**5.3 Gap detection**

The gap detection paradigm determines the minimum duration for the detection of a short period of silence (gap) embedded in a broadband noise pulse. It has been widely used to characterise the temporal resolution of the auditory system. By selecting old human subjects with no or minimal peripheral hearing loss (determined by pure tone audiometry), Snell (1997) demonstrated that mean gap detection thresholds increased with age even in the absence of peripheral hearing loss: some old subjects showed impaired performance, while others retained good temporal resolution, resulting in an increased inter-individual variability of gap detection thresholds in old human subjects. Very similar results were obtained in gerbils (Hamann et al., 2004). When tested with a noise carrier presented 30 dB above the threshold for the carrier, the minimum audible gap in young gerbils was below 4 ms, while approximately 50% of the old gerbils had gap detection thresholds above 4 ms. The variation of the threshold for the noise carrier explained less than 20% of the variation of the gap detection threshold in gerbils. This suggests that peripheral hearing loss was not the dominant cause of impaired temporal resolution. These data point to central auditory processing deficits that result in increased gap detection thresholds in normal hearing old humans and gerbils and are consistent with results obtained by ABR in gerbils (Boettcher et

The Mongolian Gerbil as a Model for

to its interaction with voltage-gated calcium channels.

regarded as a good model for strial or metabolic presbyacusis.

**6. Conclusion** 

the Analysis of Peripheral and Central Age-Dependent Hearing Loss 85

humans and gerbils with respect to gap detection and forward masking makes the gerbil an ideal model to test the effect of candidate substances on performance. Some anti-convulsive

For our first study, we chose to analyse the effect of Sabril® (vigabatrin) on gap detection (Gleich et al., 2003). Vigabatrin blocks the GABA converting enzyme GABA transaminase and consequently leads to elevated levels of GABA in the brain. The effect of vigabatrin at a dose of 50 mg/kg/day was dependent on the initial gap detection threshold. Performance in gerbils with initially low gap detection thresholds were not systematically affected by the drug, while those with initially elevated gap detection thresholds improved and normalised to a level comparable to sensitive animals. The beneficial effect of vigabatrin on impaired gap detection was reversible, with gap detection thresholds increasing after the end of the treatment. These data clearly demonstrate the potential use of pharmacotherapy for the treatment of impaired auditory temporal resolution. Unfortunately, severe side effects on the visual system prevent the therapeutic use of vigabatrin for the treatment of hearing loss. In a subsequent study, we evaluated the effect of gabapentin on gap detection and forward masking in gerbils, since other studies suggested beneficial effects of gabapentin for certain forms of tinnitus (Gleich & Strutz, 2011). Gabapentin was initially designed as a GABA analogue for the treatment of epilepsy and is also used for the treatment of neuropathic pain. In gerbils, gabapentin had no beneficial effect on impaired gap detection or on elevated masked thresholds. Unexpectedly, the data showed that gapapentin at a dose of 350 mg/kg/day increased masked thresholds in young gerbils, while it had no significant effect in old gerbils that had elevated masked thresholds before gabapentin treatment. The lack of a beneficial effect on impaired gap detection and increased forward masking in old gerbils could be due to an insufficient effect of gabapentin on the GABA system, while the increased masked thresholds of young gerbils during gabapentin treatment might be related

At the level of the cochlea, pathology begins to affect the marginal cells of the stria vascularis and eventually leads to a reduction of the endocochlear potential in old gerbils. Loss of hair cells and loss of auditory nerve fibres and spiral ganglion cells are not major contributors to age-dependent peripheral hearing loss. Consequently, gerbils can be

Behavioural and evoked potential (CAP, ABR) measures of auditory sensitivity are useful to characterise hearing status; however, the degree of age-dependent threshold elevation depends on the method used: the discrepancy between thresholds determined psychoacoustically and by evoked potentials increases with age; evoked potentials indicate

Auditory nuclei in the ascending auditory pathway of gerbils show specific and distinct agedependent structural changes, where some nuclei appear more affected than others. Structural changes in nuclei involved in binaural processing are associated with impaired auditory spatial resolution in old gerbils. For LSO and MSO, the degree of age-dependent pathology in gerbils can be correlated with age-dependent changes in human performance

more threshold loss than behavioural methods in old gerbils and old humans.

drugs in the context of epilepsy were designed to interact with the GABA system.

al., 1996). The similarity of age-dependent changes in gap detection by humans and gerbils emphasises the usefulness of the gerbil model for the analysis of impaired auditory temporal processing.

#### **5.4 Forward masking**

Forward masking is a phenomenon through which threshold for a probe that follows a signal (masker) is elevated (masked) and recovers with time (≈ 100 ms) following the end of the masker. Increased masking and delayed recovery from preceding acoustic stimulation interferes with the detection of fluctuations and transients in sound signals and might contribute to age-dependent impairment of speech perception. In the analysis of the effect of age on forward masking in gerbils (Gleich et al., 2007a) a 2.85 kHz masker presented at 40 dBSPL and repeated continuously every 1.6 seconds served as a constant background signal. Animals had to detect trials where a short 2.85 kHz probe signal (20 ms) was presented 2.5 ms after the end of the masker. In addition to the masked threshold, the threshold for the probe signal without a masker was determined to characterise peripheral hearing. In a sample of 15 gerbils between 5 and 36 months of age, threshold for the probe in quiet was independent of age (mean 12 dBSPL). These animals showed no sign of peripheral hearing loss. In contrast, the masked thresholds of these gerbils increased from around 33 dB SPL at 1 year of age to 48 dBSPL at an age of 3 years. The efficacy of the masker increased by 15 dB between 1 and 3 years of age. The increased degree of forward masking in old gerbils in the absence of elevated thresholds in the condition without a masker suggests a deficit in central, rather than peripheral, auditory processing. An analysis of forward masking using ABR in humans also demonstrated increased forward masking in old subjects with normal audiometric thresholds and led to the conclusion that this was likely due to changes in central auditory processing (Walton et al., 1999). Thus, gerbils appear to be a useful model for the analysis of the interaction of age and forward masking.

#### **5.5 Auditory spatial resolution**

Age-dependent structural changes in auditory nuclei involved in binaural processing have been discussed above (see headings 4.2.3-4.2.5). Consistent with the pathology in MNTB, MSO and LSO, auditory spatial resolution was impaired in old gerbils (Maier et al., 2008). The minimum resolvable angle in a sound lateralisation task showed a higher degree of inter-animal variability in old (32 to 51 months), as compared to young (3-8 months), gerbils. The angle for pure tones (0.5 and 8 kHz) and narrowband noise centred at 0.5 and 2 kHz was ≈ 50-60° in old gerbils, approximately twice the angle found in young gerbils. Maier et al. (2008) suggest that spongiform lesions in the VCN compromise the excitatory input, while pathology of the MNTB affects the inhibitory input to LSO and MSO and contribute to impaired auditory spatial resolution in old gerbils.

#### **5.6 Pharmacotherapy**

The available data indicate that ageing is associated with a loss of inhibition in the central auditory pathway, which could contribute to impaired auditory temporal processing (Caspary et al., 2008). Age-dependent changes in neurotransmitter systems might be influenced by pharmacotherapy and the similarity of age-dependent deficits between humans and gerbils with respect to gap detection and forward masking makes the gerbil an ideal model to test the effect of candidate substances on performance. Some anti-convulsive drugs in the context of epilepsy were designed to interact with the GABA system.

For our first study, we chose to analyse the effect of Sabril® (vigabatrin) on gap detection (Gleich et al., 2003). Vigabatrin blocks the GABA converting enzyme GABA transaminase and consequently leads to elevated levels of GABA in the brain. The effect of vigabatrin at a dose of 50 mg/kg/day was dependent on the initial gap detection threshold. Performance in gerbils with initially low gap detection thresholds were not systematically affected by the drug, while those with initially elevated gap detection thresholds improved and normalised to a level comparable to sensitive animals. The beneficial effect of vigabatrin on impaired gap detection was reversible, with gap detection thresholds increasing after the end of the treatment. These data clearly demonstrate the potential use of pharmacotherapy for the treatment of impaired auditory temporal resolution. Unfortunately, severe side effects on the visual system prevent the therapeutic use of vigabatrin for the treatment of hearing loss.

In a subsequent study, we evaluated the effect of gabapentin on gap detection and forward masking in gerbils, since other studies suggested beneficial effects of gabapentin for certain forms of tinnitus (Gleich & Strutz, 2011). Gabapentin was initially designed as a GABA analogue for the treatment of epilepsy and is also used for the treatment of neuropathic pain. In gerbils, gabapentin had no beneficial effect on impaired gap detection or on elevated masked thresholds. Unexpectedly, the data showed that gapapentin at a dose of 350 mg/kg/day increased masked thresholds in young gerbils, while it had no significant effect in old gerbils that had elevated masked thresholds before gabapentin treatment. The lack of a beneficial effect on impaired gap detection and increased forward masking in old gerbils could be due to an insufficient effect of gabapentin on the GABA system, while the increased masked thresholds of young gerbils during gabapentin treatment might be related to its interaction with voltage-gated calcium channels.
