The effects of repetitive transcranial magnetic stimulation in an animal model of tinnitus.

Tinnitus (phantom auditory perception associated with hearing loss) can seriously affect wellbeing. Its neural substrate is unknown however it has been linked with abnormal activity in auditory pathways. Though no cure currently exists, repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce tinnitus in some patients, possibly via induction of cortical plasticity involving brain derived neurotrophic factor (BDNF). We examined whether low intensity rTMS (LI-rTMS) alleviates signs of tinnitus in a guinea pig model and whether this involves changes in BDNF expression and hyperactivity in inferior colliculus. Acoustic trauma was used to evoke hearing loss, central hyperactivity and tinnitus. When animals developed tinnitus, treatment commenced (10 sessions of 10 minutes 1 Hz LI-rTMS or sham over auditory cortex over 14 days). After treatment ceased animals were tested for tinnitus, underwent single-neuron recordings in inferior colliculus to assess hyperactivity and samples from cortex and inferior colliculus were taken for BDNF ELISA. Analysis revealed a significant reduction of tinnitus after LI-rTMS compared to sham, without a statistical significant effect on BDNF levels or hyperactivity. This suggests that LI-rTMS alleviates behavioural signs of tinnitus by a mechanism independent of inferior colliculus hyperactivity and BDNF levels and opens novel therapeutic avenues for tinnitus treatment.

Influence of the paraflocculus on normal and abnormal spontaneous firing rates in the inferior colliculus.

Spontaneous firing rates of neurons in the central auditory pathway, such as in the inferior colliculus, are known to be increased after cochlear trauma. This so-called hyperactivity is thought to be involved in the generation of tinnitus, a phantom auditory perception. Recent research in an animal model suggests behavioural signs of tinnitus can be significantly reduced by silencing or removal of the paraflocculus (PF) of the cerebellum. The current study investigated the effects of acute PF removal on spontaneous firing rates recorded from single neurons in the right inferior colliculus of guinea pigs with normal hearing (which did not receive acoustic trauma) or with hearing loss caused by acoustic trauma. Spontaneous firing rates were obtained at either 2 or 13 weeks after initial surgery on the left side. In half of the animals in each group the left PF was removed immediately prior to the spontaneous firing rates recordings. In the acoustic trauma groups, spontaneous firing rates in the inferior colliculus were higher when the PF was removed compared to animals with an intact PF. This effect of PF removal was not observed in animals that did not receive acoustic trauma. These results suggest that the PF has a tonic inhibitory effect on hyperactivity in the inferior colliculus in animals with hearing loss, but not on normal spontaneous firing rates in normal hearing animals.

Spontaneous hyperactivity in the auditory midbrain: relationship to afferent input.

Hyperactivity in the form of increased spontaneous firing rates of single neurons develops in the guinea pig inferior colliculus (IC) after unilateral loud sound exposures that result in behavioural signs of tinnitus. The hyperactivity is found in those parts of the topographic frequency map in the IC where neurons possess characteristic frequencies (CFs) closely related to the region in the cochlea where lasting sensitivity changes occur as a result of the loud sound exposure. The observed hyperactivity could be endogenous to the IC, or it could be driven by hyperactivity at lower stages of the auditory pathway. In addition to the dorsal cochlear nucleus (DCN) hyperactivity reported by others, specific cell types in the ventral cochlear nucleus (VCN) also show hyperactivity in this animal model suggesting that increased drive from several regions of the lower brainstem could contribute to the observed hyperactivity in the midbrain. In addition, spontaneous afferent drive from the cochlea itself is necessary for the maintenance of hyperactivity up to about 8 weeks post cochlear trauma. After 8 weeks however, IC hyperactivity becomes less dependent on cochlear input, suggesting that central neurons transition from a state of hyperexcitability to a state in which they generate their own endogenous firing. The results suggest that there might be a "therapeutic window" for early-onset tinnitus, using treatments that reduce cochlear afferent firing.

Acoustic trauma evokes hyperactivity and changes in gene expression in guinea-pig auditory brainstem.

Hearing loss from acoustic trauma is a risk factor for tinnitus. Animal models using acoustic trauma have demonstrated hyperactivity in central auditory pathways, which has been suggested as a substrate for tinnitus. We used a guinea-pig model of unilateral acoustic trauma. Within the same animals, measurements of peripheral hearing loss, spontaneous activity of single neurons in the inferior colliculus and gene expression in cochlear nucleus and inferior colliculus were combined, acutely and after recovery from acoustic trauma. Genes investigated related to inhibitory (GABA-A receptor subunit alpha 1; glycine receptor subunit alpha 1) and excitatory neurotransmission (glutamate decarboxylase 1; glutamate receptor AMPA subunit alpha 2; glutamate receptor NMDA subunit 1), regulation of transmitter release (member of RAB family of small GTPase; RAB3 GTPase activating protein subunit 1) and neuronal excitability (potassium channel subfamily K member 15). Acoustic trauma resulted in unilateral hearing loss and hyperactivity bilaterally in inferior colliculus. Changes in expression of different mRNAs were observed in ipsilateral cochlear nucleus and in ipsi- and contralateral inferior colliculus, immediately after acoustic trauma, and after 2 and 4 weeks' recovery. Gene expression was generally reduced immediately after trauma, followed by a return to near normal levels or over-expression as recovery time increased. Different mechanisms appear to underlie the spontaneous hyperactivity observed. There is evidence of down-regulation of genes associated with neuronal inhibition in the contralateral inferior colliculus, whereas in ipsilateral cochlear nucleus, competing actions of inhibitory and excitatory systems seem to play a major role in determining overall excitability.