes conditions for simultaneously recording oscillatory neural activity while controlling for the attentional state of the animal.
Results
Tinnitus was detected in six of seven rats following systemic injection with sodium salicylate (200 mg/kg IP), a known inducer of tinnitus. Analysis of ongoing local field potentials recorded from chronically implanted electrodes in auditory cortex of a rat reporting tinnitus revealed changes in the spectrum of ongoing neural activity.
Comparison with Existing Method(s)
Existing tinnitus-detection methods were not explicitly designed for the simultaneous recording of neural activity. The behavioral method reported here is the first to provide the conditions necessary for obtaining these recordings in chronically implanted rats.
Conclusions
The behavioral assay presented here will facilitate research into the neural mechanisms of tinnitus by allowing researchers to compare the electrophysiological data in animals with confirmed tinnitus.
doi:10.1016/j.jneumeth.2013.07.021
PMCID: PMC3796950  PMID: 23933328
tinnitus; animal model; electrophysiology; auditory cortex; oscillatory activity; sodium salicylate
2.  Cisplatin ototoxicity in rat cochlear organotypic cultures 
Hearing research  2011;282(1-2):196-203.
Ototoxicity is a dose-limiting side effect of chemotherapeutic treatment with cisplatin. In a series of experiments on neonatal rat cochlear organotypic cultures, the extent of damage induced by a broad range of cisplatin treatment concentrations was examined. Paradoxically, it was found that hair cell loss was greater following 48 h exposure to low (10, 50 and 100 μM) versus high (400 and 1000 μM) concentrations of cisplatin; these findings indicate that hair cells possess intrinsic resistance to high levels of extracellular cisplatin. Using cisplatin conjugated to Alexa Fluor 488, it was found that cisplatin is readily taken up by hair cells at low concentrations, but is largely excluded at high concentrations. Recent studies indicate that the major influx of cisplatin into hair cells occurs via the copper transporter, Ctr1, whereas ATP7A and ATP7B are copper pumps responsible for cisplatin sequestration and efflux. Using immunolabeling procedures for these copper trafficking proteins, it was found that Ctr1 and ATP7B were localized in the hair cells, whereas ATP7A showed extensive labeling in the pillar cells in the organ of Corti. Additional experiments confirmed the protective effect of copper sulfate and cimetidine in attenuating cisplatin-induced hair cell loss. However, because neither copper sulfate nor cimetidine provided complete protection against cisplatin, and high levels of copper sulfate itself were found to be ototoxic, it is suggested that future therapeutic efforts may benefit from a combination of pharmacological treatments which seek to not only limit the uptake of cisplatin into cochlear cells but also increase its efflux.
doi:10.1016/j.heares.2011.08.002
PMCID: PMC3230738  PMID: 21854840
cochlear organotypic cultures; cisplatin; outer hair cell; copper trafficking proteins; copper sulfate; cimetidine
3.  Multisensory and unisensory neurons in ferret parietal cortex exhibit distinct functional properties 
Despite the fact that unisensory and multisensory neurons are comingled in every neural structure in which they have been identified, no systematic comparison of their response features has been conducted. Towards that goal, the present study was designed to examine and compare measures of response magnitude, latency, duration and spontaneous activity in unisensory and bimodal neurons from the ferret parietal cortex. Using multichannel single-unit recording, bimodal neurons were observed to demonstrate significantly higher response levels and spontaneous discharge rates than did their unisensory counterparts. These results suggest that, rather than merely reflect different connectional arrangements, unisensory and multisensory neurons are likely to differ at the cellular level. Thus, it can no longer be assumed that the different populations of bimodal and unisensory neurons within a neural region respond similarly to a given external stimulus.
doi:10.1111/ejn.12085
PMCID: PMC3604143  PMID: 23279600
Multisensory Integration; Parietal Cortex; Somatosensation; Vision; Neurophysiology
4.  The Gap-Startle Paradigm for Tinnitus Screening in Animal Models: Limitations and Optimization 
Hearing research  2012;295(1-2):150-160.
In 2006, Turner and colleagues (Behav Neurosci, 120:188–195) introduced the gap-startle paradigm as a high-throughput method for tinnitus screening in rats. Under this paradigm, gap detection ability was assessed by determining the level of inhibition of the acoustic startle reflex produced by a short silent gap inserted in an otherwise continuous background sound prior to a loud startling stimulus. Animals with tinnitus were expected to show impaired gap detection ability (i.e., lack of inhibition of the acoustic startle reflex) if the background sound containing the gap was qualitatively similar to the tinnitus pitch. Thus, for the gap-startle paradigm to be a valid tool to screen for tinnitus, a robust startle response from which to inhibit must be present. Because recent studies have demonstrated that the acoustic startle reflex could be dramatically reduced following noise exposure, we endeavored to 1) modify the gap-startle paradigm to be more resilient in the presence of hearing loss, and 2) evaluate whether a reduction in startle reactivity could confound the interpretation of gap prepulse inhibition and lead to errors in screening for tinnitus. In the first experiment, the traditional broadband noise (BBN) startle stimulus was replaced by a bandpass noise in which the sound energy was concentrated in the lower frequencies (5–10 kHz) in order to maintain audibility of the startle stimulus after unilateral high frequency noise exposure (16 kHz). However, rats still showed a 57% reduction in startle amplitude to the bandpass noise post-noise exposure. A follow-up experiment on a separate group of rats with transiently-induced conductive hearing loss revealed that startle reactivity was better preserved when the BBN startle stimulus was replaced by a rapid airpuff to the back of the rats neck. Furthermore, it was found that transient unilateral conductive hearing loss, which was not likely to induce tinnitus, caused an impairment in gap prepulse inhibition as assessed with the traditional BBN gap-startle paradigm, resulting in a false-positive screening for tinnitus. Thus, the present study identifies significant caveats of the traditional gap-startle paradigm, and describes experimental parameters using an airpuff startle stimulus which may help to limit the negative consequences of reduced startle reactivity following noise exposure, thereby allowing researchers to better screen for tinnitus in animals with hearing loss.
doi:10.1016/j.heares.2012.06.001
PMCID: PMC3505812  PMID: 22728305
acoustic startle reflex; gap detection; gap prepulse inhibition; hearing loss; tinnitus
5.  Subthreshold auditory inputs to extrastriate visual neurons are responsive to parametric changes in stimulus quality: Sensory-specific versus non-specific coding 
Brain research  2008;1242:95-101.
A new subthreshold form of multisensory processing has been recently identified that results from the convergence of suprathreshold excitatory inputs from one modality with subthreshold inputs from another. Because of the subthreshold nature of the second modality, descriptive measures of sensory features such as receptive field properties or location are not directly apparent as they are for traditional bimodal neurons. This raises the question of whether or not subthreshold signals actually convey sensory-specific receptive field information as seen in their bimodal counterparts, or if they represent non-specific effects such as arousal. The present experiment addressed this issue in visually-responsive neurons from the cat posterolateral lateral suprasylvian cortex (PLLS). Single-unit electrophysiological techniques were used to record neuronal responses to visual, auditory and combined visual-auditory stimuli while the intensity of stimulation in the subthreshold auditory modality was systematically altered. The results showed that subthreshold multisensory neurons were sensitive to changes in auditory stimulus intensity. These receptive field sensitivities are similar to those observed in bimodal neurons and thereby represent sensory-specific, not arousal-related responses. In addition, these results provide further support for the notion that multisensory processing occurs along a dynamic continuum of neuronal convergence patterns from bimodal to purely sensory-specific.
doi:10.1016/j.brainres.2008.03.086
PMCID: PMC2645081  PMID: 18479671
Crossmodal; Multisensory; Modulation; Bimodal; Arousal; Non-specific sensory activation
6.  Do Cross-Modal Projections Always Result in Multisensory Integration? 
Cerebral Cortex (New York, NY)  2008;18(9):2066-2076.
Convergence of afferents from different sensory modalities has generally been thought to produce bimodal (and trimodal) neurons (i.e., exhibit suprathreshold excitation to more than 1 sensory modality). Consequently, studies identifying cross-modal connections assume that such convergence results in bimodal (or trimodal) neurons that produce familiar forms of multisensory integration: response enhancement or depression. The present study questioned that assumption by anatomically identifying a projection from ferret auditory to visual cortex Area 21. However, electrophysiological recording within Area 21 not only failed to identify a single bimodal neuron but also familiar forms of multisensory integration were not observed either. Instead, a small proportion of neurons (9%; 27/296) showed subthreshold multisensory integration, in which visual responses were significantly modulated by auditory inputs. Such subthreshold multisensory effects were enhanced by γ-aminobutyric acid antagonism, whereby a majority of neurons (87%; 20/23) now participated in a significant, multisensory population effect. Thus, multisensory convergence does not de facto result in bimodal (or trimodal) neurons or the traditional forms of multisensory integration. However, the fact that unimodal neurons exhibited a subthreshold form of multisensory integration not only affirms the relationship between convergence and integration but also expands our understanding of the functional repertoire of multisensory processing itself.
doi:10.1093/cercor/bhm230
PMCID: PMC2517110  PMID: 18203695
auditory cortex; bicuculline methiodide; bimodal neuron; extra striate visual cortex; ferret; subthreshold facilitation
7.  Multisensory dysfunction accompanies crossmodal plasticity following adult hearing impairment 
Neuroscience  2012;214:136-148.
Until now, cortical crossmodal plasticity has largely been regarded as the effect of early and complete sensory loss. Recently, massive crossmodal cortical reorganization was demonstrated to result from profound hearing loss in adult ferrets (Allman et al., 2009a). Moderate adult hearing loss, on the other hand, induced not just crossmodal reorganization, but also merged new crossmodal inputs with residual auditory function to generate multisensory neurons. Because multisensory convergence can lead to dramatic levels of response integration when stimuli from more than one modality are present (and thereby potentially interfere with residual auditory processing), the present investigation sought to evaluate the multisensory properties of auditory cortical neurons in partially deafened adult ferrets. When compared with hearing controls, partially-deaf animals revealed elevated spontaneous levels and a dramatic increase (~2 times) in the proportion of multisensory cortical neurons, but few of which showed multisensory integration. Moreover, a large proportion (68%) of neurons with somatosensory and/or visual inputs was vigorously active in core auditory cortex in the absence of auditory stimulation. Collectively, these results not only demonstrate multisensory dysfunction in core auditory cortical neurons from hearing impaired adults but also reveal a potential cortical substrate for maladaptive perceptual effects such as tinnitus.
doi:10.1016/j.neuroscience.2012.04.001
PMCID: PMC3403530  PMID: 22516008
aging; crossmodal plasticity; hearing loss; deafness; tinnitus; cortex
8.  Early Hearing-Impairment Results in Crossmodal Reorganization of Ferret Core Auditory Cortex 
Neural Plasticity  2012;2012:601591.
Numerous investigations of cortical crossmodal plasticity, most often in congenital or early-deaf subjects, have indicated that secondary auditory cortical areas reorganize to exhibit visual responsiveness while the core auditory regions are largely spared. However, a recent study of adult-deafened ferrets demonstrated that core auditory cortex was reorganized by the somatosensory modality. Because adult animals have matured beyond their critical period of sensory development and plasticity, it was not known if adult-deafening and early-deafening would generate the same crossmodal results. The present study used young, ototoxically-lesioned ferrets (n = 3) that, after maturation (avg. = 173 days old), showed significant hearing deficits (avg. threshold = 72 dB SPL). Recordings from single-units (n = 132) in core auditory cortex showed that 72% were activated by somatosensory stimulation (compared to 1% in hearing controls). In addition, tracer injection into early hearing-impaired core auditory cortex labeled essentially the same auditory cortical and thalamic projection sources as seen for injections in the hearing controls, indicating that the functional reorganization was not the result of new or latent projections to the cortex. These data, along with similar observations from adult-deafened and adult hearing-impaired animals, support the recently proposed brainstem theory for crossmodal plasticity induced by hearing loss.
doi:10.1155/2012/601591
PMCID: PMC3409567  PMID: 22888454
9.  Salicylate-induced peripheral auditory changes and tonotopic reorganization of auditory cortex 
Neuroscience  2011;180:157-164.
The neuronal mechanism underlying the phantom auditory perception of tinnitus remains at present elusive. For over 25 years, temporary tinnitus following acute salicylate intoxication in rats has been used as a model to understand how a phantom sound can be generated. Behavioral studies have indicated the pitch of salicylate-induced tinnitus in the rat is approximately 16 kHz. In order to better understand the origin of the tinnitus pitch, in the present study, measurements were made at the levels of auditory input and output; both cochlear and cortical physiological recordings were performed in ketamine/xylazine anesthetized rats. Both compound action potentials and distortion product otoacoustic emission measurements revealed a salicylate-induced band-pass-like cochlear deficit in which the reduction of cochlear input was least at 16 kHz and significantly greater at high and low frequencies. In a separate group of rats, frequency receptive fields of primary auditory cortex neurons were tracked using multichannel microelectrodes before and after systemic salicylate treatment. Tracking frequency receptive fields following salicylate revealed a population of neurons that shifted their frequency of maximum sensitivity (i.e., characteristic frequency) towards the tinnitus frequency region of the tonotopic axis (~16 kHz). The data presented here supports the hypothesis that salicylateinduced tinnitus results from an expanded cortical representation of the tinnitus pitch determined by an altered profile of input from the cochlea. Moreover, the pliability of cortical frequency receptive fields during salicylate-induced tinnitus is likely due to salicylate’s direct action on intracortical inhibitory networks. Such a disproportionate representation of middle frequencies in the auditory cortex following salicylate may result in a finer analysis of signals within this region which may pathologically enhance the functional importance of spurious neuronal activity concentrated at tinnitus frequencies.
doi:10.1016/j.neuroscience.2011.02.005
PMCID: PMC3070811  PMID: 21310217
tinnitus; salicylate; auditory cortex; cochlea; rat
10.  Environmental Noise Affects Auditory Temporal Processing Development and NMDA-2B Receptor Expression in Auditory Cortex 
Behavioural brain research  2010;218(1):15-20.
Auditory temporal processing is essential for sound discrimination and speech comprehension. Under normal developmental conditions, temporal processing acuity improves with age. As recent animal studies have shown that the functional development of the auditory cortex (AC) is impaired by early life exposure to environmental noise (i.e., continuous, moderate-level, white noise), here we investigated whether the normal age-related improvement in temporal processing acuity is sensitive to delayed development of the AC. We used a behavioral paradigm, the gap-induced prepulse inhibition of the acoustic startle reflex, to assess the gap detection threshold, and provide a comparison of temporal processing acuity between environmental noise-reared rats and age-matched controls. Moreover, because age-related changes normally occur in the relative expression of different N-methyl-D-aspartate (NMDA) receptor subunits, we assessed the level of protein expression of NMDA-2A and 2B receptors (NR2A and NR2B respectively) in the AC after environmental noise-rearing. As hypothesized, rats reared in environmental noise showed 1) poor temporal processing acuity as adults (i.e., gap detection threshold remained elevated at a juvenile-like level), and 2) an increased level of NR2B protein expression compared to age-matched controls. This poor temporal processing acuity represented delayed development rather than permanent impairment, as moving these environmental noise-reared rats to normal acoustic conditions improved their gap detection threshold to an age-appropriate level. Furthermore, housing normally-reared, adult rats in environmental noise for two months did not affect their already-mature gap detection threshold. Thus, masking normal sound inputs with environmental noise during early life, but not adulthood, impairs temporal processing acuity as assessed with the gap detection threshold.
doi:10.1016/j.bbr.2010.11.028
PMCID: PMC3022098  PMID: 21094188
environmental noise; acoustic startle reflex; gap detection; auditory cortex; development; NMDA
11.  Salicylate toxicity model of tinnitus 
Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs, or aging, which affects ∼14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed.
doi:10.3389/fnsys.2012.00028
PMCID: PMC3341117  PMID: 22557950
salicylate; aspirin; tinnitus; hearing loss; auditory dysfunction; animal models
12.  Auditory Influences on Non-Auditory Cortices 
Hearing research  2009;258(1-2):64-71.
Although responses to auditory stimuli have been extensively examined in the well-known regions of auditory cortex, there are numerous reports of acoustic sensitivity in cortical areas that are dominated by other sensory modalities. Whether in ‘polysensory’ cortex or in visual or somatosensory regions, auditory responses in non-auditory cortex have been described largely in terms of auditory processing. This review takes a different perspective that auditory responses in non-auditory cortex, either through multisensory subthreshold or bimodal processing, provide subtle but consistent expansion of the range of activity of the dominant modality within a given area. Thus, the features of these acoustic responses may have more to do with the subtle adjustment of response gain within a given non-auditory region than the encoding of their tonal properties.
doi:10.1016/j.heares.2009.03.005
PMCID: PMC2787633  PMID: 19303926
Vision; Somatosensation; Multisensory; Subthreshold; Modulation
13.  Not Just for Bimodal Neurons Anymore: The Contribution of Unimodal Neurons to Cortical Multisensory Processing 
Brain topography  2009;21(3-4):157-167.
Traditionally, neuronal studies of multisensory processing proceeded by first identifying neurons that were overtly multisensory (e.g., bimodal, trimodal) and then testing them. In contrast, the present study examined, without precondition, neurons in an extrastriate visual area of the cat for their responses to separate (visual, auditory) and combined-modality (visual and auditory) stimulation. As expected, traditional bimodal forms of multisensory neurons were identified. In addition, however, many neurons that were activated only by visual stimulation (i.e., unimodal) had that response modulated by the presence of an auditory stimulus. Some unimodal neurons showed multisensory responses that were statistically different from their visual response. Other unimodal neurons had subtle multisensory effects that were detectable only at the population level. Most surprisingly, these non-bimodal neurons generated more than twice the multisensory signal in the PLLS than did the bimodal neurons. These results expand the range of multisensory convergence patterns beyond that of the bimodal neuron. However, rather than characterize a separate class of multisensory neurons, unimodal multisensory neurons may actually represent an intermediary form of multisensory convergence that exists along the functional continuum between unisensory neurons, at one end, and fully bimodal neurons at the other.
doi:10.1007/s10548-009-0088-3
PMCID: PMC2854489  PMID: 19326204
Multisensory convergence; Integration; Vision; Audition; Circuit
14.  Subthreshold multisensory processing in cat auditory cortex 
Neuroreport  2009;20(2):126-131.
For multisensory processing to occur, inputs from different sensory modalities must converge onto individual neurons. Traditionally, multisensory neurons have been identified as those, which were independently activated by more than one sensory modality. Recently, a different multisensory search paradigm has revealed neurons in somatosensory and visual cortex that were activated by only a single modality, whose responses were significantly affected by the presence of a second modality cue. These experiments recorded neurons in the cat auditory field of the anterior ectosylvian sulcus that also met this criterion, suggesting that subthreshold forms of multisensory processing may represent a general feature of multisensory systems.
doi:10.1097/WNR.0b013e32831d7bb6
PMCID: PMC2839368  PMID: 19057421
convergence; cortex; electrophysiology; visual
15.  Auditory projections to extrastriate visual cortex: connectional basis for multisensory processing in ‘unimodal’ visual neurons 
Neurophysiological studies have recently documented multisensory properties in ‘unimodal’ visual neurons of the cat posterolateral lateral suprasylvian (PLLS) cortex, a retinotopically organized area involved in visual motion processing. In this extrastriate visual area, a region has been identified where both visual and auditory stimuli were independently effective in activating neurons (bimodal zone), as well as a second region where visually-evoked activity was significantly facilitated by concurrent auditory stimulation but was unaffected by auditory stimulation alone (subthreshold multisensory region). Given their different distributions, the possible corticocortical connectivity underlying these distinct forms of crossmodal convergence was examined using biotinylated dextran amine (BDA) tracer methods in 21 adult cats. The auditory cortical areas examined included the anterior auditory field (AAF), primary auditory cortex (AI), dorsal zone (DZ), secondary auditory cortex (AII), field of the rostral suprasylvian sulcus (FRS), field anterior ectosylvian sulcus (FAES) and the posterior auditory field (PAF). Of these regions, the DZ, AI, AII, and FAES were found to project to the both the bimodal zone and the subthreshold region of the PLLS. This convergence of crossmodal inputs to the PLLS suggests not only that complex auditory information has access to this region but also that these connections provide the substrate for the different forms (bimodal versus subthreshold) of multisensory processing which may facilitate its functional role in visual motion processing.
doi:10.1007/s00221-008-1493-7
PMCID: PMC2827203  PMID: 18648784
Auditory; Somatosensory; Visual; Association cortex; Multisensory

Results 1-15 (15)