Salicylate toxicity model of tinnitus

Salicylate, the active component of the common drug aspirin, has mild analgesic, antipyretic, and anti-inflammatory effects at moderate doses. At higher doses, however, salicylate temporarily induces moderate hearing loss and the perception of a high-pitch ringing in humans and animals. This phantom perception of sound known as tinnitus is qualitatively similar to the persistent subjective tinnitus induced by high-level noise exposure, ototoxic drugs, or aging, which affects ∼14% of the general population. For over a quarter century, auditory scientists have used the salicylate toxicity model to investigate candidate biochemical and neurophysiological mechanisms underlying phantom sound perception. In this review, we summarize some of the intriguing biochemical and physiological effects associated with salicylate-induced tinnitus, some of which occur in the periphery and others in the central nervous system. The relevance and general utility of the salicylate toxicity model in understanding phantom sound perception in general are discussed

Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2′-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis

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

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)

Gap-induced reductions of evoked potentials in the auditory cortex: a possible objective marker for the presence of tinnitus in animals

Animal models of tinnitus are essential for determining the underlying mechanisms and testing pharmacotherapies. However, there is doubt over the validity of current behavioural methods for detecting tinnitus. Here, we applied a stimulus paradigm widely used in a behavioural test (gap-induced inhibition of the acoustic startle reflex GPIAS) while recording from the auditory cortex, and showed neural response changes that mirror those found in the behavioural tests. We implanted guinea pigs (GPs) with electrocorticographic (ECoG) arrays and recorded baseline auditory cortical responses to a startling stimulus. When a gap was inserted in otherwise continuous background noise prior to the startling stimulus, there was a clear reduction in the subsequent evoked response (termed gap-induced reductions in evoked potentials; GIREP), suggestive of a neural analogue of the GPIAS test. We then unilaterally exposed guinea pigs to narrowband noise (left ear; 8-10 kHz; 1 hour) at one of two different sound levels - either 105 dB SPL or 120 dB SPL – and recorded the same responses seven-to-ten weeks following the noise exposure. Significant deficits in GIREP were observed for all areas of the auditory cortex (AC) in the 120 dB-exposed GPs, but not in the 105 dB-exposed GPs. These deficits could not simply be accounted for by changes in response amplitudes. Furthermore, in the contralateral (right) caudal AC we observed a significant increase in evoked potential amplitudes across narrowband background frequencies in both 105 dB and 120 dB-exposed GPs. Taken in the context of the large body of literature that has used the behavioural test as a demonstration of the presence of tinnitus, these results are suggestive of objective neural correlates of the presence of noise-induced tinnitus and hyperacusis

AHC interview with Alexander Stolzberg.

March 13, 20170:00:00-0:06:50 short summary of life story0:06:50-0:08:00 grandparents0:08:00-0:08:50 grandparent's descent0:08:50-0:09:40 parents’ occupation0:09:40-0:11:05 religion0:11:05-0:11:45 Hebrew/Yiddish spoken in the family0:11:45-0:12:45 location of home in Vienna0:12:45-0:13:50 neighborhood0:13:50-0:15:15 parental friends (were they mainly Jewish?)0:15:15-0:16:05 description of home0:16:05-0:17:00 schools attended0:17:00-0:19:40 the day of the Anschluss, arrest of father0:19:40-0:20:50 fleeing Austria for Yugoslavia0:20:50-0:22:50 Germans invade Yugoslavia in 1941; flight to Hungary0:22:50-0:26:15 Belgrade and Subotica0:26:15-0:31:45 internment camp Kistarcsa, Raoul Wallenberg, Red Cross camp0:31:45-0:32:35 liberation0:32:35-0:34:15 jail in Subotica0:34:15-0:36:15 life in the Red Cross home0:36:15-0:37:15 the day of liberation0:37:15-0:41:30 liberation of Auschwitz, mother searches for Alexander and his brother0:41:30-0:44:35 London0:44:35-0:47:05 mother's search for Alexander and his brother; Hias0:47:05-0:50:00 life in London0:50:00-0:51:30 immigration to US0:51:30-56:50 life in New York56:50-57:30 November pogrom57:30-1:00:00 antisemitism after the war1:01:00-1:03:30 work in London1:03:30-1:07:15 Israel1:07:15-1:10:00 Israeli-Palestinian conflict1:10:00-1:11:15 remaining connections to Austria1:11:15-1:12:35 revisiting Austria1:12:35-1:13:45 German language1:13:45-1:14:40 children1:14:40 present political situation and final statementAlexander Stolzberg was born in 1934 in Vienna, Austria. He lived with his parents and his brother in an apartment building like many others in Vienna’s 2nd District; their home was directly above the father’s grocery store in Glockengasse. Shortly after the “Anschluss” Alexander’s father died, but the family stayed in Vienna until 1940. At that point they decided that it was necessary to leave Austria, and they fled illegally to Yugoslavia. After staying with relatives for a while, the Stolzbergs went on to Belgrade, where they lived for six months. When the Germans attacked, the family fled to Hungary, where they lived in Hungarian occupied Subotica. In 1944 they were arrested and sent to the internment camp Kistarcsa close to Budapest. After approximately four weeks, Alexander and his brother got the chance to live in a Red Cross home. This was arranged for them by Raoul Wallenberg, who saved tens of thousands of Jews in Nazi-occupied Hungary. The two brothers stayed in the Red Cross home until the Russian army liberated Budapest, and they were freed. Their mother was deported to Auschwitz, where she survived. She returned to post-war Hungary to look for her sons and found them outside of Budapest, where they had been taken care of by the organization Hias. The Stolzbergs stayed in Budapest until the middle of 1946, when relatives in London took Alexander and his brother out of Hungary. They stayed in London for a couple of years, before Alexander got a visa for the United States, where he went to College and got a government job.Austrian Heritage Collectio

Effects of neonatal deafness on resting-state functional network connectivity.

Normal brain development depends on early sensory experience. Behavioral consequences of brain maturation in the absence of sensory input early in life are well documented. For example, experiments with mature, neonatally deaf human or animal subjects have revealed improved peripheral visual motion detection and spatial localization abilities. Such supranormal behavioral abilities in the nondeprived sensory modality are evidence of compensatory plasticity occurring in deprived brain regions at some point or throughout development. Sensory deprived brain regions may simply become unused neural real-estate resulting in a loss of function. Compensatory plasticity and loss of function are likely reflected in the differences in correlations between brain networks in deaf compared with hearing subjects. To address this, we used resting-state functional magnetic resonance imaging (fMRI) in lightly anesthetized hearing and neonatally deafened cats. Group independent component analysis (ICA) was used to identify 20 spatially distinct brain networks across all animals including auditory, visual, somatosensory, cingulate, insular, cerebellar, and subcortical networks. The resulting group ICA components were back-reconstructed to individual animal brains. The maximum correlations between the time-courses associated with each spatial component were computed using functional network connectivity (FNC). While no significant differences in the delay to peak correlations were identified between hearing and deaf cats, we observed 10 (of 190) significant differences in the amplitudes of between-network correlations. Six of the significant differences involved auditory-related networks and four involved visual, cingulate, or somatosensory networks. The results are discussed in context of known behavioral, electrophysiological, and anatomical differences following neonatal deafness. Furthermore, these results identify novel targets for future investigations at the neuronal level