Reversing pathological neural activity using targeted plasticity

Frontiers in systems neuroscience, 2012

Sensory training therapies for tinnitus are based on the assumption that, notwithstanding neural changes related to tinnitus, auditory training can alter the response properties of neurons in auditory pathways. To assess this assumption, we investigated whether brain changes induced by sensory training in tinnitus sufferers and measured by electroencephalography (EEG) are similar to those induced in age and hearing loss matched individuals without tinnitus trained on the same auditory task. Auditory training was given using a 5 kHz 40-Hz amplitude-modulated (AM) sound that was in the tinnitus frequency region of the tinnitus subjects and enabled extraction of the 40-Hz auditory steady-state response (ASSR) and P2 transient response known to localize to primary and non-primary auditory cortex, respectively. P2 amplitude increased over training sessions equally in participants with tinnitus and in control subjects, suggesting normal remodeling of non-primary auditory regions in tinnit...

Hearing Research, 2015

Tinnitus, the phantom perception of sound, is physiologically characterized by an increase in spontaneous neural activity in the central auditory system. However, as tinnitus is often associated with hearing impairment, it is unclear how a decrease of afferent drive can result in central hyperactivity. In this review, we first assess methods for tinnitus induction and objective measures of the tinnitus percept in animal models. From animal studies, we discuss evidence that tinnitus originates in the cochlear nucleus (CN), and hypothesize mechanisms whereby hyperactivity may develop in the CN after peripheral auditory nerve damage. We elaborate how this process is likely mediated by plasticity of auditory esomatosensory integration in the CN: the circuitry in normal circumstances maintains a balance of auditory and somatosensory activities, and loss of auditory inputs alters the balance of auditory somatosensory integration in a stimulus timing dependent manner, which propels the circuit towards hyperactivity. Understanding the mechanisms underlying tinnitus generation is essential for its prevention and treatment.

Frontiers in Systems Neuroscience

Tinnitus is one of the most prevalent auditory disorders worldwide, manifesting in both chronic and acute forms. The pathology of tinnitus has been mechanistically linked to induction of harmful neural plasticity stemming from traumatic noise exposure, exposure to ototoxic medications, input deprivation from age-related hearing loss, and in response to injuries or disorders damaging the conductive apparatus of the ears, the cochlear hair cells, the ganglionic cells of the VIIIth cranial nerve, or neurons of the classical auditory pathway which link the cochlear nuclei through the inferior colliculi and medial geniculate nuclei to auditory cortices. Research attempting to more specifically characterize the neural plasticity occurring in tinnitus have used a wide range of techniques, experimental paradigms, and sampled at different windows of time to reach different conclusions about why and which specific brain regions are crucial in the induction or ongoing maintenance of tinnitus-related plasticity. Despite differences in experimental methodologies, evidence reveals similar findings that strongly suggest that immediate and prolonged activation of non-classical auditory structures (i.e., amygdala, hippocampus, and cingulate cortex) may contribute to the initiation and development of tinnitus in addition to the ongoing maintenance of this devastating condition. The overarching focus of this review, therefore, is to highlight findings from the field supporting the hypothesis that abnormal early activation of non-classical sensory limbic regions are involved in tinnitus induction, with activation of these regions continuing to occur at different temporal stages. Since initial/early stages of tinnitus are difficult to control and to quantify in human clinical populations, a number of different animal paradigms have been developed and assessed in experimental investigations. Reviews of traumatic noise exposure and ototoxic doses of sodium salicylate, the most prevalently used animal models to induce experimental tinnitus, indicate early limbic

Orl-journal for Oto-rhino-laryngology and Its Related Specialties, 2006

The Laryngoscope, 2017

Objective: This proof-of-concept study aimed to demonstrate therapeutic effects of deep brain stimulation (DBS) on noise-induced tinnitus. Study Design: Experimental animal study. Methods: After Institutional Animal Care and Use Committee approval, nine adult rats were implanted in the caudate nucleus with custom-made electrode array. The rats were exposed to noise to induce tinnitus. Auditory brainstem response was performed to evaluate hearing threshold changes. Noise-induced tinnitus and its suppression by DBS were evaluated using the gap-detection acoustic startle reflex behavioral paradigm and electrophysiological evaluation of modulatory effects on neural correlates of tinnitus. Various stimulation parameters were used to determine the most effective ones in affecting behavioral changes, along with corresponding neural activity in the caudate nucleus. The correlation between the caudate nucleus and auditory cortex also was determined. Analysis of variance with Bonferroni correction was performed to examine DBS-induced effects on behavioral evidence of tinnitus. Results: Bursting activity, a neural marker of tinnitus, was noted to decrease compared to baseline in tinnitus (1) animals. After stimulation, spontaneous and bursting activity increased in the tinnitus (1) animals but decreased in the tinnitus (2) animals. Behavioral data suggested suppression of tinnitus after DBS. These effects lasted up to 5 days. To our knowledge, this is the first development of an animal model to test deep brain stimulation of the caudate region for the treatment of tinnitus. Conclusions: Deep brain stimulation of the caudate nucleus can modulate tinnitus in a rat model of tinnitus.

HNO, 2015

Frontiers in Neuroscience, 2021

Tinnitus, a phantom auditory perception that can seriously affect quality of life, is generally triggered by cochlear trauma and associated with aberrant activity throughout the auditory pathways, often referred to as hyperactivity. Studies suggest that non-auditory structures, such as prefrontal cortex (PFC), may be involved in tinnitus generation, by affecting sensory gating in auditory thalamus, allowing hyperactivity to reach the cortex and lead to perception. Indeed, human studies have shown that repetitive transcranial magnetic stimulation (rTMS) of PFC can alleviate tinnitus. The current study investigated whether this therapeutic effect is achieved through inhibition of thalamic hyperactivity, comparing effects of two common clinical rTMS protocols with sham treatment, in a guinea pig tinnitus model. Animals underwent acoustic trauma and once tinnitus developed were treated with either intermittent theta burst stimulation (iTBS), 20 Hz rTMS, or sham rTMS (10 days, 10 min/day...

Brain Stimulation, 2014

Background: The final common pathway in tinnitus generation is considered to be synchronized auditory oscillatory hyperactivity. Intracranial auditory cortex stimulation (iACS) via implanted electrodes has been developed to treat severe cases of intractable tinnitus targeting this final common pathway, in the hope of being a panacea for tinnitus.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

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.

The Journal of Neuroscience, 2012

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.