Abnormalities in cortical auditory responses in children with central auditory processing disorder

Neuroscience 346 (2017) 135–148

ABNORMALITIES IN CORTICAL AUDITORY RESPONSES IN CHILDREN WITH CENTRAL AUDITORY PROCESSING DISORDER AMINEH KORAVAND, a* BENOIˆT JUTRAS a AND MARYSE LASSONDE b

measure is used to assess higher processing of auditory information in a specific time window (Cheour-Luhtanen et al., 1995). The benefit of these potentials is that they require less active participation than behavioral measures. These potentials are, however, underused in investigating the auditory functions of children with central auditory processing disorder (CAPD). CAPD is characterized as difficulties processing auditory information despite having normal hearing (ASHA, 2005). In general, central auditory processing is clinically assessed using a number of behavioral tests. Unfortunately, the criteria for CAPD diagnosis are not universally accepted (Wilson and Arnott, 2013) and these tests can be affected by non-auditory factors such as attention (Gyldenkaerne et al., 2014; Riccio et al., 1994, 1996) and motivation (Silman et al., 2000). Tomlin et al. (2015) recently demonstrated that cognitive ability has a significant influence on CAPD test performance. Many children who scored low on auditory processing tests also showed poor cognitive results (Tomlin et al., 2015). One solution would be to use neurophysiological measurements to reduce the effect of cognitive ability on test results to a certain extent. Contrary to behavioral testing, these measurements of higher level auditory processing are less affected by attention especially in a passive listening task where attention is directed elsewhere. Several studies have explored objective measurements of central auditory functions in children with CAPD using cortical auditory-evoked potentials (CAEPs) (Table 1). Jirsa (1992) conducted a study of 20 school-aged children (ages 9.5–12.5) diagnosed with CAPD who were matched with a group of 20 typically developing children. The children with CAPD were divided into two sub-groups: 10 children received individualized auditory training while the other 10 did not. The auditory training involved intensive listening exercises for auditory memory, auditory discrimination, attention, and language comprehension. The study examined CAEPs (N1 and P2) elicited by tone-burst stimuli at 65-dB nHL using the active oddball paradigm to record the P3 response (Pearce et al., 1989). The standard stimuli (1-kHz pure tone) occurred randomly with 80% probability and the target stimuli (3-kHz pure tone) occurred 20% of the time. To elicit the P3 responses, participants were instructed to keep a mental count of the number of target tones until a total of 300 trials were recorded in response to the target and standard tones. Latency (timing of stimulus processing, Luck, 2005) and amplitude (salience of processing, Luck, 2005) of the waveforms were analyzed.

E´cole d’orthophonie et d’audiologie, Universite´ de Montre´al and CHU Sainte-Justine Research Center, Canada a

b Department of Psychology, Universite´ de Montre´al and CHU Sainte-Justine Research Center, Canada

Abstract—The main objective of the present study was to identify markers of neural deficits in children with central auditory processing disorder (CAPD) by measuring latency and amplitude of the auditory cortical responses and mismatch negativity (MMN) responses. Passive oddball paradigms were used with nonverbal and verbal stimuli to record cortical auditory-evoked potentials and MMN. Twenty-three children aged 9–12 participated in the study: 10 with normal hearing acuity as well as CAPD and 13 with normal hearing without CAPD. No significant group differences were observed for P1 latency and amplitude. Children with CAPD were observed to have significant N2 latency prolongation and amplitude reduction with nonverbal and verbal stimuli compared to children without CAPD. No significant group differences were observed for the MMN conditions. Moreover, electrode position affected the results in the same manner for both groups of children. The findings of the present study suggest that the N2 response could be a marker of neural deficits in children with CAPD. N2 results suggest that maturational factors or a different mechanism could be involved in processing auditory information at the central level for these children. Ó 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Key words: cortical auditory-evoked potentials, mismatch responses, central auditory processing disorder.

INTRODUCTION Within the last decade, cortical auditory-evoked potentials have been used with clinical pediatric populations—with speech language impairment (Shafer et al., 2005, 2011), learning disabilities (Sharma et al., 2006), and hearing loss (Koravand et al., 2013)—to better understand how the central auditory system functions when listening to acoustic information. This valuable objective *Corresponding author. Address: Audiology and Speech-Language Pathology Program, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada. E-mail address: [email protected] (A. Koravand). Abbreviations: CAPD, central auditory processing disorder; MMN, mismatch negativity. http://dx.doi.org/10.1016/j.neuroscience.2017.01.011 0306-4522/Ó 2017 IBRO. Published by Elsevier Ltd. All rights reserved. 135

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underlying auditory perception (Na¨a¨ta¨nen, 1992; Alho, 1995). In the Liasis et al. (2003) study, MMN was recorded with the standard stimulus (/ba/) with a 76% probability of occurrence and target stimulus (/da/) with a 24% occurrence. The MMN latency values revealed no significant differences between children with CAPD and their control peers. These results were replicated by Roggia and Colares (2008) in their study on children, ages 9–14 years old, with and without CAPD, using pure-tone stimuli (Table 1). However, unlike Liasis et al. (2003) and Roggia and Colares (2008) did not report the amplitude values of the cortical auditory responses. Using 20 electrodes, Liasis et al. (2003) analyzed the P1, N1, P2, and N2 latency of the auditory cortical responses recorded from the Fz electrode. Results showed that N1 latency was longer in the group of children with CAPD than the control group. P1, P2, and N2 latency values were similar in both groups, however, there were larger peak to peak amplitude of the P1–N1 and P2– N2 and smaller peak to peak amplitude of the N1–P2 for the CAPD children compared to their peers. Liasis et al. (2003) reported peak to peak amplitude rather than the amplitude values for each waveform. However, Fig. 1 in their study shows children with CAPD appear to have larger P1 and N2 waveforms—i.e. greater amplitude—than their typically developing peers. Based on the findings of these studies, children with CAPD show abnormal latencies for some cortical responses, however it is still unclear whether the amplitude of these components is also affected. Passive change detection, indexed by the MMN, during passive auditory discrimination shows no discrepancy between the values obtained in children with and without CAPD. However, the results of Sharma et al. (2006) contradict these findings. They revealed that the MMN amplitude was reduced in children with CAPD and a reading disorder in comparison with the value obtained for the control group. They used four electrode positions (F3, F4, Fz, and Cz) and several types of stimuli to elicit cortical auditoryevoked responses; the stimuli consisted of pure tones (1, 1.1, and 1.5 kHz), chords (a combination of the aforementioned pure tones), and verbal stimuli (/da/, /ga/, and / a/). They also showed that the four cortical auditory responses (P1, N1, Fig. 1. Waveforms recorded at FCz electrode from two groups of children, 13 with normal hearing P2, and N2) were generally similar (Control) and 10 with central auditory processing disorder (CAPD), obtained with the standard for children within the experimental stimuli, 1-kHz pure tone, nonverbal /ba/, and verbal /ba/. Stimuli were presented at 70 dB HL for normal hearing children (solid line) and for children with central auditory processing disorder and control groups, regardless of (dashed line) in the passive listening paradigm. The top, middle, and bottom rows of waveforms stimulus type. Although the longer display the four principal components, P1, N1, P2, and N2, observed with respectively the 1-kHz latency was recorded for the propure tone, the nonverbal /ba/, and the verbal /ba/ stimuli. The amplitude scale is 10 lV and the cessing of verbal stimuli than the latency range is 100 to 700 ms. The vertical gray bars in the waveforms are 200 ms time intervals. Linked mastoids were used as a reference electrode. nonverbal, no differences were

Pre-auditory training results, obtained from one electrode placed over the parietal vertex, showed a delay for N1, P2, and P3 latencies and a smaller P3 amplitude among the children in the CAPD group compared to the control group. Furthermore, only the experimental CAPD training group showed improved latencies and amplitudes at the post-training assessment. In contrast, the untrained CAPD children and the typically developing control group showed no change in auditory P3 latency or amplitude at the post-intervention assessment. A study by Liasis et al. (2003) investigated cortical auditory responses in nine school-aged children (mean age: 9.5 years) with suspected CAPD who were matched with nine typically developing children using the passive oddball paradigm for recording mismatch negativity (MMN) (Na¨a¨ta¨nen et al., 1978). As with the P3 response, MMN is elicited by occasional deviant (target) stimuli embedded in a train of frequently presented standard stimuli (Na¨a¨ta¨nen, 1992); however, participants are instructed to disregard the both stimuli. MMN is obtained by subtracting the responses for standard stimuli from the results for the deviant responses (Na¨a¨ta¨nen, 1992). The subtraction process shows how the auditory system can automatically discriminate between the standard and the deviant stimuli (Alho, 1995). MMN, which is elicited passively, reflects the early sensory stages of sound processing and is ideal for investigating the mechanisms

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Different: N1 latency was longer in the group of children with CAPD than in the control group. Larger peak to peak amplitude of the P1-N1, P2-N2 and smaller peak to peak amplitude of the N1-P2 have been found in the CAPD children. Similar: P1, P2, N2 and MMN latencies were similar in the two groups. Fz (although 20 electrodes were used during data collection) Verbal (ba/-/da/) Passive oddball paradigm CAPD diagnostic was based on clinical profiles and results on the SCAN/SCAN-A screening test.

Different: Longer N1, P2, and P3 latencies and smaller P3 amplitude in CAPD compared to their peers Cz Tone Burst: (1–3 kHz) Active oddball paradigm

20 children with CAPD; proportion of girls and boys not specified (9.5–12.5 years old)20 age-matched children without CAPD 9 children; 4 boys and 5 girls (8– 12 years old) 9 age-matched children in the control group Jirsa (1992)

The central test battery consisted of the SAAT, the CST, and the RAS.

CAEP findings Recording electrode position CAEP stimulus/condition

The experiment was conducted at the CHU SainteJustine Research Center in Montreal and was approved by the Ethics, Administrative and Scientific Committees of CHU Sainte-Justine. Data were collected from 23 French-speaking children aged 9–12 with normal hearing: 10 with CAPD (mean age: 11 years and 2 months; SD: ±9 months) and 13 without CAPD (mean age: 11 years; SD: ±8 months). Participants with previously diagnosed CAPD were recruited from three rehabilitation centers in Quebec and a private audiology clinic. They already had a clinical diagnosis of CAPD before enrolling in the study (Table 2). That diagnosis was carried out separately from the current study. Since there are no universal criteria for diagnosing CAPD, this study applied the following conditions to identify the disorder: poor performance at two standard deviations below the mean on one or more tests in at least one ear. The clinical test battery, administered by qualified audiologists, included the French adaptation of the Staggered Spondaic Word Test (Rudmin and Normandin, 1983), the French adaptation of the Synthetic Sentence Identification-Ipsilateral Competing Message Test (Lynch and Normandin, 1983), the Pitch Pattern Test, (Musiek, 1994), the Duration Pattern Test (Musiek, 1994), and the Random Gap Detection Test (Keith, 2000). The control children were age-matched to the CAPD group and were recruited from primary schools, summer camps, and the researchers’ environment. A CAPD test battery was not administered to the control group. However, a questionnaire was used to screen for learning and reading disabilities, as well as language, cognitive, or neurological disorders. All participants, with and without CAPD, had normal hearing detection threshold at 15 dB HL or less for

Diagnosis/diagnostic criteria

Participants

Participants

EXPERIMENTAL PROCEDURES

Authors

observed between the results of the two groups (Sharma et al., 2006). Recently, conflicting evidence from Tomlin and Rance’s (2016) study demonstrated longer latencies and smaller amplitudes for the P1 and N1 responses in children with CAPD (Table 1). However it should be emphasized that the type of stimuli was different from the above investigations. Since the central auditory system processes verbal and nonverbal stimuli differently (Ceponiene et al., 2008), using different types of stimuli could produce a different response pattern. In summary, literature on the neurophysiological investigation of children with CAPD is limited and findings from these studies are not always congruent. The present study thus aimed to further explore if markers of neural deficits in children with CAPD can be identified using CAEP with verbal and nonverbal stimuli at various electrode positions on the scalp. Such markers could eventually be used to screen young children with suspected listening problems or to assess the benefits of auditory training programs in individuals with CAPD–thus making CAEPs a potentially useful addition to the diagnostic test battery for CAPD.

Table 1. Summary of five articles using the central auditory-evoked potentials (CAEP) tools in children with central auditory processing disorders (CAPD)

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Table 1 (continued) Participants

Diagnosis/diagnostic criteria

CAEP stimulus/condition

Recording electrode position

CAEP findings

Roggia and Colares (2008)

8 participants; 4 boys and 4 girls (9–14 years old) 8 age and sexmatched children in the control group

CAPD diagnosis based on APD tests done at the Audiology Clinic: Tests names have not been provided.

Fz

Similar: MMN latencies recorded with different frequencies and different durations were similar in CAPD compared to their peers.

Sharma et al. (2006)

23 children;19 boys and 4 girls (8.2–12.6 years old) 21 children in the control group: 17 boys and 4 girls (8–12.2 years old)

F3, F4, Fz, and Cz

Different: MMN amplitude was reduced in children with CAPD in comparison to the control group.

Tomlin and Rance, 2016

27 children; 16 boys, 11 girls (7–12 years old) 27 age-matched children in the control group

Four APD tests were used: DDT, FPT, RGDT, and BKB-SIN (Australian version). BKB-A sentences were presented in quiet and in 4-talker babble at 4 SNRs, with the speech level fixed at 60 dB HL: 0, 5 dB and 10 dB and in quiet Children with a reading disorder did not pass at least one behavioral test of auditory processing. The CAPD test battery used contained: DDT, FPT, GIN, MLD and the LISN-S

Tone Bursts: 2 frequencies: 750 Hz and 1 kHz 2 durations: 1 kHz: with 50 ms and 100 ms Passive oddball paradigm Pure tones: (1 kHz, 1.1 kHz, 1.5 kHz) Chords: -A combination of the aforementioned pure tones) Verbal stimuli (da/, /ga/, /a/) Passive oddball paradigm

Cz

Different: Longer latencies and smaller amplitudes for P1 and N1 responses in children with CAPD

APD: Auditory Processing Disorder. BKB-SIN (Australian version): Bamford–Kowal–Bench Speech In Noise (Australian version) (Bench and Doyle, 1979). CAPD: Central Auditory Processing Disorder. CST: Competing Sentences Test (Willeford, 1977). DDT: Dichotic Digit Test version 2 (Musiek, 1983; Guenette and Musiek, 2006). FPT: Frequency Pattern Test (Musiek, 1994). GIN: Gaps in Noise (Musiek et al., 2005). MLD: Masking Level Differences (Aithal et al., 2006). LISN-S: Listening in Spatialized Noise-Sentence test (Cameron and Dillon, 2007). RAS: Rapidly Alternating Speech Test (Willeford, 1977). RGDT: Random Gap Detection Test (Keith, 2000). SAAT: Selective Auditory Attention Competing Subtest (Cherry, 1980). SCAN: Screening Test for Auditory Processing Disorder (Keith, 1986). Consists of three subtests: FW: Filtered Words. AFG: Auditory Figure Ground. CW: Competing Words. SCAN A: Screening Test for Auditory Processing Disorders in Adolescents and Adults (Keith, 1994). Contains the SCAN subtests and CSS: Competing Sentence Subtest. SNRs: Signal-to-Noise Ratios.

Tone Bursts (500 Hz)

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Authors

Table 2. Results of ten participants with Central Auditory Processing Disorder (CAPD) on six tests (SSW, SSI-ICM, monosyllabic words in noise, PPST, DPST, RGDT) evaluating the key functions of the central auditory system (N: normal; AN: abnormal; NT: not tested; RE: Right Ear; LE: Left Ear). The age of the participants at the first session is also indicated Results of the tests of central auditory function CAPD

Age yr; mth

SSI-ICM

Mono noise

PPST

DPT

RGDT

AN at 10 RE: 60 % LE: 60% AN at 10 RE: 70 % LE: 60% AN at 10 RE: 50 % LE: 50% AN at 10 RE: 60 % LE: 50% AN at 0 (RE & LE: 80 %) and AN at 10 (RE: 60 %; LE: 50%) N 90 and/or 100% at All tested condition (+10, 0, 10) N 90 and/or 100% at All tested condition (+10, 0, 10) N 90 and/or 100% at All tested Condition (+10, 0, 10) AN at 10 RE: 60 %; LE: 50%

N

N

N

7.5

RE & LE: 80% N RE: 88% LE: 84% AN RE: 24 % LE: 36% N RE: 88% LE: 80% N RE & LE 80%

100% N 100%

100% N 100%

10

N 90%

N 100%

7.5

N 90%

N 100%

10

N 90%

NT

NT

AN RE: 24 % LE: 40%

N 100%

N 100%

7.5

N RE: 88% LE: 84%

AN (RE: 26%) (LE: 26%)

AN RE: 36% LE: 26 %

5

AN RE: 52% LE: 52%

N 90%

AN LE: 50% N RE:76%

5

N RE: 92% LE: 88%

N 90%

NT

NT

AN at 10 RE: 70 %; LE: 70%

N RE: 92% LE: 88%

AN (RE: 43%) (LE: 36%)

N 100%

7.5

1

10

AN for the right non-competing condition (22%). No significant bias

2

12;02

3

10;09

AN for the left competing (22 %) and noncompeting conditions (20 %). Significant ear order bias: H/L AN for the two competing conditions (RE: 25%; LE: 15%). No significant bias

4

10;04

AN for the two competing conditions (RE: 27%; LE: 22%). No significant bias

5

11;05

N for four conditions. No significant bias

6

11;04

N for four conditions. No significant bias

7

10;11

AN for the right competing condition: 22%. Significant bias for word order: L/H

8

11;07

AN for two competing condition: RE: 20%; LE: 25 % Significant bias for ear order: H/L

9

9;05

10

12;04

AN for two competing condition: RE: 20%; LE: 25 % AN for two non-competing condition RE: 7 %; LE: 10% No significant bias N for four conditions. No significant bias

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SSW

139

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octave frequencies from 500 Hz to 8 kHz, bilaterally, based on the American National Standards Institute (1996)’s protocol. Tympanograms were normal in all children (admittance curve with a single peak between +50 to 100 daPa using a 226-Hz probe tone). No history of otological or neurological disorders was reported for any of the children participating in the study. All children were right handed, determined according to an adapted protocol to assess laterality (De Agostini and Dellatolas, 1988). Attention and memory were not assessed, however the children did not have any diagnosed difficulties in these areas. To assess nonverbal reasoning ability, children completed the Colored Progressive Matrices Test (Raven, 1956). This test contains 36 multiplechoice items involving abstract reasoning. The mean group score on the nonverbal reasoning test was above the 80th percentile, ranging from the 75th to the 95th percentile, according to test normative values (Raven, 1956).

EXPERIMENTAL PROCEDURES Stimuli All stimuli were 250 ms in duration with 2.2-ms rise and fall times. Three sets of stimuli were designed and used in three separate experimental sessions in order to achieve a better understanding of how the brain of a child with CAPD processes simple and complex stimuli. One synthetic verbal pair, /ba/ and /da/ (Sensimetrics Corporation, 1994), and two nonverbal pairs, simple nonverbal stimuli (1-kHz and 2-kHz pure tones), and a complex nonverbal acoustic transformation of /ba/ and /da/ were used. The two verbal syllables, /ba/-/da/, were composed of three formants, sharing the same frequencies for the first formant transition between the consonant and the vowel. Dr. Speech (Tiger DSR Inc., 1998) and Mitsyn (Henke, 1993) software were used to generate the complex nonverbal stimuli. Adapted from a study by Mody et al. (1997), the nonverbal pair consisted of synthesized transformations of the verbal stimuli /ba/ and /da/, each consisting of two sine waves identical to those of the central frequencies for the second and third formant frequencies in the synthetic /ba/ and /da/. However, they differed perceptually from their corresponding speech sounds. This transformation respected the stimuli duration and the duration of the transition between the two sine-wave frequencies, reproducing the consonant–vowel transition in a nonverbal way as well as the intensity of the syllables. The two non-linguistic stimuli remain acoustically complex to process, as was the case for the verbal syllables /ba/ and /da/. Participants labeled them as a ‘‘nonverbal sound” during the study. E-Prime Psychology software (Psychology Software Tools Inc., Pittsburgh, PA, USA) was used to generate the stimulus sequences. The stimulus intensity was controlled by an audiometer (Interacoustics, AD229b). All three stimulus pairs were presented through an insert-earphone (E-A-RTONE 3A) to the right ear at 70-dB HL in a passive oddball paradigm with an interstimulus interval (ISI) of one second. The standard stimuli (syllable /ba/, nonverbal /ba/, and a 1-kHz pure tone) occurred with an 85% probability and the deviant stimuli (syllable /da/, nonverbal /da/, and a

2-kHz pure tone), with a 15% occurrence. A total of 1000 trials for each stimulus pair were recorded. Stimulus presentation order within a run was pseudo-randomized and respected three conditions: no run beginning with a deviant, no two deviants occurring in succession and a deviant stimulus was always preceded by at least three standard stimuli. Electrophysiological recordings Children were seated in an acoustically shielded and sound-attenuated booth during the data recording. Geodesic Sensor Nets (Electrical Geodesics Inc., Eugene, OR, USA) with 128 Ag/AgCl electrodes cap were used to measure continuous EEG at all 128 sites. Electrophysiological signals were acquired at a sampling rate of 250 Hz, applying an analog online band-pass filter (0.1–100 Hz), using the Net Station program running on a G4 Macintosh computer. The ground electrode and the reference electrode were located on the forehead (Fpz) and at the vertex (Cz) respectively. Vertical and horizontal eye movements were measured with frontal electrodes Fp1 (left), Fp2 (right), and electrodes placed below each eye. Electrode impedances were maintained under 20 kX, which is within the recommended range for a powerful amplifier system (Net Amps 200). Procedure A consent form was read and signed by the parents, and the children also gave their assent to participate in the study. In order to communicate with the experimenters, children were monitored through an infrared camera equipped with an integrated speaker and microphone. During the recording sessions, children were seated approximately 2 m from a computer monitor (View Sonic Professional Series P225F) and were instructed to ignore the stimuli while watching a captioned silent video. The order of presentation of the conditions was counterbalanced across participants. Short and long breaks were given as required. The total recording session lasted between 90 and 120 min, including the time for electrode placement. Electrophysiological data analysis All EEG data were processed offline using the BrainVision Analyzer program (Brain Products, Munich, Germany) on an IBM computer. Gratton and Coles’ algorithm (Gratton et al., 1983) was used to perform eye-blink correction on EEG data. The data were then digitally filtered using a band-pass filter of 1–30 Hz at 24 dB/octave. The filtered data were re-referenced to both the left and right mastoid electrodes for further analysis. Epochs with eye movements and/or other artifacts were rejected based on voltage criteria (±100 lV for all channels) and the EEG was visually inspected to ensure adequate artifact rejection. The EEG was segmented into epochs with a prestimulus interval of 100 ms and 700 ms post-stimulus. The data were baseline corrected to -50 ms and were averaged separately for each stimulus, standard and

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deviant. A peak amplitude detection manipulation was performed for each participant to measure the latency and the amplitude of the most positive and negative peaks.

RESULTS

ratio for auditory cortical responses and MMN (Gilley et al., 2005; Koravand et al. 2013), lateral electrodes have also been added to verify any lateralized differences between the two groups. P1 and N2 latency measured with standard stimuli

The analysis was restricted to P1 and N2 latency and amplitude from the standard and deviant stimulus as these waveforms were observed in all children while N1 and P2 were present in 75% of children without CAPD and 38% of children with CAPD. The MMN was also analyzed as a subtraction between the waveforms of the standard and deviant stimuli. An analysis of variance (ANOVA) for repeated measures was performed with Stimulus Type (verbal /ba/ or /da/, nonverbal /ba/ or /da/, and 1-kHz or 2-kHz pure tone) and Electrode Position (for P1 and N2: FCz, Cz, CPz, C3, and C4; for MMN: Fz, FCz, and Cz) as within-subject variables and Group (children with normal hearing and children with CAPD) as a between-subject variable. For the adjustment of degrees of freedom for sphericity, the Huynh–Feldt correction was used (Max and Onghena, 1999). Bonferroni corrections were applied to control for Type I errors during post hoc analyses. All statistical analyses were conducted with the IBM SPSS Statistics 23 software package (IBM, Armonk, NY, USA). Fig. 1 illustrates the grand average AEP responses to standard stimuli for the three stimuli (verbal /ba/, nonverbal /ba/, and 1-kHz pure tone) in the two groups of children. Midline and lateral electrodes (CPz, FCz, Cz, C3, and C4) were selected for cortical auditoryevoked responses while midline electrodes (Fz, FCz, and Cz) were selected for MMN for statistical analysis purposes. Although midline electrodes generally have the largest amplitude and the greatest signal-to-noise

No significant effect on P1 latency was observed for the three main factors (Group, Stimulus Type, and Electrode Position) or for any interactions between these factors (see Table 3). For N2 latency, results indicated a significant effect for two main factors, Stimulus Type and Group (Table 3). The N2 latency value was longer in children with CAPD (Mean 234.3, SD = 13.2 ms) than for children with normal hearing (Mean 258.3, SD = 17.3 ms) (Fig. 2). For Stimulus Type, a significant longer latency was observed between the verbal /ba/ and the nonverbal /ba/ [t (22) = 4.4, p < 0.016; g2 = 0.46] and the 1-kHz pure-tone stimulus [t (22) = 3.1, p < 0.016; g2 = 0.30]. P1 and N2 amplitude obtained with standard stimuli In regards to P1 amplitude, a significant effect was found only for the main Electrode Position factor (see Table 3). T-tests (with Bonferroni correction, p < 0.005) revealed the following: P1 amplitude was larger at FCz than at Cz [t (22) = 5.5, p < 0.005; g2 = 0.57], CPz [t (22) = 4.2, p < 0.005; g2 = 0.46], C3 [t (22) = 5.5, p < 0.005; g2 = 0.57], and C4 [t (22) = 6.8, p < 0.005; g2 = 0.67]); P1 amplitude was larger at Cz than at C3 [t (22) = 3.4, p < 0.005; g2 = 0.34] and C4 [t (22) = 4, p < 0.005; g2 = 0.42]). For N2 amplitude, significant effects were found for two of the three main factors, Stimulus Type and Electrode Position (see Table 3), and for the two-way

Table 3. Results of the three main effects – Stimulus type, Electrode position, Group –from a three-way ANOVA, with repeated measures for Stimulus type and Electrode position for auditory late responses P1 and N2 latency and amplitude. These responses were obtained with the standard stimuli used in an oddball paradigm recording P1

N2

df (between group)

df (within group)

F

P

g

df (between group)

df (within group)

F

p

g2

Latency Stimulus type (S) Electrode (E) Group (G) SE SG GE SEG

2 2.45 1 3.3 2 2.45 3.3

42 51.5 21 68.8 42 51.5 68.8

1.43 0.84 0.1 1.2 2.8 0.14 1.5

NS NS NS NS NS NS NS

0.06 0.04 0.01 0.05 0.12 0.01 0.07

2 3.6 1 4.8 2 3.6 4.8

42 76 21 100.2 42 76 100.2

9.4 1.1 14.2 1.4 0.31 0.88 1.50

0.000 NS 0.001 NS NS NS NS

0.31 0.05 0.41 0.06 0.01 0.04 0.07

Amplitude Stimulus type (S) Electrode (E) Group (G) SE SG GE SEG

2 3.2 1 5.85 2 3.2 5.85

42 67.17 21 123 42 67.17 123

1.4 24.4 0.40 1.8 0.2 1.04 0.88

NS .000 NS NS NS NS NS

0.06 0.54 0.02 0.08 0.01 0.05 0.04

2 3.04 1 7.8 2 3.04 7.8

42 64 21 164 42 64 164

20.1 60.7 0.61 5.3 2.1 2.22 1.9

0.000 0.000 NS 0.000 NS NS NS

0.51 0.74 0.03 0.20 0.09 0.11 0.08

NS = not significant (p > 0.05).

2

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= 17.6, p < 0.005; g2 = 0.90], C3 [t (22) = 9.6, p < 0.005; g2 = 0.80]) and C4 [t (22) = 8.4, p < 0.005; g2 = 0.76]; non verbal /ba/ (Cz [t (22) = 8.4, p < 0.005; g2 = 0.76], CPz [t (22) = 8.8, p < 0.005; g2 = 0.77], C3 [t (22) = 6.7, p < 0.005; g2 = 0.63]) and C4 [t (22) = 9.5, p < 0.005; g2 = 0.80]; and verbal /ba/ (Cz [t (22) = 6.9, p < 0.005; g2 = 0.68], CPz [t (22) = 10.5, p < 0.005; g2 = 0.83], C3 [t (22) = 7.2, p < 0.005; g2 = 0.71]) and C4 [t (22) = 7.8, p < 0.005; g2 = 0.73]. Moreover N2 amplitude was larger at Cz than C4 with nonverbal /ba/ [t (22) = 4.6, p < 0.005; g2 = 0.49] and verbal /ba/ [t (22) = 4.3, p < 0.005; g2 = 0.46]. P1 and N2 latency obtained with deviant stimuli

Fig. 2. The latency value and standard deviation (bars) of N2, recorded at FCz, Cz, CPz, C3, and C4, from 13 children with normal hearing (Control) and 10 children with central auditory processing disorder (CAPD), obtained with the standard stimuli, 1-kHz pure tone, nonverbal /ba/, and verbal /ba/.

interaction Stimulus Type  Electrode. An analysis of simple effects for this significant interaction indicated that Electrode Position was significant with the 1-kHz pure tone [F (4, 110) = 6.65, p < 0.001; g2 = 0.19], the nonverbal /ba/ [F (4, 110) = 5.4, p < 0.01; g2 = 0.16], and the verbal /ba/ [F (4, 110) = 5.9, p < 0.001; g2 = 0.17] stimuli. T-tests revealed that N2 amplitude was larger at FCz than at other electrodes with all three stimuli: pure tone (Cz [t (22) = 13.2, p < 0.005; g2 = 0.88], CPz [t (22)

For P1 latency, results indicated significant effects for Stimulus Type and Electrode Position (see Table 4). Additional analyses revealed significantly shorter latency for the 2-kHz pure-tone stimuli than for the nonverbal /da/ [t (22) = 2.7, p < 0.016; g2 = 0.24] and the verbal /da/ [t (22) = 3.5, p < 0.016; g2 = 0.36]. Paired t-tests with Bonferroni correction were not significant for Electrode Position (p > 0.005). For N2 latency, significant effects were observed for Stimulus Type and Group only (see Table 4). Significantly longer latency was measured for the verbal /da/ than for the nonverbal /da/ [t (22) = 3, p < 0.016; g2 = 0.29] and for the 2-kHz pure-tone stimuli [t (22) = 6.7, p < 0.016; g2 = 067]. Results showed a longer N2 latency obtained with nonverbal /da/ in comparison with 2 kHz [t (22) = 3.7, p < 0.016; g2 = 0.38]. Furthermore, N2 latency was longer in children with CAPD (Mean 253.7 ms, SD = 21.28 ms) than in children without CAPD (Mean 220.18 ms, SD = 16.15 ms) [t (21) = 4.3, p < 0.001; g2 = 0.45] (Fig. 3).

Table 4. Results of the three main effects – Stimulus type, Electrode position, Group – from a three-way ANOVA, with repeated measures for Stimulus type and Electrode position for auditory late responses P1 and N2 latency and amplitude. These responses were obtained with the deviant stimuli used in an oddball paradigm recording P1

N2

df (between group)

df (within group)

F

P

g2

df (between group)

df (within group)

F

p

g2

Latency Stimulus type (S) Electrode (E) Group (G) SE SG GE SEG

2 3.1 1 5.5 2 3.1 5.5

42 64.12 21 116.3 42 64.12 116.3

6.1 3 0.1 0.73 1.4 0.21 1.4

0.005 0.038 NS NS NS NS NS

0.23 0.12 0.004 0.03 0.06 0.01 0.06

2 2.89 1 6.3 2 2.89 6.3

42 60.6 21 132 42 60.6 132

20.3 0.84 18.5 0.82 0.71 0.71 1.2

0.000 NS 0.000 NS NS NS NS

0.52 0.04 0.47 0.04 0.02 0.03 0.05

Amplitude Stimulus type (S) Electrode (E) Group (G) SE SG GE SEG

2 4 2 8 2 4 8

42 84 21 168 42 84 168

1.42 22.6 0.44 0.75 0.22 0.63 0.93

NS 0.000 NS NS NS NS NS

0.06 0.52 0.02 0.01 0.01 0.03 0.04

2 2.65 1 6.5 2 2.65 6.5

42 55.6 21 136 42 55.6 136

2.3 29 8.6 1.7 3.7 1.99 0.83

NS 0.000 0.008 NS 0.03 NS NS

0.09 0.58 0.29 0.07 0.15 0.09 0.04

NS = not significant (p > 0.05).

A. Koravand et al. / Neuroscience 346 (2017) 135–148

Fig. 3. The latency value and standard deviation (bars) of N2, recorded at FCz, Cz, CPz, C3, and C4, from 13 children with normal hearing (Control) and 10 children with central auditory processing disorder (CAPD), obtained with the deviant stimuli, 2-kHz pure tone, nonverbal /da/, and verbal /da/.

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Fig. 4. The N2 amplitude value and standard deviation (bars), recorded at FCz, Cz, CPz, C3, and C4 electrodes, from 13 children with normal hearing (Control) and 10 children with central auditory processing disorder (CAPD), obtained with the deviant stimuli, 2-kHz pure tone, nonverbal /da/, and verbal /da/.

P1 and N2 amplitude obtained with deviant stimuli Regarding P1 amplitude, a significant effect was found only for the main Electrode factor (Table 4). T-tests revealed that P1 amplitude was larger at FCz than at Cz [t (22) = 5, p < 0.005; g2 = 0.50], CPz [t (22) = 7.5, p < 0.005; g2 = 0.70], C3 [t (22) = 6.6, p < 0.005; g2 = 0.66], and C4 [t (22) = 8.1, p < 0.005; g2 = 0.74]). Moreover, results demonstrated larger P1 amplitude at Cz than at CPz [t (22) = 4.6, p < 0.005; g2 = 0.49], C3 [t (22) = 4.2, p < 0.005; g2 = 0.44], and C4 [t (22) = 3.5, p < 0.005; g2 = 0.36]). For N2 amplitude, significant effects were found for Electrode Position and Group factors and for the twoway interaction Stimulus Type  Group (see Table 4). Analysis of paired t-test comparisons (p < 0.005) revealed larger N2 amplitude at FCz than at Cz [t (22) = 7.7, p < 0.005; g2 = 0.73], CPz [t (22) = 9.6, p < 0.005; g2 = 0.80], C3 [t (22) = 6.4, p < 0.005; g2 = 0.65], and C4 [t (22) = 5.4, p < 0.005; g2 = 0.57]). Larger N2 amplitude was found at Cz than at CPz [t (22) = 8.6, p < 0.005; g2 = 0.77] and at CPz than at C3 [t (22) = 3.4, p < 0.005; g2 = 0.34]) (Fig. 4). An analysis of simple effects for the significant interaction Stimulus Type  Group indicated a significant amplitude reduction for 2-kHz pure tones in children with CAPD (Mean 2.5 lV, SD = 2.01 lV) compared to children without CAPD (Mean 5.75 lV, SD = 2.5 lV) [F (1, 21) = 10.9, p < 0.01, g2 = 0.34].

Fig. 5. The latency value and standard deviation (bars) of MMN, recorded at FCz, Fz, and Cz, from 13 children with normal hearing (Control) and 10 children with central auditory processing disorder (CAPD), is presented with the three pairs of stimuli: Tone (1–2-kHz pure tones), NV (nonverbal /ba/-/da/), and Verbal (/ba/-/da/).

MMN MMN latency and amplitude were shown in Figs. 5 and 6. Latency – Significant latency prolongation was observed for the following comparison; verbal /ba/-/da/ pair with the 1-kHz and 2-kHz pure-tone pair [t (22) = 12.3, p < 0.016; g2 = 0.87]; verbal with the nonverbal /ba/-/da/ pair [t (22) = 4.9, p < 0.016;

Fig. 6. The amplitude value and standard deviation (bars) of MMN, recorded at FCz, Fz, and Cz, from 13 children with normal hearing (Control) and 10 children with central auditory processing disorder (CAPD), are presented with the three pairs of stimuli: Tone (1–2-kHz pure tones), NV (nonverbal /ba/-/da/), and Verbal (/ba/-/da/).

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Table 5. Results of the three main effects Group  Type of stimulus  Electrode position from a three-way ANOVA, with repeated measures for type of stimulus and electrode position. These responses were obtained with the mismatch negativity (MMN) Latency

Stimulus type (S) Electrode (E) Group (G) SE SG GE SEG

Amplitude

df (between group)

df (within group)

F

P

g2

df (between group)

df (within group)

F

p

g2

1.7 1.3 1 2.3 1.7 1.3 2.3

36.1 27.1 21 48.9 36.1 27.1 48.9

53.2 0.05 0.2 3.13 1.2 0.83 1.1

0.000 NS NS NS NS NS NS

0.71 0.00 0.01 0.13 0.06 0.04 0.05

2 2 1 4 2 2 4

42 42 21 84 42 42 84

20.3 6.9 1.8 7.7 2.4 0.81 1.1

0.000 0.003 NS 0.000 NS NS NS

0.51 0.25 0.08 0.30 0.11 0.01 0.05

NS = not significant (p > 0.05).

g2 = 0.50] and nonverbal /ba/-/da/ pair with the 1-kHz and 2-kHz puretone pair [t (22) = 5.23, p < 0.016; g2 = 0.55]. Amplitude – Significant effects were observed for Stimulus Type and Electrode Position as well as for the two-way interaction Electrode  Stimulus Type [F (4, 84) = 7.7, p < 0.001; g2 = 0.30] (Table 5).

Z Score calculation for the N2 responses

Fig. 7. N2 latency data of 10 children with CAPD were distributed on a Z-Score scale. This scale was calculated from data of 13 children without CAPD, collapsed for electrode site (FCz, Cz, CPz, C3, and C4) recorded with standard stimuli; 1 kHz (A), nonverbal /ba/ (B) and verbal /ba/ (C).

Fig. 8. N2 latency data of 10 children with CAPD were distributed on a Z-Score scale. This scale was calculated from data of 13 children without CAPD, collapsed for electrode site (FCz, Cz, CPz, C3, and C4) recorded with deviant stimuli; 2 kHz (A), with nonverbal /da/ (B) and with verbal /da/ (C).

In order to look at the individual data of children with CAPD, a Z score was calculated for the two most significant results between the two groups: (1) latency of N2 responses recorded with the standard and with the deviant stimuli (Figs. 7 and 8), and (2) N2 amplitude with responses recorded with the 2 kHz of deviant stimuli. Figs. 7 and 8 represent the Z score of 10 children with CAPD measured for N2 latency responses averaged for five electrode positions (CPz, FCz, Cz, C3, and C4). Depending on the data obtained with Pure Tones 1 kHz and 2 kHz and nonverbal /ba/-/da/, between 10% and 50 % of children with CAPD had their N2 latency responses at more than 2 standard deviations (SDs) above the mean of their peers without CAPD (A and B sections of the Figs. 7 and 8). In regard to the data recorded with verbal /ba/ and / da/ stimuli, results showed that between 50% and 80% of the children with CAPD had their N2 latency responses at more than 2 SDs above the mean of their peers without CAPD (C section of the Figs. 7 and 8).

A. Koravand et al. / Neuroscience 346 (2017) 135–148

Fig. 9. N2 amplitude data of 10 children with CAPD were distributed on a Z-Score scale. This scale was calculated from data of 13 children without CAPD, collapsed for electrode site (FCz, Cz, CPz, C3, and C4). Data were recorded with deviant /da/ stimulus.

The observation of the data recorded with the 2-kHz stimulus demonstrated that only 20% of CAPD children had their N2 amplitude at more than 2 SDs compared to their peers (Fig. 9).

DISCUSSION The objective of this study was to identify neural markers of cortical deficits by recording late auditory-evoked responses in children with normal hearing sensitivity who have trouble processing auditory information. The main findings of the present study suggest that the N2 auditory cortical response may be a marker of neural deficits in children with CAPD. Indeed, patterns of N2 latency and amplitude appear to have a specific neural signature in children with CAPD. It is possible that the N2 latency and amplitude differences reflect an immature cortical response in the children with CAPD. The four obligatory late latency-evoked responses are subject to long and complex maturational processes in children (Wunderlich et al., 2006; Sussman et al., 2008). In young children, only one positive (P1) waveform and one negative (N2) waveform are measured (Ponton et al., 2000; Wunderlich et al., 2006; Sussman et al., 2008). P1 decreases systematically in latency and amplitude, nearing adult values at age 14 or 15 (Ponton et al., 2000; Wunderlich et al., 2006; Sussman et al., 2008) or at age 20 (Sharma et al., 1997). Meanwhile N1 and P2 are absent in young children and emerge between ages 8 and 11 (Ponton et al., 2000; Wunderlich et al., 2006; Sussman et al., 2008). Furthermore, N2 latency decreases systematically until late adolescence (Ponton et al., 2000; Sussman et al., 2008). N2 amplitude increases between ages 5 and 11 (Ponton et al., 2000) followed by a gradual decline from late childhood to mid-adolescence (Cˇeponiene_ et al., 2002), reaching adult values by age 17 (Ponton et al., 2000). Thus, changes in the morphology, latency, and amplitude of the four obligatory auditory response waveforms continue into

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adulthood. During childhood and adolescence, primary auditory connections form with adjacent cortices and the contralateral hemisphere (Moore and Linthicum, 2007). The auditory system matures through the continued development of the auditory cortex, such as axonal density and volumetric changes (Moore and Guan, 2001) as well as maturation of synaptic efficacy and continued myelin formation along axons (Eggermont, 1985, 1988). The CAEP differences observed in the present study could differ from that of younger children. Longitudinal studies and more extensive normative data are needed to test these hypotheses. Alternatively, prolongation of N2 latency may be a sign of slower processing mechanisms. The efficiency of auditory processing is highly dependent on neural timing (latency) and neural magnitude (amplitude). The latency and amplitude of a waveform represent the speed and magnitude of processing by the central auditory system (Hillyard and Picton, 1987; Na¨a¨ta¨nen and Picton, 1987; Luck, 2005). Latency prolongation and amplitude reduction indicate a decline in the number of contributing neurons, fewer synchronized responses, changes in synaptic density, intra-cortical myelination, or structural/ orientation changes to auditory pathways (Cˇeponiene_ et al., 2002). The N2 generators are not yet entirely understood. A study by Bruneau and Gomot (1998), using scalp current density analysis, suggests that the auditory N2 has bilateral sources in the supratemporal auditory cortex. Furthermore, the caudal and motor anterior cingulate cortices may be involved as a source of N2 responses, suggesting that N2 reflects general inhibitory responses (Mathalon et al., 2003). Bertoli and Probst (2005) and recently Stothart and Kazanina (2016) have demonstrated that the N2 response was generally absent or significantly reduced in older adults than in younger participants. This abnormality could be related to a deficit in inhibitory processing (Bertoli and Probst, 2005; Stothart and Kazanina, 2016). The standard and the deviant N2 are recorded in response to two stimuli that are ignored during the experiment. The less efficient ability or inability to inhibit the processing of the irrelevant information would affect the characteristics of the N2 responses (Stothart and Kazanina, 2016). The longer N2 latency and the N2 amplitude reduction observed in CAPD children could be a manifestation of a deficit in inhibitory processing. As reported above, significant differences between groups where obtained with the standard and deviant waveforms, but no significant differences were observed between the two groups for MMN latency and amplitude. These results corroborate the studies by Liasis et al. (2003) and Roggia and Colares (2008) and suggest that MMN data should be investigated not only using MMN parameters, but also with those associated with the standard and deviant waveforms. In fact, a great deal of important information may be lost by limiting the analysis to the conventional method of calculating MMN. The second factor that may explain the lack of significant difference for the MMN parameters could be related to the large inter-individual variability between and within groups. However, Dalebout and Fox’s (2001)

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study showed that even with a high rate of replicability for the standard and deviant waveforms across testing sessions for each participant, MMN identification was poor across the sessions at the individual level. These authors added that there is need to rethink the way to quantify the difference between the two types of waveforms in order to reduce the variability associated with MMN results. This, in turn, could limit its application in clinics. The present study also explored whether the cortical signal recorded with multiple electrodes is an indication of abnormal processing of auditory information based on electrode location on the scalp. The findings showed that central regions have more robust responses than lateral regions, as supported by earlier studies (Ponton et al., 2000; Sussman et al., 2008; Koravand et al., 2013). Furthermore, this processing pattern was similar across all children with and without CAPD. Based on the results of this study, N2 and MMN differ by stimulus type. These findings are reported in other studies indicating that the central auditory system requires extra time and effort to process complex stimuli (verbal /ba/-/da/) than to process simple ones (1-kHz and 2-kHz pure tones) (Sebastian and Yasin, 2008; Koravand et al., 2013; Paquette et al., 2015). N2 and MMN had an earlier latency and greater amplitude with simple stimuli than with more complex stimuli. The two groups show similar patterns of results for the majority of stimuli.

language or reading difficulties. Also, diagnosis of other conditions was based on parent reports rather than results from formal auditory working memory and attention testing. Furthermore, normally developing children were not evaluated with the APD behavioral tests.

DISCLOSURE Portions of the work described here were presented as follows: Koravand A, Jutras B, Lassonde M (2013), Auditory event related potentials in children with peripheral hearing loss. Clin Neurophysiol 124(7): 1439– 1447. Acknowledgments—The first author is grateful to the Fonds de la recherche en sante´ du Que´bec (FRSQ) and the CHU SainteJustine Research Centre for their financial support through scholarships. This research was funded in part by the Canadian Institutes of Health Research, the Re´seau provincial de recherche en adaptation-re´adaptation (REPAR), the CHU Sainte-Justine Research Centre, The Hearing Foundation of Canada, and the Canadian Foundation for Innovation. The authors are grateful to the children and parents who invested considerable time and effort to participate in this research project. We are very grateful to Phetsamone Vannasing, Marie-Claude Godin, Wafaa Rhoualem, and Marie-Miche`le Be´liveau for their assistance with this research study.

CONCLUSION AND CLINICAL IMPLICATIONS Although the abnormal N2 latency and amplitude may be considered a characteristic neuro-marker of central auditory deficiency, this information is indicative of a non-specific auditory dysfunction. Such results do not indicate which central auditory capacities are affected, and would therefore not lead to a specific auditory intervention program. More work is needed to refine the protocol and achieve the ultimate goal of finding an objective, sensitive screening tool to help clinicians identify these children before they begin primary school. Although impaired auditory capacity would not be identified, the risk of a potential deficit would be. In addition to this, clinicians can measure potential changes in N2 waveforms before and after an auditory intervention program to document its benefits. Furthermore, significant group results do not imply clinical significance. In the present study, individual data of children with CAPD for N2 latency and amplitude were examined. The most revealing results showed that half of these children obtained results at or above two standard deviations compared to the mean of children without CAPD for latency measures of both standard and deviant stimuli. A study with a larger sample can help to determine the sensitivity and the specificity of the present protocol in order to identify within the clinic, children at risk of CAPD.

LIMITATION Limitations were small sample size due to the requirement that participants did not have comorbid

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(Received 7 February 2016, Accepted 6 January 2017) (Available online 18 January 2017)