Perinatal Asphyxia Affects Rat Auditory Processing: Implications for Auditory Perceptual Impairments in Neurodevelopmental Disorders

Perinatal asphyxia, a naturally and commonly occurring risk factor in birthing, represents one of the major causes of neonatal encephalopathy with long term consequences for infants. Here, degraded spectral and temporal responses to sounds were recorded from neurons in the primary auditory cortex (A1) of adult rats exposed to asphyxia at birth. Response onset latencies and durations were increased. Response amplitudes were reduced. Tuning curves were broader. Degraded successive-stimulus masking inhibitory mechanisms were associated with a reduced capability of neurons to follow higher-rate repetitive stimuli. The architecture of peripheral inner ear sensory epithelium was preserved, suggesting that recorded abnormalities can be of central origin. Some implications of these findings for the genesis of language perception deficits or for impaired language expression recorded in developmental disorders, such as autism spectrum disorders, contributed to by perinatal asphyxia, are discussed

Generative processing underlies the mutual enhancement of arithmetic fluency and math-grounding number sense

International audienceNumber skills are popularly bound to arithmetic knowledge in its symbolic form, such as " five + nine = fourteen, " but mounting evidence suggests that these symbolic relations are actually grounded, i.e., computed (see Harnad, 1990) on noisy internal magnitude representations that bear our general understanding of numbers and further improve with math experience (Figure 1). Multiple lines of evidence support the idea of semantics-based arithmetic, including behavioral research on humans (Gallistel and Gelman, 1992), animals (Gallistel and Gelman, 2000; Rugani et al., 2009), development (Halberda et al., 2008), mathematical disability, i.e., dyscalculia (Butterworth, 1999; review, Butterworth et al., 2011), and computational model-ing (Stoianov et al., 2004; review, Zorzi et al., 2005). Even more intimate relation between the number skills and the internal noisy magnitudes was recently demonstrated in several studies showing finer magnitude representations in subjects with greater arithmetic fluency (e.g., Nys et al., 2013; Piazza et al., 2013), also caused by extensive math studying during higher education (Lindskog et al., 2014). Here we discuss how these findings could be explained within a generative framework of cognition, according to which top-down predictive connections play a key role in the computing of low-to high-level representations (e.g., Friston, 2010; Clark, 2013). The noisy internal magnitude representations also known as Approximate Number System (ANS), or Number Sense are systematically found in the intraparietal silcus and prefrontal cor-tices (Dehaene, 1997; Viswanathan and Nieder, 2013) and one principle method to investigate them is to characterize the ability to quickly and approximately estimate the number of objects seen (Jevons, 1871). This phylogenetic ability is qualified as a visual sense (Burr and Ross, 2008), the mechanism of which emerged in generative neural networks that learn to efficiently encode visual numerosities (Stoianov and Zorzi, 2012). One crucial property of the internal magnitude representations is their systematically increasing imprecision (Figure 1; Gallistel and Gelman, 2000; Dehaene, 2003) characterized by a subject-specific constant known as ANS acuity (Halberda et al., 2008), which at the behavioral level is associated with log-linear performance decrement as the magnitude increases. In numerosity comparison, the probability to select the greater numerosity is a sigmoid function of the log-ratio of the compared magnitudes that is characterized by a dis-criminability (Weber) fraction w describing the slope of the sigmoid, whereby the better the discriminability, the closer is the sigmoid to a step-function, for which w = 0 (Piazza et al., 2013; Cappelletti et al., 2014). The behavioral discriminabil-ity coefficient w is closely related to the internal ANS acuity (Piazza et al., 2013). The ANS acuity progressively improves along with development, with corresponding w = 1 in the first few months of life to about w = 0.24 in healthy adults (Piazza et al., 2010), to worsen then with ageing to more than w = 0.30 (Cappelletti et al., 2014). The intriguing question we explore here is whether ANS improves along with refinement of the mathematical knowledge it supports, that is, whether math-studying improves general quantity understanding. A hint about this was provided by a study on a curious Amazonian Mundurucù population with two levels of math education (Piazza et al., 2013). The effect of math-studying on ANS acu-ity, controlling for age, was impressive: w = 0.31 for adults that had never studied math and w = 0.19 for math-educated adults. Sure, this is a study on a particular population, with an educational system that permitted to find subjects allowing the dissociation between age and education (see also Nys et al., 2013), and it remained unclear whether prolonged math schooling in cultures with broad educational system is associated with further improvement of the ANS. Lindskog et al. (2014) investigated this issue with first-and third-year university students majoring in disciplines with various levels of initial math-expertise and amount of math-studying, ranked in the order: humanity-disciplines, with expected basic math-background, and no math-studying, business-disciplines with average math-background and applied math-studying, and math-disciplines with high math proficiency and mostly theoretical math-studying. The ANS-acuity of the students was evaluated using visual numerosity comparison tasks and supplementary assessment measured their arithmetic fluency. Overall, the arithmetic fluency increased along with the rank of the math-expertise and similarly, th

Perinatal asphyxia affects rat auditory processing: implications for auditory perceptual impairments in neurodevelopmental disorders.

Perinatal asphyxia, a naturally and commonly occurring risk factor in birthing, represents one of the major causes of neonatal encephalopathy with long term consequences for infants. Here, degraded spectral and temporal responses to sounds were recorded from neurons in the primary auditory cortex (A1) of adult rats exposed to asphyxia at birth. Response onset latencies and durations were increased. Response amplitudes were reduced. Tuning curves were broader. Degraded successive-stimulus masking inhibitory mechanisms were associated with a reduced capability of neurons to follow higher-rate repetitive stimuli. The architecture of peripheral inner ear sensory epithelium was preserved, suggesting that recorded abnormalities can be of central origin. Some implications of these findings for the genesis of language perception deficits or for impaired language expression recorded in developmental disorders, such as autism spectrum disorders, contributed to by perinatal asphyxia, are discussed

Altered inhibitory mechanisms in PA rats.

<p>(<b>A</b>) TC tips recorded for three best frequencies in control (grey) and PA (black) rats. The peak of each tip, derived from a single neurons sample, represents the CF or preferred frequency. Lines, connecting peaks and TC edges 20 dB above threshold, represent bandwidth of TCs 10 and 20 dB above each neuron's threshold (BW10 and BW20 respectively). TC bandwidths 10 and 20 dB above thresholds were significantly broader in PA rats. (<b>B</b>) Plot summarizing differences in bandwidth measured in octaves. A1 neuronal BW10 and BW20 were significantly broader in PA rats (asterisks; <i>U-test</i> p<0.05). (<b>C</b>) <i>Left panels</i> show representative examples of TCs obtained from one control (<i>Upper</i>) and one PA rat (<i>Lower</i>) with similar spectral features. <i>Center</i> and <i>right</i> show representative examples of simultaneous (<i>Center</i>) and forward (<i>Right</i>) masking inhibitions obtained with two-tone stimuli paradigms. (<b>D</b>) Plot summarizing the number of responses to probes inhibited by maskers played simultaneously (SMI) or preceding the probe (FMI). SMI was significantly increased in PA rats, that is, maskers randomly distributed across the intensity-frequency field suppressed a greater number of probe responses. FMI was instead significantly reduced in PA rats.</p

PA affects response strength and duration but not cortical bursting properties.

<p>(<b>A</b>) Plot summarizing response amplitudes to tone pips calculated as average spike rates at PSTHs peaks shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015326#pone-0015326-g001" target="_blank"><b>Fig. 1B</b></a>. Response amplitudes decreased monotonically with decreasing intensities for both groups. (<b>B</b>) Inter-spike intervals calculated between the 1^st-2^nd, 2^nd-3^rd, and 3^rd-4^th spikes of the burst response. Note that mean ISIs did not differ between control (dashed grey lines) and PA (black solid lines) rats. In PA neurons the probability of detecting those ISIs was reduced at most intensities tested. Interestingly, the maximal probability was similar in all ISI examined. X-axis represents ISI values in ms, with a bin of 0.2 ms; y-axis the probability for a given ISI-bin-value at different intensities. (<b>C</b>) Plot summarizing response durations calculated as average time in ms at PSTHs onset-to-offset shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015326#pone-0015326-g001" target="_blank"><b>Fig. 1B</b></a>. Asterisks mark significant differences. (<b>D</b>) <i>Left panel</i>. Post-burst inhibition (PBI) recorded after excitatory responses illustrated for three different sound levels (75, 45 and 15 dB). Grey dashed lines represent controls; black solid lines represent data from PA rats. The magnitudes of PBI were a function of sound intensity and proportional to response amplitude; inhibition was the strongest when it followed high-intensity stimulation, decreasing monotonically with decreasing intensity. <i>Right panel</i>. PBI vs. intensity function. PBI was calculated as average firing rate in spike-per-sec across a post-firing window ranging between 10 and 50 ms after the excitatory response. Post-burst rates were below average spontaneous activity rates in both groups. Note the rightward shift in the PBI vs. intensity function in PA neurons, suggesting that PBI recorded from PA rats was sharply reduced.</p

Immunostaining of the hair cells of the basal turn of the organ of Corti. <i>Left panels</i>.

<p>Green indicates calbindin staining of three rows of outer hair cells (OHC) and one row of inner hair cells (IHC). Calbindin was selected in order to assess cellular loss in the cochlear sensory epithelium in rats exposed to PA. Calbindin immunostaining revealed no difference in the number of either inner or outer hair cells between control and experimental cochleae. <i>Center panels</i>. Red indicates TRIC-phalloidin staining of the F-actin filament expressed by OHC, IHC and pillar cells, a variety of support cells of the organ of Corti. F-actin expression was similar in control and PA rats suggesting the integrity of the stereocilia of the cochlear epithelium. <i>Right panels</i>. Merged images with FITC-green and TRITC phalloidin-red. Scale bars correspond to 50 µm.</p

Tone evoked response latency differences in control and PA rats.

<p>(<b>A</b>) Panels showing the rasterized responses to tone pips for each recorded neuron in control (grey, bottom part) and PA rats (black, top part) at 3 test intensity levels: 75 (left) 45 (center) and 15 (right) dB. Each line corresponds to a single experiment. Below the raster plots their respective cumulative PSTHs derived from all responses. Grey represents controls and black PA. The same color code was used in all following illustrations. (<b>B</b>) Superimposed PSTHs derived from responses obtained for all intensity levels. Note amplitudes and peak latencies differences between controls and anoxics. (<b>C</b>) Plot summarizing response latencies calculated as average time in ms at PSTHs onsets shown in B. Response latencies decreased monotonically with increasing intensities in both groups. (<b>D</b>) Plots showing onset latency cumulative probability for three different intensities (75 dB left; 45 dB center and 15 dB right) in controls (dashed lines) and PA (solid line) rats. An increase in longer-latency response neurons in PA rats is highlighted by the rightward shift of their cumulative distribution. It is worth noting that, in PA rats, by decreasing the sound intensity there is an increase in shorter-latency responses. X-axis represents onset latency in ms; y-axis the probability for a given onset latency value.</p

Tuning curves temporal dynamics.

<p>(<b>A</b>) Representative tuning curve examples obtained from one control (left) and one PA rat (right); PSTHs for those neurons are shown at the right of each example. Dashed lines mark the time windows selected for reconstructing response tuning dynamics based on a 2 ms bin. Note that response onset latency was increased in the sample PA neurons, while response strengths were reduced. (<b>B</b>) Temporal sequences of instantaneous tuning for single neurons recorded from one control (top) and one anoxic (bottom) rat. High-intensity tones corresponded to shorter latencies responses contributing to the PSTH's earlier phase; lower intensity tones corresponded to increasingly longer latency responses, contributing to the later phase of the PSTH. Time-slice per panel is 2 ms.</p

PA affects ability to process high-rate repetitive stimuli.

<p>(<b>A</b>) Dot raster plots of cortical responses to pulsed noises presented at different repetition rates (ordinate) recorded from a control (upper) and a PA (lower) rats. Most normal (control) A1 neurons could follow repetitive noise bursts up to 12.5 pulse-per-sec (p.p.s.), responding with similar spiking to all six noise-burst events and some neurons could follow rates up to about 20 p.p.s. (e.g., top panel). By contrast, in adult PA rats, most neurons responded in a similar manner to noise burst rates of 10 p.p.s. or lower, but fewer could follow rates of 12.5 p.p.s. and higher (e.g. as in the sample shown in the lower panel). In PA neurons, altered response pattern could be already noted at rates as low as 4 p.p.s.. PBI after spiking-bursts was particularly evident in controls. Total spike numbers recorded after the first noise pulse were not significantly different between the two groups. (<b>B</b>) Temporal modulation transfer function of cortical responses from 92 sites in control animals and 76 in PA rats. tMTF in PA rats was significantly reduced at most rates presented. Asterisks mark significantly different values. (<b>C</b>) Cumulative frequency histogram showing average highest temporal rates at which cortical responses were half of their maximum (f_h1/2) for controls (grey) and PA (black) rats. Cumulative distribution showed a significant leftward shift for PA compared to controls rats [<i>t</i>-test p<0.001 (1.4766e-14)]. (<b>D</b>) Vector strength of cortical responses, a measure of phase-locking to repetitive noise pulses or entrainment. Entrainment was very similar in control and PA rats for low rate repetitive stimuli. For repetition rates of 7 Hz or higher, phase locking capabilities were significantly reduced in PA neurons. (<b>E–F</b>) Asynchronous responses to repetitive noise pulses, calculated as the mean firing rate recorded 40 ms after each stimulus onset to the onset of the following stimulus (<b>E</b>) and after subtracting the average spontaneous (background) firing rate (<b>F</b>). In PA rats significantly larger asynchronous responses paralleled the higher background noise recorded. The level of suppression appeared significantly stronger in PA rats (<b>F</b>) because it resulted from the subtraction of a greater spontaneous activity. (<b>G</b>) Response dynamics of cortical neurons before and after neurons were activated by repetitive pulsed noise. The arrow shows an average faster return to the baseline in agreement with reduced post-firing suppression in PA rats.</p