Neural substrates of tinnitus in animal and human cortex : cortical correlates of tinnitus.

Animal models of tinnitus complement human findings and potentially deepen our insight into the neural substrates of tinnitus. The fact that animal data are largely based on recordings from the auditory system, in particular from subcortical structures, makes comparison with human electrophysiological data from predominantly cortical areas difficult. Electro/magnetoencephalography and imaging data extend beyond the auditory cortex. The most challenging link to be made is the one between the macroscopic data in humans and the microscopic (single neuron action potentials) and mesoscopic (local field potentials) results obtained in animal models. Since invasive recordings in humans are rare, a bridge needs to be built on the basis of changes in brain rhythms in animals with putative tinnitus.

Spontaneous firing rate changes in cat primary auditory cortex following long-term exposure to non-traumatic noise: tinnitus without hearing loss?

Changes of neural activity in animal models have been correlated with tinnitus in humans. For instance, increased spontaneous firing rates (SFR), increased spontaneous neural synchrony, and cortical tonotopic map reorganization may underlie this phantom auditory percept. The aim of this study is to quantify the changes in SFR activity in the cat primary auditory cortex, after long-term exposure to different types of non-traumatic acoustic environments. For that purpose, four different groups of adult cats were exposed to moderate-level (~70dB SPL), behaviorally irrelevant sounds for several weeks to months, and their SFRs were compared with those in control cats. The sounds consisted of random multi-frequency tone pip ensembles with various bandwidths (2-4kHz, 4-20kHz, and a pair of third-octave bands centered at 4 and 16kHz), as well as a "factory noise". Auditory brainstem response (ABR) thresholds, ABR wave 3 amplitudes at ~55 and 75dB SPL, and distortion product otoacoustic emission (DPOAE) amplitudes were unaffected by the exposure. However, we found that the SFR decreased within the exposure frequency range and increased outside the exposure range. This increased SFR for units with characteristic frequencies outside the exposure frequency range, which was slow to reverse after the exposure offset, suggests a mechanism for tinnitus in the absence of hearing loss.

Differential contribution of the Na(+)-K(+)-2Cl(-) cotransporter NKCC1 to chloride handling in rat embryonic dorsal root ganglion neurons and motor neurons.

Plasma membrane chloride (Cl(-)) pathways play an important role in neuronal physiology. Here, we investigated the role of NKCC1 cotransporters (a secondary active Cl(-) uptake mechanism) in Cl(-) handling in cultured rat dorsal root ganglion neurons (DRGNs) and motor neurons (MNs) derived from fetal stage embryonic day 14. Gramicidin-perforated patch-clamp recordings revealed that DRGNs accumulate intracellular Cl(-) through a bumetanide- and Na(+)-sensitive mechanism, indicative of the functional expression of NKCC1. Western blotting confirmed the expression of NKCC1 in both DRGNs and MNs, but immunocytochemistry experiments showed a restricted expression in dendrites of MNs, which contrasts with a homogeneous expression in DRGNs. Both MNs and DRGNs could be readily loaded with or depleted of Cl(-) during GABA(A) receptor activation at depolarizing or hyperpolarizing membrane potentials. After loading, the rate of recovery to the resting Cl(-) concentration (i.e., [Cl(-)](i) decrease) was similar in both cell types and was unaffected by lowering the extracellular Na(+) concentration. In contrast, the recovery on depletion (i.e., [Cl(-)](i) increase) was significantly faster in DRGNs in control conditions but not in low extracellular Na(+). The experimental observations could be reproduced by a mathematical model for intracellular Cl(-) kinetics, in which DRGNs show higher NKCC1 activity and smaller Cl(-)-handling volume than MNs. On the basis of these results, we conclude that embryonic DRGNs show a higher somatic functional expression of NKCC1 than embryonic MNs. The high NKCC1 activity in DRGNs is important for maintaining high [Cl(-)](i), whereas lower NKCC1 activity in MNs allows large [Cl(-)](i) variations during neuronal activity.

Spectrotemporal receptive fields during spindling and non-spindling epochs in cat primary auditory cortex.

It was often thought that synchronized rhythmic epochs of spindle waves disconnect thalamo-cortical system from incoming sensory signals. The present study addresses this issue by simultaneous extracellular action potential and local field potential (LFP) recordings from primary auditory cortex of ketamine-anesthetized cats during spindling activity. We compared cortical spectrotemporal receptive fields (STRF) obtained during spindling and non-spindling epochs. The basic spectro-temporal parameters of "spindling" and "non-spindling" STRFs were similar. However, the peak-firing rate at the best frequency was significantly enhanced during spindling epochs. This enhancement was mainly caused by the increased probability of a stimulus to evoke spikes (effectiveness of stimuli) during spindling as compared with non-spindling epochs. Augmented LFPs associated with effective stimuli and increased single-unit pair correlations during spindling epochs suggested higher synchrony of thalamo-cortical inputs during spindling that resulted in increased effectiveness of stimuli presented during spindling activity. The neuronal firing rate, both stimulus-driven and spontaneous, was higher during spindling as compared with non-spindling epochs. Overall, our results suggests that thalamic cells during spindling respond to incoming stimuli-related inputs and, moreover, cause more powerful stimulus-related or spontaneous activation of the cortex.

Multi-frequency auditory stimulation disrupts spindling activity in anesthetized animals.

It is often implied that during the occurrence of spindle oscillations, thalamocortical neurons do not respond to signals from the outside world. Since recording of sound-evoked activity from cat auditory cortex is common during spindling this implies that sound stimulation changes the spindle-related brain state. Local field potentials and multi-unit activity recorded from cat primary auditory cortex under ketamine anesthesia during successive silence-stimulus-silence conditions were used to investigate the effect of sound on cortical spindle oscillations. Multi-frequency stimulation suppresses spindle waves, as shown by the decrease of spectral power within the spindle frequency range during stimulation as compared with the previous silent period. We show that the percentage suppression is independent of the power of the spindle waves during silence, and that the suppression of spindle power occurs very fast after stimulus onset. The global inter-spindle rhythm was not disturbed during stimulation. Spectrotemporal and correlation analysis revealed that beta waves (15-26 Hz), and to a lesser extent delta waves, were modulated by the same inter-spindle rhythm as spindle oscillations. The suppression of spindle power during stimulation had no effect on the spatial correlation of spindle waves. Firing rates increased under stimulation and spectro-temporal receptive fields could reliably be obtained. The possible mechanism of suppression of spindle waves is discussed and it is suggested that suppression likely occurs through activity of the specific auditory pathway.

Cortical tonotopic map reorganization and its implications for treatment of tinnitus.

CONCLUSION: There appears to be a definite link between reorganization of the cortical tonotopic map and increased spontaneous firing rates. The results have implications for the reduction of noise-induced hearing loss and in the prevention of noise-induced tinnitus in humans. OBJECTIVES: To review animal and human studies related to neural correlates of tinnitus. Among those are increased spontaneous firing rate, enhanced neural synchrony, and reorganization of the cortical frequency-place (tonotopic) map. MATERIALS AND METHODS: To separate these issues one would want to have a situation where hearing loss is present but without reorganization of the cortical frequency-place map. For that purpose, noise-exposed cats were placed, immediately after the trauma and for at least 3 weeks, either in a quiet or in a high-frequency or low-frequency enriched acoustic environment. RESULTS: In exposed cats that were placed in the quiet environment there was an increase in spontaneous firing rate and synchrony of neurons in primary auditory cortex. In contrast, exposed cats placed in the high-frequency-enriched acoustic environment did not show any significant difference in spontaneous firing rate or synchrony compared to the non-traumatized controls.

Neural correlates of an auditory afterimage in primary auditory cortex.

The Zwicker tone (ZT) is defined as an auditory negative afterimage, perceived after the presentation of an appropriate inducer. Typically, a notched noise (NN) with a notch width of 1/2 octave induces a ZT with a pitch falling in the frequency range of the notch. The aim of the present study was to find potential neural correlates of the ZT in the primary auditory cortex of ketamine-anesthetized cats. Responses of multiunits were recorded simultaneously with two 8-electrode arrays during 1 s and over 2 s after the presentation of a white noise (WN) and three NNs differing by the width of the notch, namely, 1/3 octave (NN1), 1/2 octave (NN2), and 2/3 octave (NN3). Both firing rate (FR) and peak cross-correlation coefficient (p) were evaluated for time windows of 500 ms. The cortical units were grouped according to whether their characteristic frequency (CF) was inside ("In" neurons) or outside ("Out" neurons) a 1-octave-wide frequency band centered on the notch center frequency. The ratios between the FRs and the rhos for each NN and the WN condition and for each group of neurons were then statistically evaluated. The ratios of FRs were significantly increased during and after the presentation of the NN for the "In" neurons. In contrast, the changes for the t" neurons were small and most often insignificant. The ratios of the p values differed significantly from 1 in the "In-In" and "In-Out" groups during stimulation as well as after it. We also found that the ps of "Out" neurons were dependent on the type of NN. Potentially, a combination of increased p and increased FR might be a neurophysiological correlate of the ZT.

Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus.

Changes in spontaneous activity, recorded over 15-min periods before, immediately after and within hours after an acute acoustic trauma, were studied in primary auditory cortex of ketamine-anesthetized cats. We focused on the spontaneous firing rate (SFR), the peak cross-correlation coefficient (rho) and burst-firing activity. Multi-units (MUs) were grouped according to characteristic frequency (CF): MUs with a CF below the trauma-tone frequency (TF) were labeled as Be, those with a CF within 1 octave above the TF were labeled as Ab1 and those with a CF more than 1 octave above the TF were labeled as Ab2. Immediately after the trauma, the SFR was not significantly changed. The percentage of time that neurons were bursting, the mean burst duration, the number of spikes per burst and the mean inter-spike interval in a burst were enhanced. rho was locally increased in the Ab1-Ab2 and Ab2-Ab2 groups. A few hours post trauma, the SFR was increased in the Be and Ab2 groups, whereas burst-firing returned to pre-exposure levels. Moreover, rho was elevated in the Be-Ab2, Ab1-Ab2 and Ab2-Ab2 groups; this increase was significantly correlated to the changes in SFR. The results are discussed in the context of a neural correlate of tinnitus.

Chloride influx aggravates Ca2+-dependent AMPA receptor-mediated motoneuron death.

AMPA receptor-mediated excitotoxicity has been implicated in the pathogenesis of stroke, neurotrauma, epilepsy, and many neurodegenerative diseases such as motoneuron disease. We studied the role of Cl- in AMPA receptor-mediated Ca2+-dependent excitotoxicity in cultured rat spinal motoneurons. Using the gramicidin perforated patch-clamp technique, the intracellular Cl- concentration could be calculated from the reversal potential of the GABA-induced current. The membrane depolarization caused by AMPA receptor stimulation resulted in Cl- influx through 5-nitro-2(3-phenylpropyl-amino) benzoic acid- and niflumic acid-sensitive Cl- channels. Cl- influx during AMPA receptor stimulation aggravated excitotoxic motoneuron death by two mechanisms: an increase of AMPA receptor conductance and an elevation of the Ca2+ driving force through a partial repolarization. The Cl- influx during AMPA receptor stimulation was enhanced by coadministration of GABA. This resulted in an increased Ca2+ influx and an enhanced cell death, suggesting that concomitant GABAergic stimulation may aggravate excitotoxic motoneuron death.

Na(+) entry through AMPA receptors results in voltage-gated k(+) channel blockade in cultured rat spinal cord motoneurons.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents, evoked with the agonist kainate, were studied with the gramicidin perforated-patch-clamp technique in cultured rat spinal cord motoneurons. Kainate-induced currents could be blocked by the AMPA receptor antagonist LY 300164 and displayed an apparent strong inward rectification. This inward rectification was not a genuine property of AMPA receptor currents but was a result of a concomitant decrease in outward current at potentials positive to -40.5 +/- 1.3 mV. The AMPA receptor current itself was nearly linear (rectification index 0.91). The kainate-inhibited outward current had a reversal potential close to the estimated K(+) equilibrium potential and was blocked by 30 mM tetraethylammonium. When voltage steps were applied, it was found that kainate inhibited both the delayed rectifier K(+) current K(V) and the transient outward K(+) current, K(A). The kainate-induced inhibition of K(+) currents was dependent on ion flux through the AMPA receptor, because no change in the membrane conductance was noticed in the presence of LY 300164. Removing extracellular Ca(2+) had no effect, whereas replacing extracellular Na(+) or clamping the membrane close to the estimated Na(+) equilibrium potential during kainate application attenuated the inhibition of the K(+) current. Sustained Na(+) influx induced by application of the Na(+) ionophore monensin could mimic the effect of kainate on K(+) conductance. These findings demonstrate that Na(+) influx through AMPA receptors results in blockade of voltage-gated K(+) channels.

Between sound and perception: reviewing the search for a neural code.

This review investigates the roles of representation, transformation and coding as part of a hierarchical process between sound and perception. This is followed by a survey of how speech sounds and elements thereof are represented in the activity patterns along the auditory pathway. Then the evidence for a place representation of texture features of sound, comprising frequency, periodicity pitch, harmonicity in vowels, and direction and speed of frequency modulation, and for a temporal and synchrony representation of sound contours, comprising onsets, offsets, voice onset time, and low rate amplitude modulation, in auditory cortex is reviewed. Contours mark changes and transitions in sound and auditory cortex appears particularly sensitive to these dynamic aspects of sound. Texture determines which neurons, both cortical and subcortical, are activated by the sound whereas the contours modulate the activity of those neurons. Because contours are temporally represented in the majority of neurons activated by the texture aspects of sound, each of these neurons is part of an ensemble formed by the combination of contour and texture sensitivity. A multiplexed coding of complex sound is proposed whereby the contours set up widespread synchrony across those neurons in all auditory cortical areas that are activated by the texture of sound.

Spontaneous burst-firing in three auditory cortical fields: its relation to local field potentials and its effect on inter-area cross-correlations.

Burst-firing refers to epochs of sharply elevated neural discharge. It has been suggested that correlated firing in different cortical areas in anesthetized animals results from spontaneous burst-firing related to electroencephalogram spindling activity and state of drowsiness. To investigate this, simultaneous recordings of spontaneous firings of neurons in the primary (AI), secondary (AII) and anterior (AAF) fields of the auditory cortex in the lightly anaesthetized cat were obtained. This allowed a study of bursting behavior in the three cortical areas under exactly the same anesthetic state. Burst occurrences were detected using the Poisson-surprise method, and were typically highly synchronized with local field potentials (LFPs) and with burst-firing of other neurons recorded on the same electrode. Burst-firing occurred in 85% of 371 units studied, and in 48 (15%) thereof there were at least 100 bursts per 15 min. Neurons in Al were bursting at a significantly higher rate, but with fewer spikes per burst, than units in AII. The average percentage of the time that a spontaneously firing neuron is in the bursting state is only about 3% (range 0.004, 29%). The average peak cross-correlation coefficients between spikes and LFP triggers were largest for burst-onset spikes, followed by those between all burst spikes and LFP triggers, and smallest when all spikes of the single unit were used in the correlation. This was the case for within- and between-area conditions. Burst-onset times in different auditory fields were not correlated. Thus, the major cause of the observed correlation of spontaneous firing in different cortical areas is not synchronous burst-firing.

Inhibition of volume-regulated anion channels by dominant-negative caveolin-1.

Caveolae are flask-shaped invaginations of the plasma membrane formed by the association of caveolin proteins with lipid rafts. In endothelial cells, caveolae function as signal transduction centers controlling NO synthesis and mechanotransduction. We now provide evidence that the endothelial volume-regulated anion channel (VRAC) is also under the control of the caveolar system. When calf pulmonary artery endothelial (CPAE) cells were transfected with caveolin-1 Delta1-81 (deletion of amino acids 1 to 81), activation of VRAC by hypotonic cell swelling was strongly impaired. Concomitantly, caveolin-1 Delta1-81 disturbed the formation of caveolin-1 containing lipid rafts as evidenced by sucrose density gradient centrifugation. In nontransfected cells, endogenous caveolin-1 typically associated with low-density, detergent-resistant lipid rafts. However, transient expression of caveolin-1 Delta1-81 caused a redistribution of endogenous caveolin-1 to high-density, detergent-soluble membrane fractions. We therefore conclude that the interaction between caveolin-1 and detergent-resistant lipid rafts is an important prerequisite for endothelial VRAC activity.

Inhibition of VRAC by c-Src tyrosine kinase targeted to caveolae is mediated by the Src homology domains.

We used the whole cell patch-clamp technique in calf pulmonary endothelial (CPAE) cells to investigate the effect of wild-type and mutant c-Src tyrosine kinase on I(Cl,swell), the swelling-induced Cl- current through volume-regulated anion channels (VRAC). Transient transfection of wild-type c-Src in CPAE cells did not significantly affect I(Cl,swell). However, transfection of c-Src with a Ser3Cys mutation that introduces a dual acylation signal and targets c-Src to lipid rafts and caveolae strongly repressed hypotonicity-induced I(Cl,swell) in CPAE cells. Kinase activity was dispensable for the inhibition of I(Cl,swell), since kinase-deficient c-Src Ser3Cys either with an inactivating point mutation in the kinase domain or with the entire kinase domain deleted still suppressed VRAC activity. Again, the Ser3Cys mutation was required to obtain maximal inhibition by the kinase-deleted c-Src. In contrast, the inhibitory effect was completely lost when the Src homology domains 2 and 3 were deleted in c-Src. We therefore conclude that c-Src-mediated inhibition of VRAC requires compartmentalization of c-Src to caveolae and that the Src homology domains 2 and/or 3 are necessary and sufficient for inhibition.

Ca(2+)-activated Cl- channels in Ehrlich ascites tumor cells are distinct from mCLCA1, 2 and 3.

Using the whole-cell patch-clamp technique, we have studied the electrophysiological and pharmacological properties of the Ca(2+)-activated Cl- current present in Ehrlich cells. The currents activated slowly upon depolarization, deactivated upon hyperpolarization, and showed strong outward rectification. An increase in [Ca2+]i activated the current with an EC50 of 165.2 nM. Extracellular application of niflumic acid (100 microM) rapidly blocked the current in a voltage-dependent manner whereas sulfhydryl-modifying agents such as dithiothreitol (DTT, 1-2 mM) and N-ethylmaleimide (NEM, 100 microM) had no effect on Ca(2+)-activated currents in Ehrlich cells. Members of the recently discovered CLCA gene family are the only molecular candidates for Ca(2+)-activated Cl- channels cloned so far. Using RT-PCR we demonstrated that the appearance of a Ca(2+)-activated Cl- current in Ehrlich cells is not associated with the expression of the murine members of the CLCA family (mCLCA1-mCLCA3). Correspondingly, the kinetic and pharmacological properties of the Ca(2+)-activated current in Ehrlich cells differ from those of CLCA-associated currents, which are time independent and DTT sensitive. Thus, phenotypic differences in combination with RT-PCR data point to the existence of different molecular species for Ca(2+)-activated Cl- channels.

Cellular function and control of volume-regulated anion channels.

Restoration of cell volume after cell swelling in mammalian cells is achieved by the loss of solutes (K+, Cl-, and organic osmolytes) and the subsequent osmotically driven efflux of water. This process is generally known as regulatory volume decrease (RVD). One pathway for the swelling induced loss of Cl- (and also organic osmolytes) during RVD is the volume-regulated anion channel (VRAC). In this review, we discuss the physiological role and cellular control of VRAC. We will first highlight evidence that VRAC is more than a volume regulator and that it participates in other fundamental cellular processes such as cell proliferation and apoptosis. The second part concentrates on the Rho/Rho kinase/myosin phosphorylation cascade and on compartmentalization in caveolae as modulators of the signal transduction cascade that controls VRAC gating in vascular endothelial cells.

Of kittens and kids: altered cortical maturation following profound deafness and cochlear implant use.

Profoundly deaf children who use a cochlear implant (CI) provide a unique opportunity to investigate the effects of auditory sensory deprivation on the maturing human central nervous system. Previous results suggest that children fitted with a CI show evidence of altered auditory cortical maturation, based on evoked potentials. This altered maturation was characterized by both latency delays and morphological changes in the cortical auditory evoked potentials (AEPs). Based on prolonged P(1) latencies compared to age-matched normal-hearing (NH) peers, these data suggested a delayed maturation nearly equivalent to the period of deafness. However, rates of maturation for this AEP peak were essentially the same in NH and CI children. This suggests that, given enough time, the AEPs of CI children would assume the characteristic morphology found in older NH teens and NH adults. However, the data also indicated a substantial alteration of the typical set of obligatory P(1)-N(1b)-P(2) peaks, specifically related to the absence of the N(1) potential. Recent analyses of more extensive sets of longitudinal and cross-sectional data indicate that even after many years of implant use, the AEPs of CI users in their late teens remain very different from those of their NH peers. The P(1) peak latency remains prolonged and P(1) amplitude remains much larger in CI users than in age-matched NH teens. These findings suggested that age-related changes in the P(1) peak are completed by 12 years of age. In addition, the normal N(1b) peak fails to emerge in virtually all of the CI children tested in our laboratory. A major new interpretation of the abnormal maturation of AEP waveforms in CI children is presented. It is based on direct evidence showing that a persistent immaturity of the superficial layer axons has persistent negative effects on the generation of the N(1b) and, consequently, on the morphology of the AEPs. A comparison of scalp-recorded AEPs from implanted children with local field potentials measured from the cortical surface in deaf white kittens suggests the effects of deafness and CI use are similar across these mammalian species. For both species, a period of profound deafness followed by CI stimulation reveals a substantial immaturity in cortical activation even after a period of electrical stimulation by the CI.

The endothelial volume-regulated anion channel, VRAC.

We discuss in this short review properties of a volume-regulated anion channel that we have described in vascular endothelial cells. This channel, VRAC (volume-regulated anion channel) is outwardly rectifying with single channel conductances between 10-20pS for inward currents and 40-50pS for outward currents. VRAC is permeable for a wide range of anions, amino acids and organic osmolytes. The estimated pore diameter is approximately 1.1nm. VRAC is gated by a probably complex mechanism in which changes in ionic strength, tyrosine phosphorylation, the cytoskeletal organiser RhoA and possibly caveolin are essentially involved. The molecular candidate for this channel is still elusive. The functional impact of VRAC as a possible mechano-sensor in endothelium and as a regulatory component in the cell cycle, endothelial cell proliferation and possible angiogenesis will be discussed.

Differential expression of volume-regulated anion channels during cell cycle progression of human cervical cancer cells.

This study investigated the volume-regulated anion channel (VRAC) of human cervical cancer SiHa cells under various culture conditions, testing the hypothesis that the progression of the cell cycle is accompanied by differential expression of VRAC activity. Exponentially growing SiHa cells expressed VRACs, as indicated by the presence of large outwardly rectifying currents activated by hypotonic stress with the anion permeability sequence I- > Br- > Cl-. VRACs were potently inhibited by tamoxifen with an IC50 of 4.6 [mu]M. Fluorescence-activated cell sorting (FACS) experiments showed that 59 +/- 0.5, 5 +/- 0.5 and 36 +/- 1.1% of unsynchronized, exponentially growing cervical cancer SiHa cells were in G0/G1, S and G2/M stage, respectively. Treatment with aphidicolin (5 [mu]M) arrested 88 +/- 1.4% of cells at the G0/G1 stage. Arrest of cell growth in the G0/G1 phase was accompanied by a significant decrease of VRAC activity. The normalized hypotonicity-induced current decreased from 48 +/- 5.2 pA pF-1 at +100 mV in unsynchronized cells to 15 +/- 2.6 pA pF-1 at +100 mV in aphidicolin-treated cells. After removal of aphidicolin, culturing in medium containing 10% fetal calf serum triggered a rapid re-entry into the cell cycle and a concomitant recovery of VRAC density. Pharmacological blockade of VRACs by tamoxifen or NPPB caused proliferating cervical cancer cells to arrest in the G0/G1 stage, suggesting that activity of this channel is critical for G1/S checkpoint progression. This study provides new information on the functional significance of VRACs in the cell cycle clock of human cervical cancer cells.

Spontaneous firing activity of cortical neurons in adult cats with reorganized tonotopic map following pure-tone trauma.

We hypothesized that moderate sensorineural hearing loss resulting from acoustic trauma would cause (i) a change in the cortical tonotopic map, (ii) an increase in spontaneous activity in the reorganized region and (iii) increased inter-neuronal synchrony within the reorganized part of the cortex. Five kittens were exposed to a 126 dB sound pressure limit tone of 6 kHz for 1 h at both 5 and 6 weeks of age. Recordings were performed 7-16 weeks after the exposure. Auditory brainstem response thresholds for frequencies above 12 kHz were increased by 30 dB on average relative to those in normal cats. Tonotopic maps in the primary auditory cortex were reorganized in such a way that the area normally tuned to frequencies of 10-40 kHz was now entirely tuned to 10 kHz. Spontaneous firing rates were significantly higher in reorganized areas than in normal areas. In order to test for changes in inter-neuronal synchrony, cross-correlation analysis was done on 225 single-unit pairs recorded in the traumatized cats. For the single- and dual-electrode pairs there was no significant difference in peak cross-correlation coefficients for the firings of simultaneously recorded cells between normal and reorganized areas. However, the percentage of correlations that differed significantly from zero was higher in the reorganized area than in the normal area. This suggests a potential correlation between cortical reorganization, increased spontaneous firing rate and inter-neuronal synchrony that might be related to tinnitus found in high-frequency hearing loss induced by acoustic trauma.