Seth D. Koehler

Dorsal cochlear nucleus responses to somatosensory stimulation are enhanced after noise‐induced hearing loss

Multisensory neurons in the dorsal cochlear nucleus (DCN) achieve their bimodal response properties [Shore (2005) Eur. J. Neurosci., 21, 3334–3348] by integrating auditory input via VIIIth nerve fibers with somatosensory input via the axons of cochlear nucleus granule cells [Shore et al. (2000) J. Comp. Neurol., 419, 271–285; Zhou & Shore (2004)J. Neurosci. Res., 78, 901–907]. A unique feature of multisensory neurons is their propensity for receiving cross‐modal compensation following sensory deprivation. Thus, we investigated the possibility that reduction of VIIIth nerve input to the cochlear nucleus results in trigeminal system compensation for the loss of auditory inputs. Responses of DCN neurons to trigeminal and bimodal (trigeminal plus acoustic) stimulation were compared in normal and noise‐damaged guinea pigs. The guinea pigs with noise‐induced hearing loss had significantly lower thresholds, shorter latencies and durations, and increased amplitudes of response to trigeminal stimulation than normal animals. Noise‐damaged animals also showed a greater proportion of inhibitory and a smaller proportion of excitatory responses compared with normal. The number of cells exhibiting bimodal integration, as well as the degree of integration, was enhanced after noise damage. In accordance with the greater proportion of inhibitory responses, bimodal integration was entirely suppressive in the noise‐damaged animals with no indication of the bimodal enhancement observed in a sub‐set of normal DCN neurons. These results suggest that projections from the trigeminal system to the cochlear nucleus are increased and/or redistributed after hearing loss. Furthermore, the finding that only neurons activated by trigeminal stimulation showed increased spontaneous rates after cochlear damage suggests that somatosensory neurons may play a role in the pathogenesis of tinnitus.

Noise overexposure alters long-term somatosensory-auditory processing in the dorsal cochlear nucleus-possible basis for tinnitus-related hyperactivity?

The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory integration. Previous studies have shown that stimulation of somatosensory pathways results in immediate suppression or enhancement of subsequent acoustically evoked discharges. In the unimpaired auditory system suppression predominates. However, damage to the auditory input pathway leads to enhancement of excitatory somatosensory inputs to the cochlear nucleus, changing their effects on DCN neurons (Shore et al., 2008; Zeng et al., 2009). Given the well described connection between the somatosensory system and tinnitus in patients we sought to determine whether plastic changes in long-lasting bimodal somatosensory-auditory processing accompany tinnitus. Here we demonstrate for the first time in vivo long-term effects of somatosensory inputs on acoustically evoked discharges of DCN neurons in guinea pigs. The effects of trigeminal nucleus stimulation are compared between normal-hearing animals and animals overexposed with narrow band noise and behaviorally tested for tinnitus. The noise exposure resulted in a temporary threshold shift in auditory brainstem responses but a persistent increase in spontaneous and sound-evoked DCN unit firing rates and increased steepness of rate-level functions. Rate increases were especially prominent in buildup units. The long-term somatosensory enhancement of sound-evoked responses was strengthened while suppressive effects diminished in noise-exposed animals, especially those that developed tinnitus. Damage to the auditory nerve is postulated to trigger compensatory long-term synaptic plasticity of somatosensory inputs that might be an important underlying mechanism for tinnitus generation.

Neural mechanisms underlying somatic tinnitus

Somatic tinnitus is clinically observed modulation of the pitch and loudness of tinnitus by somatic stimulation. This phenomenon and the association of tinnitus with somatic neural disorders indicate that neural connections between the somatosensory and auditory systems may play a role in tinnitus. Anatomical and physiological evidence supports these observations. The trigeminal and dorsal root ganglia relay afferent somatosensory information from the periphery to secondary sensory neurons in the brainstem, specifically, the spinal trigeminal nucleus and dorsal column nuclei, respectively. Each of these structures has been shown to send excitatory projections to the cochlear nucleus. Mossy fibers from the spinal trigeminal and dorsal column nuclei terminate in the granule cell domain while en passant boutons from the ganglia terminate in the granule cell domain and core region of the cochlear nucleus. Sources of these somatosensory-auditory projections are associated with proprioceptive and cutaneous, but not nociceptive, sensation. Single unit and evoked potential recordings in the dorsal cochlear nucleus indicate that these pathways are physiologically active. Stimulation of the dorsal column and the cervical dorsal root ganglia elicits short- and long-latency inhibition separated by a transient excitatory peak in DCN single units. Similarly, activation of the trigeminal ganglion elicits excitation in some DCN units and inhibition in others. Bimodal integration in the DCN is demonstrated by comparing responses to somatosensory and auditory stimulation alone with responses to paired somatosensory and auditory stimulation. The modulation of firing rate and synchrony in DCN neurons by somatatosensory input is physiological correlate of somatic tinnitus.

Stimulus timing-dependent plasticity in dorsal cochlear nucleus is altered in tinnitus

Tinnitus and cochlear damage have been associated with changes in somatosensory-auditory integration and plasticity in the dorsal cochlear nucleus (DCN). Recently, we demonstrated in vivo that DCN bimodal plasticity is stimulus timing-dependent, with Hebbian and anti-Hebbian timing rules that reflect in vitro spike timing-dependent plasticity. In this in vivo study, we assessed the stimulus timing dependence of bimodal plasticity in a tinnitus model. Guinea pigs were exposed to a narrowband noise that produced a temporary elevation of auditory brainstem response thresholds. A total of 60% of the guinea pigs developed tinnitus as indicated by gap-induced prepulse inhibition of the acoustic startle. After noise exposure and tinnitus induction, stimulus timing-dependent plasticity was measured by comparing responses to sound before and after paired somatosensory and auditory stimulation presented with varying intervals and orders. In comparison with Sham and noise-exposed animals that did not develop tinnitus, timing rules in verified tinnitus animals were more likely to be anti-Hebbian and broader for those bimodal intervals in which the neural activity showed enhancement. Furthermore, units from exposed animals with tinnitus were more weakly suppressed than either Sham animals or exposed animals without tinnitus. The broadened timing rules in the enhancement phase in animals with tinnitus, and in the suppressive phase in exposed animals without tinnitus was in contrast to narrow, Hebbian-like timing rules in Sham animals. These findings implicate alterations in DCN bimodal spike timing-dependent plasticity as underlying mechanisms in tinnitus, opening the way for a therapeutic target.

Somatosensory inputs modify auditory spike timing in dorsal cochlear nucleus principal cells.

In addition to auditory inputs, dorsal cochlear nucleus (DCN) pyramidal cells in the guinea pig receive and respond to somatosensory inputs and perform multisensory integration. DCN pyramidal cells respond to sounds with characteristic spike‐timing patterns that are partially controlled by rapidly inactivating potassium conductances. Deactivating these conductances can modify both spike rate and spike timing of responses to sound. Somatosensory pathways are known to modify response rates to subsequent acoustic stimuli, but their effect on spike timing is unknown. Here, we demonstrate that preceding tonal stimulation with spinal trigeminal nucleus (Sp5) stimulation significantly alters the first spike latency, the first interspike interval and the average discharge regularity of firing evoked by the tone. These effects occur whether the neuron is excited or inhibited by Sp5 stimulation alone. Our results demonstrate that multisensory integration in DCN alters spike‐timing representations of acoustic stimuli in pyramidal cells. These changes likely occur through synaptic modulation of intrinsic excitability or synaptic inhibition.

Multi-sensory integration in brainstem and auditory cortex

Tinnitus is the perception of sound in the absence of a physical sound stimulus. It is thought to arise from aberrant neural activity within central auditory pathways that may be influenced by multiple brain centers, including the somatosensory system. Auditory-somatosensory (bimodal) integration occurs in the dorsal cochlear nucleus (DCN), where electrical activation of somatosensory regions alters pyramidal cell spike timing and rates of sound stimuli. Moreover, in conditions of tinnitus, bimodal integration in DCN is enhanced, producing greater spontaneous and sound-driven neural activity, which are neural correlates of tinnitus. In primary auditory cortex (A1), a similar auditory-somatosensory integration has been described in the normal system (Lakatos et al., 2007), where sub-threshold multisensory modulation may be a direct reflection of subcortical multisensory responses (Tyll et al., 2011). The present work utilized simultaneous recordings from both DCN and A1 to directly compare bimodal integration across these separate brain stations of the intact auditory pathway. Four-shank, 32-channel electrodes were placed in DCN and A1 to simultaneously record tone-evoked unit activity in the presence and absence of spinal trigeminal nucleus (Sp5) electrical activation. Bimodal stimulation led to long-lasting facilitation or suppression of single and multi-unit responses to subsequent sound in both DCN and A1. Immediate (bimodal response) and long-lasting (bimodal plasticity) effects of Sp5-tone stimulation were facilitation or suppression of tone-evoked firing rates in DCN and A1 at all Sp5-tone pairing intervals (10, 20, and 40 ms), and greater suppression at 20 ms pairing-intervals for single unit responses. Understanding the complex relationships between DCN and A1 bimodal processing in the normal animal provides the basis for studying its disruption in hearing loss and tinnitus models. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Bimodal stimulus timing-dependent plasticity in primary auditory cortex is altered after noise exposure with and without tinnitus.

Central auditory circuits are influenced by the somatosensory system, a relationship that may underlie tinnitus generation. In the guinea pig dorsal cochlear nucleus (DCN), pairing spinal trigeminal nucleus (Sp5) stimulation with tones at specific intervals and orders facilitated or suppressed subsequent tone-evoked neural responses, reflecting spike timing-dependent plasticity (STDP). Furthermore, after noise-induced tinnitus, bimodal responses in DCN were shifted from Hebbian to anti-Hebbian timing rules with less discrete temporal windows, suggesting a role for bimodal plasticity in tinnitus. Here, we aimed to determine if multisensory STDP principles like those in DCN also exist in primary auditory cortex (A1), and whether they change following noise-induced tinnitus. Tone-evoked and spontaneous neural responses were recorded before and 15 min after bimodal stimulation in which the intervals and orders of auditory-somatosensory stimuli were randomized. Tone-evoked and spontaneous firing rates were influenced by the interval and order of the bimodal stimuli, and in sham-controls Hebbian-like timing rules predominated as was seen in DCN. In noise-exposed animals with and without tinnitus, timing rules shifted away from those found in sham-controls to more anti-Hebbian rules. Only those animals with evidence of tinnitus showed increased spontaneous firing rates, a purported neurophysiological correlate of tinnitus in A1. Together, these findings suggest that bimodal plasticity is also evident in A1 following noise damage and may have implications for tinnitus generation and therapeutic intervention across the central auditory circuit.

Stimulus-timing-dependent modifications of rate-level functions in animals with and without tinnitus.

Tinnitus has been associated with enhanced central gain manifested by increased spontaneous activity and sound-evoked firing rates of principal neurons at various stations of the auditory pathway. Yet, the mechanisms leading to these modifications are not well understood. In a recent in vivo study, we demonstrated that stimulus-timing-dependent bimodal plasticity mediates modifications of spontaneous and tone-evoked responses of fusiform cells in the dorsal cochlear nucleus (DCN) of the guinea pig. Fusiform cells from sham animals showed primarily Hebbian learning rules while noise-exposed animals showed primarily anti-Hebbian rules, with broadened profiles for the animals with behaviorally verified tinnitus (Koehler SD, Shore SE. J Neurosci 33: 19647-19656, 2013a). In the present study we show that well-timed bimodal stimulation induces alterations in the rate-level functions (RLFs) of fusiform cells. The RLF gains and maximum amplitudes show Hebbian modifications in sham and no-tinnitus animals but anti-Hebbian modifications in noise-exposed animals with evidence for tinnitus. These findings suggest that stimulus-timing bimodal plasticity produced by the DCN circuitry is a contributing mechanism to enhanced central gain associated with tinnitus.

Dorsal Cochlear Nucleus: Somatosensory–Auditory Interactions in Tinnitus

In normal individuals, phantom auditory sensations like tinnitus can develop during head, neck, and jaw muscle contractions (Levine et al., 2003). In more than two thirds of people with chronic tinnitus, active and passive manipulations of these regions, such as jaw clenching or tensing the neck muscles, can alter the loudness, pitch, and location of the tinnitus (Pinchoff et al., 1998; Levine, 1999), and tinnitus can occur after somatosensory insults (Rubinstein et al., 1990). These observations led to the definition of a “somatic tinnitus” syndrome (Levine et al., 2003) in which an imbalance of bimodal somatosensory–auditory integration was hypothesized as its underlying cause (Levine, 1999; Shore et al., 2007). After noise-induced tinnitus, somatic tinnitus is the second most common type of tinnitus (Eggermont, 2005).