The rationale for recording neural responses in ACx is that it reflects both information generated locally and as well as that inherited from subthreshold inputs. Therefore, recording from sensory cortex allows us to assess the information available to higher decision-making and pre-motor areas [56,57]. Differences in the AM-related information available in ACx is likely to reflect that available in the entire system. A second reason for recording in ACx is that CHL, identical to that studied here, produces synaptic and biophysical changes in ACx [10,12,13], and at least some of these persist in adults [14]. Thus ACx should be one neural region that would explain differences in encoding and ultimately perception. Furthermore, synaptic changes in ACx were not induced by adult-onset CHL [58]. If these and similar changes subserve the effects seen here, adult-manipulated animals would not be expected to differ from controls. Testing adult-onset CHL animals will establish whether hearing loss alone is responsible for the behavioral and neural deficits, or whether the manipulation must occur during development. Ultimately, our data indicate only that auditory deprivation diminishes the neural information about slow sAM signals that is available to the animal. Our physiological recordings were obtained from awake untrained animals, and our neural data indicated that CHL animals have diminished sensory information available to them prior to any training (Fig. 6). It remains to be tested whether training would increase or decrease the magnitude of this deficit. Training can rescue performance and alter tonotopicity and receptor expression in noise-reared animals [59,60,61]. However, it is unknown whether training on an auditory detection task would have the same effect on the neural properties of animals that were manipulated during development, as it would on normal animals. To this point, functional assessments in deprived animals have only employed anesthetized, untrained animals. Although more challenging, the ideal comparison to behavior would be to record from performing, rather than passively listening, trained animals, since responses depend on behavioral state [62,63]. Experiments in awake, performing animals can clarify whether neural encoding continues to reflect behavioral deficits following a period of training. The auditory stimuli used for behavior differed from those used for physiology: for behavior, sAM noise was preceded by broadband noise, whereas for physiology, sAM tones at BF were preceded by silence. A noise carrier was used for the behavior to eliminate the potential for sidebands to evoke a pitch percept at higher MFs, and force the animals to rely on temporal cues. Therefore, it is important to consider whether the differences observed for neural sensitivity could have been enhanced or diminished by the choice of stimulus parameters. The first concern is that the behavioral stimuli contained no sudden transient increase in stimulus energy. To minimize the contribution of the transient onset component to our neurophysiological results, we excluded the first period of each sAM response from our analyses. A second concern is the relative level of response adaptation that would be induced by a continuous signal (behavior) versus a transient signal (neurophysiology). In fact, in vitro analyses suggest that short tem depression of cortical synapses is greater following hearing loss [10,12]. Thus, had we used continuous stimuli for the neurophysiological assay, we might have expected a greater difference between control and CHL neurons; that is, we may have underestimated the neural coding changes effected by CHL. A third concern is the difference in carrier. Published results suggest that there is considerable between-neuron response variability whether AM responses are assessed with tonal or noise carriers. In separate studies, AM responses were characterized in the same, awake species (Rhesus macaque), using tone or noise Hearing Loss Disrupts AM Processing carriers; in a different study, noise and tone carriers were compared in the same anesthetized species (cat) [64,65,66]. There were no systematic differences in responses to noise- versus tone- carrier sAM that would lead us to expect a different result had we chosen to use a noise carrier for our neurophysiological assay. Therefore, we conclude that the differences in neural coding reflect the effects of prolonged hearing loss, although there is some reason to believe that we have underestimated the magnitude of the effect. Effect of Hearing Loss on Modulation Frequency Threshold Amplitude modulation detection thresholds are consistently higher for faster modulation frequencies across many species. Thresholds for 100 Hz MF are typically 5–15% MD higher than those for 5 Hz MF [21,29,67]. This was the case for CTRs, but did not hold true for CHL animals. CTR thresholds were significantly lower (by ,9% MD) for 5 Hz than for 100 Hz, but CHL thresholds were not different across these two modulation frequencies (Fig. 1). Thus, CHL animals were as good as CTRs in detecting fast modulations, and impaired only for slow modula- tions. This poor performance for the CHLs at the lower MF suggests that early-onset hearing loss changes the shape of the temporal modulation transfer function, rather than shifting the entire curve towards higher thresholds. Cortical MTFs parallel this result: while both CTR and CHL MTFs showed bandpass characteristics typical of responses in many species, CHL responses were reduced at lower MFs more than higher (Fig. 5A). Notably, this behavioral effect has also been demonstrated in a study comparing hearing-impaired cochlear implant users: those with early hearing loss displayed higher sAM thresholds primarily at slower modulation frequencies [25]. sAM detection in adult humans with sensorineural hearing loss (SNHL) is not significantly impaired, when effective bandwidth is controlled for, consistent with the idea that the developmental deprivation is necessary for an impairment [68,69,70]. Dyslexic children and adults are similarly impaired in detecting slow compared with fast modula- tions [71,72,73,74]. One implication of this result is that low MF detection is a separate neural process from high MF detection, and that the development of this network is more vulnerable to disuse or other disorders. Locus of Neural Impairment In principle, the poorer sAM detection thresholds displayed by ACx neurons could be due to changes anywhere along the auditory pathway. To address this issue, a comparison can be made to recordings from auditory nerve (AN) fibers. Although AN responses to sAM stimuli following developmental CHL are not available, there is a quantitative assessment of sAM coding in adult animals with noise-induced SNHL. For AN fibers with increased thresholds, envelope coding at 100% MD is enhanced (i.e., better phase-locking) compared to control AN fibers [75]. The AN response characteristics following SNHL differ from those reported here for developmental CHL. They are more consistent with the lack of sAM impairment in SNHL adults, particularly with one study showing increased sAM sensitivity at very low stimulus amplitudes [69]. Although this may reflect a differential effect of age of hearing loss, there are other fundamental dissimilarities in experimental design (e.g., the AN recordings presented 100% MD sAM to anesthetized chinchillas with non- developmental noise-induced hearing loss). The effects reported here may be due, in part, to changes in central processing. The CHL surgery (malleus removal) attenuates sound transmission to the inner ear, but should not compromise PLoS ONE | www.plosone.org 11 July 2012 | Volume 7 | Issue 7 | e41514