Spatial selectivity to intracochlear electrical stimulation in the inferior colliculus is degraded after long-term deafness in cats

In an animal model of electrical hearing in prelingually deaf adults, this study examined the effects of deafness duration on response thresholds and spatial selectivity (i.e., cochleotopic organization, spatial tuning and dynamic range) in the central auditory system to intracochlear electrical stimulation. Electrically evoked auditory brain stem response (EABR) thresholds and neural response thresholds in the external (ICX) and central (ICC) nuclei of the inferior colliculus were estimated in cats after varying durations of neonatally induced deafness: in animals deafened <1.5 yr (short-deafened unstimulated, SDU cats) with a mean spiral ganglion cell (SGC) density of approximately 45% of normal and in animals deafened >2.5 yr (long-deafened, LD cats) with severe cochlear pathology (mean SGC density <7% of normal). LD animals were subdivided into unstimulated cats and those that received chronic intracochlear electrical stimulation via a feline cochlear implant. Acutely deafened, implanted adult cats served as controls. Independent of their stimulation history, LD animals had significantly higher EABR and ICC thresholds than SDU and control animals. Moreover, the spread of electrical excitation was significantly broader and the dynamic range significantly reduced in LD animals. Despite the prolonged durations of deafness the fundamental cochleotopic organization was maintained in both the ICX and the ICC of LD animals. There was no difference between SDU and control cats in any of the response properties tested. These findings suggest that long-term auditory deprivation results in a significant and possibly irreversible degradation of response thresholds and spatial selectivity to intracochlear electrical stimulation in the auditory midbrain.     

Interdependence of spatial and temporal coding in the auditory midbrain

To date, most physiological studies that investigated binaural auditory processing have addressed the topic rather exclusively in the context of sound localization. However, there is strong psychophysical evidence that binaural processing serves more than only sound localization. This raises the question of how binaural processing of spatial cues interacts with cues important for feature detection. The temporal structure of a sound is one such feature important for sound recognition. As a first approach, we investigated the influence of binaural cues on temporal processing in the mammalian auditory system. Here, we present evidence that binaural cues, namely interaural intensity differences (IIDs), have profound effects on filter properties for stimulus periodicity of auditory midbrain neurons in the echolocating big brown bat, Eptesicus fuscus. Our data indicate that these effects are partially due to changes in strength and timing of binaural inhibitory inputs. We measured filter characteristics for the periodicity (modulation frequency) of sinusoidally frequency modulated sounds (SFM) under different binaural conditions. As criteria, we used 50% filter cutoff frequencies of modulation transfer functions based on discharge rate as well as synchronicity of discharge to the sound envelope. The binaural conditions were contralateral stimulation only, equal stimulation at both ears (IID = 0 dB), and more intense at the ipsilateral ear (IID = -20, -30 dB). In 32% of neurons, the range of modulation frequencies the neurons responded to changed considerably comparing monaural and binaural (IID =0) stimulation. Moreover, in approximately 50% of neurons the range of modulation frequencies was narrower when the ipsilateral ear was favored (IID = -20) compared with equal stimulation at both ears (IID = 0). In approximately 10% of the neurons synchronization differed when comparing different binaural cues. Blockade of the GABAergic or glycinergic inputs to the cells recorded from revealed that inhibitory inputs were at least partially responsible for the observed changes in SFM filtering. In 25% of the neurons, drug application abolished those changes. Experiments using electronically introduced interaural time differences showed that the strength of ipsilaterally evoked inhibition increased with increasing modulation frequencies in one third of the cells tested. Thus glycinergic and GABAergic inhibition is at least one source responsible for the observed interdependence of temporal structure of a sound and spatial cues.     

Auditory cortical responses to electrical stimulation of the inferior colliculus: implications for an auditory midbrain implant

The success and limitations of cochlear implants (CIs) along with recent advances in deep brain stimulation and neural engineering have motivated the development of a central auditory prosthesis. In this study, we investigated the effects of electrical stimulation of the inferior colliculus central nucleus (ICC) on primary auditory cortex (A1) activity to determine the potential benefits of an auditory midbrain implant (AMI). We recorded multiunit activity in A1 of ketamine-anesthetized guinea pigs in response to single-pulse (200 µs/phase) monopolar stimulation of the ICC using multisite silicon-substrate probes. We then compared measures of threshold, dynamic range, and tonotopic spread of activation for ICC stimulation with that of published data for CI stimulation. Our results showed that compared with cochlear stimulation, ICC stimulation achieved: 1) thresholds about 8 dB lower; 2) dynamic ranges 4 dB greater; and 3) more localized, frequency-specific activation, even though frequency specificity was partially lost at higher stimulus levels for low-frequency ICC regions. Our results also showed that stimulation of rostral ICC regions elicited lower thresholds but with greater activation spread along the tonotopic gradient of A1 than did stimulation of more caudal regions. These results suggest that an AMI may improve frequency and level coding with lower energy requirements compared with CIs. However, a trade-off between lower perceptual thresholds and better frequency discrimination may exist that depends on location of stimulation along the caudorostral dimension of the ICC. Overall, this study provides the foundation for future AMI research and development.     

Atherosclerosis induced in rabbits by prolonged electrical stimulation of the hypothalamus

The effect of prolonged electrical stimulation of emotiogenic zones of the hypothalamus in rabbits on their blood lipid level and the development of atherosclerosis was studied with the aid of a specially designed autonomous system. A negative emotional state observed during stimulation was accompanied by hyperlipemia and by the development of atherosclerosis in one third of uncastrated and two thirds of castrated animals.Department of Pathological Physiology and Central Scientific-Research Laboratory, Leningrad Sanitary Hygiene Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR P. N. Beselkin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 11, pp. 1294–1296, November, 1976.     

Temporal properties of chronic cochlear electrical stimulation determine temporal resolution of neurons in cat inferior colliculus

As cochlear implants have become increasingly successful in the rehabilitation of adults with profound hearing impairment, the number of pediatric implant subjects has increased. We have developed an animal model of congenital deafness and investigated the effect of electrical stimulus frequency on the temporal resolution of central neurons in the developing auditory system of deaf cats. Maximum following frequencies (Fmax) and response latencies of isolated single neurons to intracochlear electrical pulse trains (charge balanced, constant current biphasic pulses) were recorded in the contralateral inferior colliculus (IC) of two groups of neonatally deafened, barbiturate-anesthetized cats: animals chronically stimulated with low-frequency signals (< or = 80 Hz) and animals receiving chronic high-frequency stimulation (> or = 300 pps). The results were compared with data from unstimulated, acutely deafened and implanted adult cats with previously normal hearing (controls). Characteristic differences were seen between the temporal response properties of neurons in the external nucleus (ICX; approximately 16% of the recordings) and neurons in the central nucleus (ICC; approximately 81% of all recordings) of the IC: 1) in all three experimental groups, neurons in the ICX had significantly lower Fmax and longer response latencies than those in the ICC. 2) Chronic electrical stimulation in neonatally deafened cats altered the temporal resolution of neurons exclusively in the ICC but not in the ICX. The magnitude of this effect was dependent on the frequency of the chronic stimulation. Specifically, low-frequency signals (30 pps, 80 pps) maintained the temporal resolution of ICC neurons, whereas higher-frequency stimuli significantly improved temporal resolution of ICC neurons (i.e., higher Fmax and shorter response latencies) compared with neurons in control cats. Furthermore, Fmax and latencies to electrical stimuli were not correlated with the tonotopic gradient of the ICC, and changes in temporal resolution following chronic electrical stimulation occurred uniformly throughout the entire ICC. In all three experimental groups, increasing Fmax was correlated with shorter response latencies. The results indicate that the temporal features of the chronically applied electrical signals critically influence temporal processing of neurons in the cochleotopically organized ICC. We suggest that such plastic changes in temporal processing of central auditory neurons may contribute to the intersubject variability and gradual improvements in speech recognition performance observed in clinical studies of deaf children using cochlear implants.     

Cardiovascular and respiratory responses to electrical stimulation of the midbrain in the rat

In descending through the midbrains of rats with stimulation electrodes, we have observed some remarkable reversals of pressor and depressor autonomic effects as the electrode was moved from one locus to another. Autonomic effects of stimulating in the midbrain areas that we studied are of special interest because stimulations in some of these midbrain loci have pain-relieving effects (Hosobuchi et al., 1977, 1979; Mayer et al., 1971; Soper, 1976). Our observations of cardiac arrest are of particular concern because of the use that is being made of midbrain electrical stimulation to relieve pain in human patients.     

Effects of medial olivocochlear efferent stimulation on the activity of neurons in the auditory midbrain

Medial olivocochlear (MOC) efferents are known to suppress spontaneous activity and sound-evoked responses of primary afferents by their actions on outer hair cells in the cochlea. This study investigated the effects of MOC activation on the responses of single neurons in the central nucleus of the inferior colliculus (CNIC) of anaesthetized guinea pigs. Extracellular responses of CNIC neurons to contralateral tones were recorded with and without MOC stimulation in normal animals and in animals acutely treated with gentamicin to eliminate peripheral effects of MOC activation. In normal animals, input–output functions of CNIC neurons showed a variety of changes. Some effects resembled qualitatively those reported for primary afferents. However, other effects were also observed, including an increase of firing rates at medium- to high-tone levels and in a small number of neurons (10%), an increase in spontaneous activity. In addition, larger threshold shifts and larger reductions of spontaneous firing rates were observed as compared to effects seen in the periphery. In gentamicin-treated animals, activation of MOC efferents did not produce any changes in the input–output functions or spontaneous activity of CNIC neurons. This observation is consistent with the majority of MOC-induced changes in monaural responses in the CNIC being mediated by the actions of MOC terminals in the cochlea and resulting from the interplay between altered afferent input and central circuitry.     

Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation

There is an accumulating body of evidence suggesting that the periaqueductal grey (PAG) is involved in the pathophysiology of migraine. Positron emission tomography (PET) studies in humans have shown that the caudal ventrolateral midbrain, encompassing the ventrolateral PAG, has activations during migraine attacks. The PAG may well be involved not only through the descending modulation of nociceptive afferent information, but also by its ascending projections to the pain processing centres of the thalamus. In this study the intranuclear oncogene protein Fos was used to mark cell activation in the PAG following stimulation of the trigeminally-innervated superior sagittal sinus (SSS) in both cats and in nonhuman primates ( Macaca nemestrina ). Fos expression in the PAG increased following stimulation to a median of 242 cells (interquartile range 236–272) in the cat and 155 cells (range 104–203) in the monkey, compared with control levels of 35 cells (21–50) and 26 cells (18–33), respectively. Activation was predominantly in the ventrolateral area of the caudal PAG suggesting that the PAG is involved following trigeminally-evoked craniovascular pain.     

Neuronal responses in cat primary auditory cortex to electrical cochlear stimulation. III. Activation patterns in short- and long-term deafness

The effects of auditory deprivation on the spatial distribution of cortical response thresholds to electrical stimulation of the adult cat cochlea were evaluated. Threshold distributions for single- and multiple-unit responses from the middle cortical layers were obtained on the ectosylvian gyrus in three groups of animals: adult, acutely implanted animals ("acute group"); adult animals, 2 wk after deafening and implantation ("short-term group"); adult, neonatally deafened animals ("long-term group") implanted after 2-5 years of deafness. For all three groups, we observed similar patterns of circumscribed regions of low response thresholds in the region of primary auditory cortex (AI). A dorsal and a ventral region of low response thresholds were found separated by a narrow, anterior-posterior strip of elevated thresholds. The two low-threshold regions in the acute and the short-term group were arranged cochleotopically. This was reflected in a systematic shift of the cortical locations with minimum thresholds as a function of cochlear position of the radial and monopolar stimulation electrodes. By contrast, the long-term deafened animals maintained only weak or no signs of cochleotopicity. In some cases of this group, significant deviations from a simple tri-partition of the dorsoventral axis of AI was observed. Analysis of the spatial extent of the low-threshold regions revealed that the activated area in acute cases was significantly smaller than the long- and the short-term cases for both dorsal and ventral AI. There were no significant differences in the rostrocaudal extent of activation between long- and short-term deafening, although the total activated area in the short-term cases was larger than in long-term deafened animals. The width of the narrow high-threshold ridge that separated the dorsal and ventral low-threshold regions was the widest for the acute cases and the narrowest for the short-term deafened animals. The findings of relative large differences in cortical response distributions between the acute and short-term animals suggests that the effects observed in long-term deafened animals are not solely a consequence of loss of peripheral innervation density. The effects may reflect electrode-specific effects or reorganizational changes based on factors such as differences in excitatory and inhibitory balance.     

Neuron discharges in the rat auditory cortex during electrical intracortical stimulation

Studies were carried out in rats anesthetized with ketamine or nembutal, with recording of multicellular activity (with separate identification of responses from individual neurons) in the primary auditory cortex before and after electrical intracortical microstimulation. These experiments showed that about half of the set of neurons studied produced responses to short tonal bursts, these responses having two components—initial discharges arising in response to the sound, and afterdischarge occurring after pauses of 50–100 msec. Afterdischarges lasted at least several seconds, and were generally characterized by a rhythmic structure (with a frequency of 8–12 Hz). After electrical microstimulation, the level of spike activity increased, especially in afterdischarges, and this increase could last up to 4 h. Combined peristimulus histograms, cross-correlations, and gravitational analyses were used to demonstrate interactions of neurons, which increased after electrical stimulation and were especially pronounced in the response afterdischarges. Department of Neurosciences, Faculty of Medicine, University of Pennsylvania, Philadelphia, USA. Laboratory of Auditory Physiology, I. P. Pavlov Institute of Physiology, 6 Makarov Bank, 199034 St. Petersburg, Russia. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 82, No. 5-6, pp. 3–17, May–June, 1996.     

Paraventricular nucleus magnocellular neuronal responses following electrical stimulation of the midbrain dorsal raphe

Summary In order to determine the responses of paraventricular nucleus magnocellular neurones following activation of central serotonergic pathways, single unit activity was recorded and responses following electrical stimulation of the midbrain dorsal raphe nucleus were examined. Approximately one third (32%) of the phasically active, vasopressin-secreting neurones were inhibited by the stimulation, the remaining such cells being nonresponsive. In contrast, only two of the non-phasic cells (13%) were inhibited by the stimulation whilst 53% were excited (p< 0.005, chi²-test). The onset latency of both inhibitory and excitatory responses were similar, whilst offset of the inhibitory responses was about twice that of the excitatory responses (p < 0.005, t-test). Two of the nonphasic cells were antidromically identified as projecting to the dorsal raphe. The results obtained indicate a role for dorsal raphe projections to the paraventricular nucleus in the regulation of neurohypophysial hormone secretion. The observation that different sub-populations of the cells recorded showed different responses, suggests that several mechanisms may be involved in the control of neuronal activity in the region recorded, in response to activation of the central serotonergic pathway examined. The results obtained are intended to further clarify the neural mechanisms regulating the secretion of vasopressin and oxytocin from the neurohypophysis.     

Response properties of neighboring neurons in the auditory midbrain for pure-tone stimulation: a tetrode study

The complex anatomical structure of the central nucleus of the inferior colliculus (ICC), the principal auditory nucleus in the midbrain, may provide the basis for functional organization of auditory information. To investigate this organization, we used tetrodes to record from neighboring neurons in the ICC of anesthetized cats and studied the similarity and difference among the responses of these neurons to pure-tone stimuli using widely used physiological characterizations. Consistent with the tonotopic arrangement of neurons in the ICC and reports of a threshold map, we found a high degree of correlation in the best frequencies (BFs) of neighboring neurons, which were mostly <3 kHz in our sample, and the pure-tone thresholds among neighboring neurons. However, width of frequency tuning, shapes of the frequency response areas, and temporal discharge patterns showed little or no correlation among neighboring neurons. Because the BF and threshold are measured at levels near the threshold and the characteristic frequency (CF), neighboring neurons may receive similar primary inputs tuned to their CF; however, at higher levels, additional inputs from other frequency channels may be recruited, introducing greater variability in the responses. There was also no correlation among neighboring neurons' sensitivity to interaural time differences (ITD) measured with binaural beats. However, the characteristic phases (CPs) of neighboring neurons revealed a significant correlation. Because the CP is related to the neural mechanisms generating the ITD sensitivity, this result is consistent with segregation of inputs to the ICC from the lateral and medial superior olives.     

Topographic organization in the auditory brainstem of juvenile mice is disrupted in congenital deafness

There is an orderly topographic arrangement of neurones within auditory brainstem nuclei based on sound frequency. Previous immunolabelling studies in the medial nucleus of the trapezoid body (MNTB) have suggested that there may be gradients of voltage-gated currents underlying this tonotopic arrangement. Here, our electrophysiological and immunolabelling results demonstrate that underlying the tonotopic organization of the MNTB is a combination of medio-lateral gradients of low-and high-threshold potassium currents and hyperpolarization-activated cation currents. Our results also show that the intrinsic membrane properties of MNTB neurones produce a topographic gradient of time delays, which may be relevant to sound localization, following previous demonstrations of the importance of the timing of inhibitory input from the MNTB to the medial superior olive (MSO). Most importantly, we demonstrate that, in the MNTB of congenitally deaf mice, which exhibit no spontaneous auditory nerve activity, the normal tonotopic gradients of neuronal properties are absent. Our results suggest an underlying mechanism for the observed topographic gradient of neuronal firing properties in the MNTB, show that an intrinsic neuronal mechanism is responsible for generating a topographic gradient of time-delays, and provide direct evidence that these gradients rely on spontaneous auditory nerve activity during development.     

Social regulation of serotonin in the auditory midbrain

The neuromodulator serotonin regulates auditory processing and can increase within minutes in response to stimuli like broadband noise as well as nonauditory stressors. Little is known about the serotonergic response in the auditory system to more natural stimuli such as social interactions. Using carbon-fiber voltammetry, we measured extracellular serotonin in the auditory midbrain of resident male mice during encounters with a male intruder. Serotonin increased in the inferior colliculus (IC) over the course of a 15 minute interaction, but not when mice were separated with a perforated barrier. Several behaviors, including the amount of immobility and anogenital investigation performed by the resident, were correlated with the serotonergic response. Multiple intrinsic factors associated with individual mice also correlated with the serotonergic response. One of these was age: older mice had smaller serotonergic responses to the social interaction. In a second interaction, individual identity predicted serotonergic responses that were highly consistent with those in the first interaction, even when mice were paired with different intruders. Serotonin was also significantly elevated in the second social interaction relative to the first, suggesting a role for social experience. These findings show that during social interaction, serotonin in the IC is influenced by extrinsic factors such as the directness of social interaction and intrinsic factors including age, individual identity, and experience.     

Hyperactivity in the auditory midbrain after acoustic trauma: dependence on cochlear activity

Plasticity in the adult mammalian brain can occur after damage to peripheral nerves and has also been described in the auditory system. Acoustic trauma, resulting in a loss of cochlear sensitivity, can lead to elevated levels of spontaneous activity, that is hyperactivity, in central nuclei such as the inferior colliculus. The current view is that this hyperactivity is centrally generated as a result of altered input. We investigated acute and chronic effects of acoustic trauma on cochlear sensitivity and development of hyperactivity in the inferior colliculus of guinea pigs. In addition, we investigated whether hyperactivity in the inferior colliculus, once established, is dependent on neural activity in the cochlea. Acoustic trauma (1 h continuous, 10 kHz tone at 124 dB SPL) resulted in a small but permanent, frequency restricted threshold loss in the cochlea up to 6 weeks post-exposure (maximum recovery time used). This was accompanied by hyperactivity in restricted frequency areas of the inferior colliculus, broadly corresponding to the cochlear threshold loss. We found that hyperactivity in the inferior colliculus depended on neural activity in the cochlea at all recovery times, since it disappeared after cochlear ablation and treatments blocking spontaneous firing of primary afferents. We suggest that the dependency of the central hyperactivity on the integrity of the peripheral receptor indicates hyperexcitability within the CNS resulting in greater neuronal firing in response to normal levels of peripheral spontaneous activity.     

Leading inhibition to neural oscillation is important for time-domain processing in the auditory midbrain

A number of central auditory neurons exhibit paradoxical latency shift (PLS), a response characterized by longer response latencies at higher sound levels. PLS neurons are known to play a role in target ranging for echolocating bats that emit frequency-modulated sounds. We recently reported that early inhibition of unit's oscillatory discharges is critical for PLS in the inferior colliculus (IC) of little brown bats. The goal of this study was to determine in echolocating bats and in non-echolocating animals (frogs): 1) the detailed characteristics of PLS and whether PLS was dependent on sound level, frequency, and duration; 2) the time course of inhibition underlying PLS using a paired-pulse paradigm. We found that 22% of IC neurons in bats and 15% in frogs exhibited periodic discharge patterns in response to tone pulses at high sound levels. The firing periodicity was unit specific and independent of sound level and duration. Other IC neurons (28% in bats; 14% in frogs) exhibited PLS. These PLS neurons shared several response characteristics: 1) PLS was largely independent of sound frequency and 2) the magnitude of shift in first-spike latency was either duration dependent or duration tolerant. For PLS neurons, application of bicuculline abolished PLS and unmasked the unit's periodical firing pattern that served as the building block for PLS. In response to paired sound pulses, PLS neurons exhibited delay-dependent response suppression, confirming that high-threshold leading inhibition was responsible for PLS. Results also revealed the timing of excitatory and inhibitory inputs underlying PLS and its role in time-domain processing.