Reductions in cortical alpha activity, enhancements in neural responses and impaired gap detection caused by sodium salicylate in awake guinea pigs

Abstract

Tinnitus chronically affects between 10-15% of the population but, despite its prevalence, the underlying mechanisms are still not properly understood. One experimental model involves administration of high doses of sodium salicylate, as this is known to reliably induce tinnitus in both humans and animals. Guinea pigs were implanted with chronic electrocorticography (ECoG) electrode arrays, with silver-ball electrodes placed on the dura over left and right auditory cortex. Two more electrodes were positioned over the cerebellum to monitor auditory brainstem responses (ABRs). We recorded resting-state and auditory evoked neural activity from awake animals before and 2 h following salicylate administration (350 mg/kg; i.p.). Large increases in click-evoked responses (> 100%) were evident across the whole auditory cortex, despite significant reductions in wave I ABR amplitudes (in response to 20 kHz tones), which are indicative of auditory nerve activity. In the same animals, significant decreases in 6-10 Hz spontaneous oscillations (alpha waves) were evident over dorsocaudal auditory cortex. We were also able to demonstrate for the first time that cortical evoked potentials can be inhibited by a preceding gap in background noise [gap-induced pre-pulse inhibition (PPI)], in a similar fashion to the gap-induced inhibition of the acoustic startle reflex that is used as a behavioural test for tinnitus. Furthermore, 2 h following salicylate administration, we observed significant deficits in PPI of cortical responses that were closely aligned with significant deficits in behavioural responses to the same stimuli. Together, these data are suggestive of neural correlates of tinnitus and oversensitivity to sound (hyperacusis).

Effects of the cannabinoid CB 1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs

“…Contrastingly, cortical evoked responses are enhanced following salicylate administration ( Yang et al., 2007 , Sun et al., 2009 , Norena et al., 2010 , Berger et al., 2017 ), suggestive of a neural correlate of hyperacusis. Furthermore, reductions in alpha band activity are evident in the auditory cortex of animals following salicylate administration ( Stolzberg et al., 2013 , Berger et al., 2017 ), which have been suggested as a correlate of reduced inhibition related to the presence of tinnitus in humans ( Weisz et al., 2005 , Lorenz et al., 2009 ).…”

“… Jastreboff et al., 1988 , Lobarinas et al., 2006 , Berger et al., 2013 , Berger et al., 2017 ), as opposed to the variability observed following noise exposure. Furthermore, these effects are rapid, evident within 2 h in an animal model ( Stolzberg et al., 2011 , Berger et al., 2017 ). It is therefore a useful tool to enable researchers to more easily test whether particular drugs are effective in attenuating neural effects relating to these conditions.…”

“…Sodium salicylate, the primary metabolite of aspirin in the body ( Proost et al., 1983 ), is commonly used experimentally in animals, as it is known to cause a variety of auditory effects, including tinnitus, hyperacusis and temporary hearing loss ( Mongan et al., 1973 , Mcfadden et al., 1984 , Day et al., 1989 , Cazals, 2000 , Zhang et al., 2014 ). Ototoxic effects of salicylate are evident in (1) reduced distortion product otoacoustic emissions (DPOAEs) ( Wier et al., 1988 , Stolzberg et al., 2011 ), indicative of reduced outer hair cell activity; 2) a reduction in wave I auditory brainstem responses (ABRs; Berger et al., 2017 ), indicative of reduced spiral ganglion activity; and 3) reduced amplitude of cochlear compound action potentials ( Muller et al., 2003 , Stolzberg et al., 2011 ), indicative of reduced cochlear sensitivity, particularly at high frequencies. Contrastingly, cortical evoked responses are enhanced following salicylate administration ( Yang et al., 2007 , Sun et al., 2009 , Norena et al., 2010 , Berger et al., 2017 ), suggestive of a neural correlate of hyperacusis.…”

“…Ototoxic effects of salicylate are evident in (1) reduced distortion product otoacoustic emissions (DPOAEs) ( Wier et al., 1988 , Stolzberg et al., 2011 ), indicative of reduced outer hair cell activity; 2) a reduction in wave I auditory brainstem responses (ABRs; Berger et al., 2017 ), indicative of reduced spiral ganglion activity; and 3) reduced amplitude of cochlear compound action potentials ( Muller et al., 2003 , Stolzberg et al., 2011 ), indicative of reduced cochlear sensitivity, particularly at high frequencies. Contrastingly, cortical evoked responses are enhanced following salicylate administration ( Yang et al., 2007 , Sun et al., 2009 , Norena et al., 2010 , Berger et al., 2017 ), suggestive of a neural correlate of hyperacusis. Furthermore, reductions in alpha band activity are evident in the auditory cortex of animals following salicylate administration ( Stolzberg et al., 2013 , Berger et al., 2017 ), which have been suggested as a correlate of reduced inhibition related to the presence of tinnitus in humans ( Weisz et al., 2005 , Lorenz et al., 2009 ).…”

“…While there may be differences in the mechanisms underlying the effects of salicylate and noise exposure, which is the primary cause of these conditions in humans, salicylate is particularly useful as it reliably induces tinnitus, hyperacusis and hearing loss in animals when administered at a high dose (e.g. Jastreboff et al., 1988 , Lobarinas et al., 2006 , Berger et al., 2013 , Berger et al., 2017 ), as opposed to the variability observed following noise exposure. Furthermore, these effects are rapid, evident within 2 h in an animal model ( Stolzberg et al., 2011 , Berger et al., 2017 ).…”