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14 Clinical Measurement and Application of Cortical Auditory Evoked Responses
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
ABR, AMLR, and ALR and reported a smaller Nb and a delayed Na
in LD compared to the control group. Additionally, Frizzo et al21
compared the AMLR between 25 children with LD and 25 normal
children. The Na, Pa, and Nb components were detected in all subjects; however, the Nb latency on the left hemisphere was longer
in the LD compared to the control group.
More recently, Romero et al22 reported contralateral prolongation of Pa latency in, and a correlation between the AMLR and
phonological awareness abilities in, children with LD aged from
8 to 10 years old, suggesting that auditory and phonological
abilities are related to each other. Al-Saif and colleagues23 found
no significant dierence in AMLR parameters between 19 children
with specific language impairment and 15 children with typical language development. Based on the obtained findings, the
authors concluded that the primary auditory cortex, as the origin
of AMLR, is probably not aected in children with delayed language development. Similarly, Leite et al24 observed no dierence
in Na-Pa amplitude between a group of children with phonologic
disorders and the control group.
14.4.7 Monitoring Depth of Anesthesia
Many surgical procedures require the patient to enter a state
of general anesthesia. Both underdosage and overdosage of
anesthetic agents have major consequences. Inadequate depth
of anesthesia may result in the patient remaining aware during
the surgery and remembering intraoperative events. On the other
hand, overdosage of anesthetic agents may lead to prolonged
recovery and serious postoperative cognitive complications.
The use of AMLR in monitoring depth of anesthesia is promising
because AMLR cortical components are susceptible to the eects
of sedation in a graded manner. This application of AMLR has been
studied mostly in adults for about 20 years, but there is paucity
of data on monitoring the level of unconsciousness in children.
Prosser and Arslan25 recorded ABR and AMLR in nine anesthetized children and reported unstable AMLR with gross abnormalities and delayed detected components, even though the ABR was
clearly detectable in all subjects. Daunderer et al26 recorded AMLR
before, during, and after general anesthesia in 49 children aged
from 2 to 12 years and found that latencies of AMLR increased
significantly during general anesthesia in all cases and returned
to the baseline values after anesthesia; however, the amplitude
changes were inconsistent. The authors concluded that the AMLR
can be successfully used as a tool for monitoring the unconsciousness level during pediatric surgical procedures.
14.5 Auditory Late Response (ALR)
Well over a dozen specific components or responses can be
recorded within the general latency region described by the
rather vague term “auditory late responses.” As noted at the
outset of this chapter, a variety of terms have been coined to
refer to the responses in the ALR time frame. The general “late
response” time frame extends approximately from 50 ms until
1,000 ms after the presentation of acoustic stimuli. An extensive
literature consisting of many thousands of papers has accumulated since the discovery of the auditory late response in 1939.
The focus of the following brief review is the ALR waveform, consisting of an N1 and a P2 component elicited with tonal or rather
simple speech stimuli, with an emphasis on developmental or
maturational changes in the response. For more detailed information on these many and varied auditory responses within the
late region, the reader is referred to textbooks
published review articles (search http://www.nlm.nih.gov).
2,3
and, especially,
14.5.1 Measurement
A full discussion of the stimulus and acquisition parameters used
in ALR measurement is far beyond the scope of this chapter. The
topic will only be introduced here. A clinical protocol for recording N1 and P2 components of the ALR along with the rationale
for selection of each test parameter can be found in a recent
textbook devoted to the topic of auditory electrophysiology.
We should point out that the literature reveals inconsistencies in
protocols for ALR measurement. Electrode options oer an excellent example of the dierences among protocols. As many as 30
or more electrodes are often utilized in recordings conducted in
laboratory experiments, yet ALR measurement is feasible with as
few as two or three electrodes. The reader is referred to a recent
textbook with an entire chapter devoted to the explanation of a
practical protocol for clinical measurement of the ALR in children and adults.
3
Pearl
The auditory late response can be eectively elicited with speech
stimulation including consonant-vowel combinations such as
/da/ and /ga/.
3
14.4.8 Other Studies of AMLR in Pediatric
Populations
Although this is by no means a clinical application of AMLR, the
P50 component has been used to study sensory gating, the ability
of the brain in “gating in” the novel information and “filtering”
the irrelevant sensory input, in children with dierent disorders,
including autism spectrum disorder (ASD), attention-deficit/
hyperactivity disorder (ADHD), and pervasive developmental
disorder, or PDD (see the textbook3 for a review).
14.5.2 Analysis
A typical ALR waveform with the P1, N1, and P2 components
evoked with a tone burst or speech signal and recorded with a
single-channel electrode array is depicted in Fig. 14.2. Analysis
consists of first confidently detecting in repeatable waveforms
the major components N1 and P2, and then careful calculations
of latency and amplitude values for those components. A recent
textbook provides a systematic step-by-step review of a simple
analysis process used for the ALR.3 Abnormal ALR findings
151
II Diagnosing Hearing Disorders in Infants and Children
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
Fig. 14.2 Typical auditory late response waveform showing major
components. (Courtesy of Hall JW III. eHandbook of Auditory Evoked
Responses. New York, NY: Kindle Direct Publishing; 2015.)
include reductions in amplitude and prolongations in latency,
polarity reversal for selected components, and total absence of
one or more components. The rather strict type of criteria used
in analysis of shorter-latency responses, such as ABR, are not
appropriate for ALR because of the inherent normal response
variability. Even interaural dierences in response parameters
are not applicable in most cases because binaural stimulation is
often employed. ALR morphology, latency, and amplitude may
vary substantially even in subjects with normal hearing and
neurologic function. The normal variations among subjects and
within subjects from one averaged waveform to the next in a
single test session are, to some extent, due to the susceptibility
of the response to uctuations in subject state. Waveform morphology, for example, is very dierent if a subject is awake and
a
lert versus awake and drowsy.
14.5.3 Nonpathologic Factors
Major nonpathologic or subject factors inuencing the ALR that
must be taken into account in the analysis and interpretation of
findings include:
These factors are reviewed further in the following sections
of the chapter. As with AMLR measurement, subject state of
arousal is an important factor in ALR measurement. The strategy
of encouraging the patient to view a video on a DVD or another
format is useful when recording the ALR from young children.
Pitfalls
Sleep has a signicant inuence on ALR recordings.
•
A popular strategy for facilitating an awake yet quiet status
•
when recording ALR in young children is to allow the patient to
watch a favorite video or cartoon.
14.5.4 ALR in Pediatric Populations
Morphology of the ALRs diers significantly between children and adults. In addition, throughout childhood there are
substantial maturational changes in ALR latency, amplitude,
and morphology. The dierences between ALRs recorded with
maturation in childhood and in adults go beyond dierences
in latency, amplitude, and relative amplitude of components to
include also refractoriness, emergence of certain components,
and complex changes in morphology and scalp distribution.
Knowledge of morphologic dierences in the ALR associated
with development in children is important, as it guides the
selection of test protocols, stimuli, and acquisition parameters
and collection of normative data.
ALR in Children with Normal Hearing
A number of investigations have focused on emergence of and
age-related changes in major ALR components. There are variations in results from one study to the next due to methodological
variables known to aect the waveform, such as the type of
stimuli used, number of repetitions, rate and interstimulus
interval, and acquisition parameters.3 The developmental course
of the P1, N1, and P2 components of the ALR have been studied
with respect to their latencies, absolute and relative amplitudes,
and morphology. When we consider the ALR as a clinical tool,
it is important to note that ALR components are easy to record
even in young children who are not voluntarily responding to
the stimulus. As emphasized at the outset of this chapter, ALR
measurement is a valuable addition to the pediatric hearing
test battery largely because the P1, N1, and P2 components are
objective measures of cortical auditory functioning. ALR components have in recent years gained importance as markers of
neuromaturation.
17,2 7
27
Age and neurologic maturation
•
Attention
•
Sleep
•
Eects of intervention
•
General Developmental Changes in the ALR
Although developmental changes in the ALR are numerous
and rather complex, a few general statements are possible and
152
14 Clinical Measurement and Application of Cortical Auditory Evoked Responses
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
necessary for meaningful clinical pediatric application of the
response. First of all, the P1 component of the ALR decreases in
latency with increasing age. Latencies appear to decrease rapidly
in the first decade of life and then more gradually in the second
decade of life.
are characterized by prominent P1 and N2 waves. In contrast,
the N1-P2 complex is prominent when recorded from adult
subjects.
followed by an almost adultlike P2 and a clear and often robust
N2 by the age of 3 to 6 years.3 It is likely that the P1 component
appearing in the ALR recorded from infants and young children
corresponds to the Pb or P50 component of the AMLR. This observation underscores a challenge of categorizing cortical auditory
evoked responses on the basis of latency, a point stressed at the
beginning of the chapter.
The N2 is often robustly present in the ALR of young normal
hearing children even in the absence of a clear N1-P2 component.28 The P1-N2 response appears to be responsive to changes in
stimulus characteristics such as spectral content and voice onset
time. Almeqbel
istics of P1 and N2 in normal children were dierent across three
natural speech tokens (/g/, /m/, and /t/), indicating that the ALR
could be an objective index of spectral processing at cortical level.
It is important to point out that age-related dierences are not
uniform across all the waves even though the latency of all ALR
components decreases and amplitude increases with age.
17,2 7,28
Also, ALR waveforms recorded from children
3,27
The P1 component first appears developmentally,
30
observed that latency and amplitude character-
Pearl
A reliable and robust cortical response such as the P50 component or P1 wave can be recorded in infants and young children.
Developmental Changes in Scalp Distribution
Electrode location on the scalp is another factor that plays a
role in the developmental patterns of the ALR. Most research
studies employ a rather large number of recording electrodes. As
an example, Ponton et al29 recorded ALR from 30 dierent scalp
electrode locations in 118 subjects between the ages of 5 and 20
years of age. For analysis, subjects were divided into groups so
that cross-sectional data for each year in between could be analyzed. For subjects of approximately 10 years of age, the authors
found abrupt changes in P1, P1-N1b, and N2 peak amplitudes
at the electrodes C3 and C4. No such changes were reported at
the midline electrodes Cz and Fz. There were interhemispheric
amplitude dierences for the N1b peak. In all the age groups
except the 9-year-olds and 15-year-olds, the contralateral N1b
measured at C4 was on average negative compared to the pre-
stimulus baseline. The ipsilateral N1b amplitude did not become
negative until the age of 16 years. Also, the P2 wave showed
age-related dierence in amplitude as a function of electrode
location.
Up to the age of 10 years, the P2 component was more clearly
visible at electrode location Pz compared to more anterior
locations such as Cz and Fz. For older children, the P2 became more
prominent at anterior locations and less prominent at posterior
locations. The N2 latency increased significantly as a function of
age at electrodes Cz, C3, and C4 but showed no changes with age at
the frontal electrode Fz. Based on their findings, Ponton and colleagues suggested that N2 has several source components and “if
the
neural generators underlying N2 have dierent orientations
toward the scalp, the distinct patterns of N2 maturation observed
at central and frontal electrode locations may reect the dierential maturation of the generators contributing to this peak.”
These authors also noted that dierences in maturation observed
for the components of ALR depended on recording electrode
placement or the locations on the scalp. This is an important point
to consider for the application of ALR in clinical populations such
as children with hearing impairment, learning problems, or CAPD.
28[232]
Developmental Changes in Morphology and
Refractoriness
Cortical neurons giving rise to the ALR have a refractory
period, that is, the time required for them to revert to their
preconduction state. During this recovery period the neuron’s
capacity to fire again is limited. The refractoriness of a neuron
changes developmentally with factors such as myelination. The
formation of myelin on the axon directly inuences the speed of
transmission or conduction velocity of a neuron and, thus, can
aect the ability of the neuron to conduct successive stimuli at a
high rate. Neural refractory periods or recovery times for the ALR
are relatively long. Hence, the interstimulus interval (ISI) rather
than number of stimuli per second should be used to describe
the rate factor for the ALR.2 In ALR measurement longer ISIs
produce larger amplitudes of the N1 and P2 components, but ISI
appears to have no significant eect on ALR latencies.3 This eect
on the ALR is interpreted as a reection of the time required by
neurons to recover after being activated by a stimulus. However,
refractory periods of individual neurons are significantly shorter
than those for the N1 and P2 components of the ALR.
3
Maturational Changes in Anatomy and Physiology
One would logically assume that neurological maturation correlates with anatomic and physiologic changes that occur developmentally and that these changes are related to age-related
changes in the ALR. Research using histologic evidence confirms
neuromaturation of the auditory cortex in normal hearing
children and clinical populations.31 The ability to process speech
in degraded acoustic environments is significantly enhanced in
normal-hearing children beyond the age of 7 years. Eggermont
and Ponton32 point out that it is not surprising for children under
the age of 7 years to have no N1 component except at very slow
stimulus rates of under 1 per second, considering the timeline of
development. Age-related alteration of the ALR and appearance
of the N1 coincide with maturation of the upper cortical layers.33
The N1 component, as already mentioned, matures well into
adolescence and seems to originate from the upper layer II of the
32
cortex.
153
II Diagnosing Hearing Disorders in Infants and Children
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
Pitfall
Age must be taken into account in deciding on the test protocol
for recording ALR and in analysis of test results.
14.5.5 Clinical Applications of ALR in
Pediatric Populations
A substantial number of published papers describe dierences
between ALRs recorded from normal-hearing individuals versus
various clinical populations. Dierences in clinical populations
are described for latency and amplitude of dierent components,
as well as presence versus absence of dierent components. As
noted already, ALR is an attractive objective test tool for assessing the integrity of higher-order auditory processing in children,
specifically at the level of the auditory cortex. ALRs have proven
diagnostic utility, but they also can eectively be used as objec-
tive outcome measures for children who undergo hearing aid
fitting or cochlear implantation.
to documentation of the benefits of auditory training in children
with CAPD and learning problems.
Space does not permit a detailed review of each of the papers
reporting data in support of the clinical application of ALR in
pediatric populations, or even all of the major publication. We
will here briey describe results from only one or two papers on
the most often studied topics. Readers are encouraged to read
comprehensive reviews of the literature found in recent books
on clinical measurement and application of auditory evoked
responses.3 Original research articles appearing in peer-reviewed
journals are without doubt the most valuable source of additional
information on the application of the ALR in clinical populations.
34,35
In addition, ALRs contribute
36
auditory behavior or lack of it should logically have a correlate in
terms of presence or absence of a particular brain activity.
In some of the earliest published studies on the topic, Jirsa and
colleagues reported significant dierences in the mean latencies
of ALR N1 and P2 components and the P3 response between
children with and without symptoms of auditory processing di-
37,38
culties.
were significantly longer in children with behaviors consistent
with processing problems.37 Jirsa and Clontz38 studied ALRs in
children with auditory processing deficits and compared the
findings with a control group of children with normal hearing,
matched for age, intelligence, and sex. There was a significant
latency increase for the ALR N1 and P2 waves and the P3 response
in the group with auditory processing disorder. In addition, the
interpeak latency interval for P2-P3 was significantly longer in the
CAPD group. Among the amplitude measures, only P3 amplitude
diered significantly between the groups. It is possible, then, that
children with CAPD may be reecting the eect of an immature
auditory nervous system. Findings of abnormalities in ALR were
reported even in adults with auditory problems consistent with
the presence of CAPD.39 In contrast, however, other studies have
found no relationship between the P1, N1, and P2 components of
ALR and fine-grained speech sound perception.
More recently, Almeqbel and McMahon29 explored the possible clinical utility of the N2 component in identifying temporal
processing problems in children. Their rationale was that the N1
component is an objective indicator of discrimination ability that
is often not clearly present even in young children with normal
hearing. The authors reported a significantly shorter N2 latency
for the voiced consonant /d/ in comparison with its voiceless
counterpart /t/. N2 latency also increased as signal-to-noise ratio
became adverse. Further N2 latency did not show any consistent
changes as a function of amplitude modulation depth. Overall,
the authors concluded that the N2 had potential as an objective
tool for identifying temporal processing problems in children,
especially when behavioral test measures were not feasible.
Jirsa found that the mean latencies of the components
40
Central Auditory Processing Disorder
154
The 2010 American Academy of Audiology (AAA) Clinical Practice
Guidelines on (C)APD clearly support the application of cortical
auditory evoked responses in the diagnosis and management
of this common clinical population. The “C” in the acronym
refers to CNS auditory processing disorders, although peripheral
auditory dysfunction may co-exist with CNS involvement. To
quote the guidelines: “Auditory evoked responses (AER) from
the auditory brainstem response (ABR) through higher level
cortical auditory evoked responses have clinical value in the
evaluation of (C) APD.”
guidelines also note: “There is a growing literature describing
many auditory evoked responses with latencies beyond 50-ms
elicited with non-speech and speech signals. Those most relevant to clinical assessment of (C)APD include the auditory late
response (ALR), which is comprised [sic] of the N1 and P2 evoked
potentials and the P300 response. The cortical auditory evoked
responses reect the function of sites suspected of dysfunction
in the majority of children with (C)APD.”
and peer-reviewed document confirms the rationale for use of
objective measures such as ALRs to diagnose CAPD is that every
18[19]
In refer ring specifically to the ALR, the
18[20 ]
This evidence-based
Objective Documentation of Improvement in
Auditory Processing
ALR also shows potential as an eective tool for objective assessment of change in cortical functioning as a result of either signal
enhancement with, for example, FM technology or a training
program targeted at improving auditory processing at the level
of the cortex. Cunningham and coworkers40 studied the eect of
“cue enhancement” on behavioral auditory performance as well
as electrophysiologic measures in a sample of normal children
and children with learning problems (LP). They studied the
eects of enhancing specific speech cues at the syllable level
in order to examine which cues resulted in better auditory
perception of the stop consonants /d/ and /g/ incorporated in
the syllables /ada/ and /aga/. They also examined corresponding
dierences in ABR, frequency following response (FFR) and
ALRs.40 The authors reported that the dierences between the
normal control and the LP group on ALRs were eliminated by the
use of cue-enhanced stimuli. This was an encouraging finding,
implying that ALRs might contribute to development of more
eective therapy techniques and strategies.
14 Clinical Measurement and Application of Cortical Auditory Evoked Responses
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
In another study a few years later, Hayes and colleagues investigated changes in the central auditory pathways and cognitive
skills of children with LP as a result of training.
41
Learning and Language Disorders
In addition to the studies already cited for auditory processing
disorder, a sizable number of papers describe ALR findings in
children with “learning and language disorders.” As an example,
Gilley et al42 investigated ALRs recorded from 26 children with
LP. The authors reported that a majority of the children had
abnormal responses. Vanvooren and colleagues43 investigated
the ALR evoked with syllable and phoneme rate modulations in
two groups of 5-year-old children: typically developing children
and children at high hereditary risk for dyslexia. There was
no significant overall dierence between the two groups with
regard to hemispheric asymmetry of cortical responses. They
concluded that for 5-year-old children who could be considered
to be in a prereading stage, hemispheric specialization for
syllable rate modulation is mature, whereas that for phoneme
modulation rate is yet immature.
ALR evoked with traditional tonal stimulation also contributes
to assessment of children with learning or language disorders.
Davies and coworkers44 recorded from normal adults and children
the ALR in response to 1,000-Hz and 3,000-Hz tones presented
in blocks of tones. Children with sensory processing disorders
showed the most disorganized ALR patterns. This finding could
explain the sensory overload that such children face in day-today environments where there is a high demand for processing
rapidly occurring sequential sensory information.
Auditory Deprivation
Given the previously reviewed investigations of ALR as an
index of auditory cortex maturation and development, one
would suspect a potential application of the response in documenting the adverse impact of auditory deprivation during
infancy and young childhood. Most investigations focus on
the eects of deprivation on behavioral and electrophysiologic
measures.
early synaptogenesis is intrinsically controlled and, therefore,
largely independent of a child’s auditory experiences. These
authors did, however, point out that learning and memory aect
the formation of synapses in later life and that onset of functions
of the cerebral cortex seems to occur during the late phase of
rapid synaptogenesis. Hence, cortical-level auditory processing
and ALRs should logically be dependent on auditory experience
or lack of it due to hearing impairment.
31,32,34,45
Huttenlocher and Dabholkar31 suggested that
Attention-Decit/Hyperactivity Disorder
As noted in the next section, research on cortical auditory
evoked responses in children with ADHD has largely focused on
event-related responses such as the P300 and the mismatch negativity (MMN) response. There are, however, some studies that
include ALR measurements. Oades46 reported a larger amplitude
for the ALR P2 component in some children with the diagnosis
of ADHD. The authors also point out the possibility of a smaller
P2 component that normalized after medical management.
There are discrepancies in outcomes among studies, probably
because children with ADHD are not a homogeneous population.
Oades suggested that large P2 amplitudes were consistent with
impulsivity.
the drugs used in the therapy of ADHD is methylphenidate. Some
researchers have measured ALRs and event-related responses
before and after treatment with methylphenidate in an attempt
to document objective evidence of neurophysiologic changes.
46
Hyperactivity is often treated medically. One of
Autism Spectrum Disorder
Bruneau et al47 investigated the relation between ALRs elicited
with tone burst stimulation and recorded at temporal sites
and verbal and nonverbal abilities in children with ASD. These
researchers reported a correlation between the amplitude of the
right temporal N1c responses and the verbal and nonverbal communication abilities. The authors suggested that, in autism, there
is an aberrant reorganization of the functions of the right and left
hemispheres, with activation of the right hemisphere for tasks
in which the left hemisphere should be activated normally. One
of the diculties in such studies is the dierential diagnosis of
intellectual disability versus ASD due to overlapping behavioral
characteristics in both groups. Although intellectual disability
and ASD can coexist, it is often dicult to separate the eects
of both when diagnosing a child with one or the other condition.
In an earlier paper, Seri et al48 reported findings for a study of
ALRs in a subset of children who met Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria for
ASD. The authors reported that the N1 component of the ALR had
a significantly prolonged latency and lower amplitude in all the
children with ASD. These children, as opposed to the nonautistic
children, had magnetic resonance imaging (MRI) documentation
of lesions on one or both temporal lobes. The MMN had a longer
latency in the autistic subgroup.
Auditory Neuropathy Spectrum Disorder
Some investigators have longitudinally documented the progress of implanted children with ANSD using ALR as an outcome
measure.49 ALR findings can provide clinically valuable infor-
mation on whether hearing aids are providing adequate benefit
or whether cochlear implantation should be considered. There
is clear evidence documenting various clinical applications of
ALR in children with the diagnosis of ANSD.
review simply highlights one of these studies.
Rance et al51 conducted a study of 18 children with the diagnosis
of “auditory neuropathy.” The purpose of the study was to investigate a relationship between the presence of ALRs and speech
perception performance. A direct relation between presence
versus absence of the ALR and speech perception abilities was
evident. Poor speech perception was associated with absent ALR,
whereas responses of children with better speech perception abilities were normal in latency. Rance et al suggested that obligatory
cortical auditory evoked response test results “may oer a means
50, 51,52
The following
155
II Diagnosing Hearing Disorders in Infants and Children
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
of predicting perceptual skills”
with auditory neuropathy. The presence of normal ALRs appeared
to predict a possibility of some speech perception benefit with
amplification. ALRs could be useful in deciding treatment options
and hearing aid fitting strategies in infants with ANSD.
51[239]
in young children diagnosed
50
Pearls
The ALR can contribute importantly to diagnosis of ANSD and
•
verifying integrity of neural pathways.
ALR can also play a role in documenting the most eective
•
management strategy for ANSD, such as amplication versus
cochlear implantation.
CIs can be a viable treatment option for children with ANSD.
Speech perception outcomes, may, however, be variable. ALR is
an important clinical tool for longitudinally tracking the progress
of children with ANSD whose intervention includes hearing aids
or CIs.
14.6 P300 Response
The P300 is a response elicited with specific stimuli and detected
within the ALR time frame or window. The P300 response was
first introduced and investigated in 1965 as an “event related
potential (ERP)” associated with an unpredictable stimulus,
reecting the active process of decision making.3 This approach
for distinguishing between signals that vary according to a single
physical attribute is also referred to as the “oddball paradigm.”
In its most traditional form, Ritter and Vaughan53 described the
oddball paradigm as requiring two stimuli. One of these stimuli,
referred to as the “frequent” or “background” stimulus, has a
high degree of presentation probability. It is typically present
80% of the time. The second stimulus is referred to as the “rare”
or “target” stimulus and has a low degree of presentation probability, usually present 20% of the time, and is presented in an
unpredictable manner. Researchers have referred to the P300 as
an “endogenous” response, meaning that the recorded electrical
cortical activity is not related to the physical attributes of the
signal as much as it is related to its conscious subjective perception. In this section, we focus on the auditory route of stimulation
with an emphasis on topics relevant to a pediatric population
and for the purposes of pediatric auditory assessment.
In auditory assessment, the distinguishing attributes of the
P300 include the frequency and intensity of the signal, although
other attributes may also be important in evoking the response.
For example, voice onset time is a critical attribute for stimuli
consisting of speech phonemes. Although the P300 has been
investigated intensively in the adult population, its developmental
characteristics have received less attention.3 Van Dinteren and
colleagues54 published a very useful comprehensive review of
P300 development through the lifespan. We recommend their
paper for further information on the topic.
14.6.1 Variants of the P300 Response
Researchers studying the P300 commonly make the distinction
between active and passive responses in both pediatric and adult
population. Most often, the task used in these studies is called an
“active” task because the subject is asked to attend consciously
to the stimulus, for example, by counting out loud the number of
occurrences of the infrequent stimulus or pressing on a button
every time it arises.
latency region of 300 ms is what has become known as the P300.
The participant does not need to count the number of presentations correctly, but the requirement to attend to the stimulus
maintains conscious focus on the task at hand. Consequently, the
P300 component arises slightly later on the latency range and
is labeled the “P3b” variant of the response. It is important to
note here that most literature on the P300 actually describes
the P3b response. In addition to the traditional P300, a P3a peak
has been reported with a slightly shorter latency and smaller
amplitude compared to the standard P300.
is more frontally oriented topographically. The P3a wave has primarily been linked to stimulus novelty or its alerting attributes
ithout the generation of an active response. When this wave
w
is recorded, the patient may be asked to read a book or watch a
video to divert his or her attention. Given the simplistic nature
of the task, this methodology may be preferable for evaluation of
young children.
3,53
The response to the task occurring in the
55
Also, the P3a wave
3,56
Pitfall
Special equipment or equipment options are required to record
the P300 response, whereas ABR systems can be used to record
the AMLR or ALR.
14.6.2 Cognitive Processes
The emergence of a P300 is evidence of a person’s conscious
distinction between stimuli.57 Throughout the literature, P300
has established itself as a measure reecting several cognitive
processes, and many theories have been developed to pinpoint
which processes are implicated in its generation. It is dicult
to nominate a single process, because the response by itself is
very dependent on non-task-related factors such as arousal
level, and it can be mediated by factors such as body temperature or drug and food intake. Even without a clear explanation
he underlying processes, evidence from studies of patients
of t
with dementia show longer P300 latency times associated with
decline in cognitive but not motor function.3 This would suggest
that superior cognitive performance is related to shorter latency
time and larger amplitude. While the P3a component appears
to be linked to orienting reactions and involuntary attention to
environmental changes, the P3b component reects recognition
and decision-making processes. In summary, it is agreed that
P300 reects activities of updating of working memory, event
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copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
categorization and discrimination, and attentional resource
allocation as well as attentional reorientation, sequential information processing, and decision making. All of these aspects of
cognition are necessary for auditory processing.
57
14.6.3 Neurochemical and
Neuroanatomic Generators
Historically, researchers have stipulated that the P300 must be
generated from a single cortical site because it is usually the
strongest in terms of amplitude as measured by the electrodes
covering the parietal lobe, more precisely the Pz location.
However, more recent studies on auditory electrophysiology
show evidence that, aside from ABR wave I and wave II, all the
auditory electrophysiologic responses have multiple neural sites
of generation. Although there is no clear answer yet as to which
cortical or subcortical regions are responsible for the generation
of the P300, more recent research reveals that excitatory neurotransmitters such as glutamate and inhibitory neurotransmit-
ters (acetylcholine) re ect intracortical postsynaptic potentials
as well as a number of neural generators contributing to the
formation of the waveform. Those generators include the reticular formation, lemniscus, inferior colliculus, thalamus, primary
cortex, frontal cortex, central parietal cortex, temporoparietal
cortex, and possibly the hippocampus.
The variety of neural generators is a re ection of the multiple
cognitive processes that are engaged in the appearance of the
P300, namely attention, memory, and temporal auditory processing.57 It should also be noted that these generator sites seem to
vary depending on whether the P3a or the P3b is being recorded.
Studies have shown that the P3a waveform is most prominent at
the Fz and Cz electrode locations, as it seems to have a frontal
site of generation and relies mostly on dopaminergic pathways.
Conversely, the P3b response seems to have a more parietal site of
generation, as it is most prominently recorded at the Pz electrode
site relying mostly on norepinephrinergic pathways.
58,59
56
Fig. 14.3 Typical auditory P300 response waveform showing major
components. (Courtesy of Hall JW III. eHandbook of Auditory Evoked
Responses. New York, NY: Kindle Direct Publishing; 2015.)
Amplitude
The frequent stimulus and the rare or target stimulus need to be
noticeably di erent to generate a large P300 amplitude. Eliciting
the P300 with a set of frequent and rare stimuli that are harder
to distinguish results in an amplitude reduction. For example, a
larger amplitude is produced when the P300 response is elicited
with a frequency stimulus of 1,000 Hz and a target stimulus
frequency of 2,000 Hz than if the standard was 1,000 Hz and
the target 1,100 Hz.
amplitude, as higher intensity for stimuli generated greater
amplitude. Finally, amplitudes of P300 components decrease as
the stimulus rate is increased above 1 or 0.5 stimulus/second.
3,60
There is also an e ect of intensity on the
3,60
14.6.4 P300 Response Characteristics
The P300 response is recorded by averaging time-locked mea-
sured brain electrical activity in the EEG. The averaged waveform
for the background or frequent stimulus appears as a series of P1,
N1, P2, and N2 waves. We are interested here in the appearance
of a large positive waveform, the P300, that emerges following
the presentation of the infrequent stimulus, as illustrated in
Fig. 14.3. According to the literature, the P300 response usually
develops at around 300 ms, but it may appear anywhere between
250 and 400 ms and up to 900 ms in infants.3 Intersubject as
well as intrasubject variability is common in P300 data for
normal-hearing persons. The criteria of an abnormal P300 are
often described in terms of delayed latency and reduced amplitude in the absence of any confounding subtle, subjective factors
such as inattentiveness or state of arousal.
3
Latency
Response latency is also a ected by the di culty of distin-
guishing the target stimulus from the frequent one. The more
distinct the di erence between frequent versus target stimuli,
the shorter the latency measured. Conversely, the closer the
frequent and rare stimuli are, the longer the latency.60 Stimuli
with higher intensities also produce a shorter latency. Also,
latency of the P300 response increases with the increase of the
interval between stimuli. Finally, a subject’s hearing threshold
must be determined prior to testing, especially when frequencies are used as stimuli to produce similar sensation levels
for both sounds.
measurement in patient populations that are likely to have
hearing loss in one frequency region and not another, such as
elderly patients with age-related high-frequency hearing loss.
3,61
This point is particularly relevant for P300
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copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
Whenever feasible, definition of hearing sensitivity with pure
tone audiometry should always precede P300 measurement.
14.6.5 P300 in Childhood
Developmental Factors
Understanding of developmental changes in the P300 response
is very helpful in the clinical setting to determine whether a
response is abnormal due to auditory or language impairments
or simply a reection of normal developmental maturation
timeline and increased eciency in information processing.
Therefore, age must be taken into account when recording the
P300 response in pediatric populations, just as it is for other
electrophysiologic measures. Confirming this point, researchers
have shown evidence of a decrease in latency, an augmentation
in amplitude, and an improvement in morphology as the chronological age increases, regardless of the used paradigm.3 Most
reported studies were conducted with school-aged children, but
the findings also are relevant to younger children and infants.62
We should also note that peak amplitude is generally reached
before latency reaches its minimum. Despite those quantitative
age-related dierences, topography of the P300 remains similar
in children and adults.
Studies suggest that the decrease in latency constitutes evidence of neuromaturation of cognitive-related processes, contrib-
uting to increased eciency of information processing, namely, an
increase in speed of detection and categorization of the stimulus.
P300 amplitude depends on neuronal firing synchronization and
indexes attentional resource allocation.54 Interestingly, Rozhkof et
al63 found that the most significant changes in P300 parameters
were observed in children aged from 7 to 12 years, suggesting that
this period can be regarded as “critical” in the development of
learning skills. These investigators also found a nonlinear relationship between age and P300 latency. That is, greatest changes were
seen in children of the youngest school age; then P300 latency was
relatively stable after the age of puberty, although it continued
to decrease somewhat until the age of 25 years.54 As for the rate
of change, the general findings indicate that with increasing age,
the latency decreases at an approximate rate of about 19 ms per
year. Given the maturation process that is thought to be complete
around adolescence, analysis of P300 findings with reference to
normative data for monthly increments are recommended for
children aged 1 to 24 months. Yearly ranges can be considered for
children between 2 to 8 years. Children aged between 8 and 18
years can be grouped into 2-year age categories.
Polich and colleagues64 conducted a thorough investigation of
factors inuencing P300 measurement including age, memory
span, and size of the head. Unlike age and memory variables,
head size seemed to have a very small eect.64 Also, as the skull
thickens with growth, only the P3b amplitude decreases and not
the P3a. These findings suggest that skull thickness could play
a modulating eect in the pediatric population when using the
active tasking protocol and may explain why amplitude measure
reaches its maximum before latency does.
3, 57,6 1
3
54
Pearl
The auditory P300 response oers a clinical tool for objective
documentation of high-level central auditory nervous system
function and, to an extent, cognitive status.
Sex
Bakos et al65 conducted a study to examine dierences in P300
amplitude between adolescent girls and boys aged 13 to 18 years.
They found that P300 amplitude among girls was significantly
decreased compared to boys, regardless of electrode recording
sites. They further suggest, based on their findings, that adolescent boys might be more attentive to relevant auditory stimuli
than adolescent girls. Interestingly, Bakos et al65 also noted that
unlike boys, who do not seem to show an age eect on the P300
amplitude, girls show greater P300 amplitude with increasing
age. This finding implies that cognitive processes responsible for
generating the P300 in boys may mature earlier than in girls.
14.6.6 Test Protocol
Stimulus Parameters
As noted earlier, the optimal probability of presentation is 20%
for the infrequent stimulus and 80% for the frequent stimuli.
A test protocol with an explanation of the rationale for each
parameter can be found in the recent textbook.3 In addition to
the two stimulus paradigms, some researchers have used more
complex ones such as the use of three dierent stimuli, whereas
other researchers have used more simplistic ones such as the use
of only a rare stimulus in silence. This latter mode of stimulation
also elicited a P300 response similar to that of adults. According
to Polich and colleagues,
adigm along with a passive response generated P3a responses
in younger children and infants similar to what would be seen
in adults. Finally, among the variety of auditory stimuli to be
used, using speech stimuli may be very attractive to the clinical
audiologist, as the presence of a P300 after speech stimulation
indicates linguistic discrimination at the conscious level.
14.6.7 Analysis
A consistent approach in identifying and labeling the waves and
calculating latency and amplitude values for each component
is essential in clinical settings. Major steps in analysis of the
P300 response are illustrated in Fig . 14. 3. For the sake of clinical practice and utility we present in this review the general
guidelines for identifying the wave in terms of latency and
amplitude. Again, the reader is referred to the recent textbook3
for a thorough review of suggested recording parameters. A
P300 response is expected to appear at a latency of 250 to 400
56,60,64
the use of a single-stimulus par-
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Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
ms, but it may appear with a latency up to 900 ms, especially
for infants. The latency is usually calculated in milliseconds from
the start of the stimulus to the peak of the P300. Given the fact
that the P300 waveform often appears as a collection of multiple peaks, the measurement point will be set at the midpoint
of the collection. As with the latency measurement, there are
also many ways to calculate amplitude. However, amplitude
calculation from baseline to peak is most common. To minimize
the eect of background noise, allowing a prestimulus baseline
period greater than 100 ms is recommended. Finally, the normal
response amplitude generally ranges between 10 and 20 µV.
Nonpathologic subjective factors are:
Age
•
Sensory status
•
Cognitive status
•
Medication/drugs
•
State of arousal
•
14.6.8 Clinical Applications in the
Pediatric Population
Like other auditory electrophysiologic measures, the P300
constitutes an objective, relatively inexpensive and noninvasive
technique for evaluation of auditory CNS maturation or pathol-
ogies that may aect auditory processing at the cortical level.
The P300 is particularly well suited for objective measurement
of cognitive processes such as memory and attention in the pediatric and adult population alike. Furthermore, P300 recording is
done without sedation, which is safer and more convenient in a
pediatric population.
Even though intersubject variability is greater than intrasubject
variability within the pediatric population, the P300 response
is considered generally reliable, as recorded in research as well
as in clinical settings.66 As noted already, P300 can be useful in
assessing development of cognitive function as well as delayed
neuromaturation. Another focus of investigations in pediatric
populations is to determine the usefulness of the P300 as a tool
in dierentiating among subtypes of disorders. In certain cases,
such information is helpful not only in establishing a dierential
diagnosis but also in planning interventions designed to lessen
severity of auditory processing deficits and communication disorders caused by selected disorders.
Auditory Processing Disorders
Although nonauditory factors aect the P300 component, it
remains a sensitive measure of dysfunction within the auditory
cortical regions. Recognizing evidence in research publications,
and the value of the P300 response as an objective and electrophysiologic auditory measure, an AAA task force cited the P300
response in its peer-reviewed 2010 clinical practice guidelines,
specifically identifying the P300 as one technique for establishing the diagnosis of (C)APD.
18
Jirsa was among the first to conduct a study with a pediatric
population diagnosed with (C)APD.38 He found significantly
longer latencies for ALR and the P300 and decreased P300 amplitude in comparison to control subjects. Speech perception in
noise is an ability extensively evaluated in auditory processing.
Krishnamurti67 found that adults diagnosed with (C)APD demon-
strated a significantly delayed P300 latency compared to normal
subjects when exposed to contralateral noise stimulation. Ubiali
et al,68 in a study conducted on normal-hearing children, found
significantly delayed P300 latency as well. There is a need for additional studies to examine whether other P300 patterns are likely
in children with (C)APD. Wilson and colleagues69 also conducted a
study examining evidence of improvement after auditory therapy
in children diagnosed with (C)APD. Examining the P300 waveform,
these researchers concluded that electrophysiologic measures can
be sensitive to behavioral changes induced by auditory therapy.
Specic Language Impairment
Specific language impairment (SLI) is a diagnosis attributed to
children who exhibit diculty acquiring and using language
in the absence of an identifiable etiology. A study conducted
by Evans et al70 explored the P300 as an index of processing
speed and working memory in the auditory and visual domains
in children with SLI. They found a decrease in P300 amplitude
as well as increase in reaction time with increased demands
on working memory, in both modalities, compared to normal
children. Another study found that P300 latency, and not earlier
ALR peaks, were delayed for children diagnosed with SLI as well
as their parents, suggesting a hereditary transmission of slower
information processing.
71
Attention-Decit/Hyperactivity Disorder
To this date, no clear consensus has been reached regarding
P300 patterns in ADHD. Inconsistently reported findings include
smaller amplitude compared to normal individuals and longer
latency, but dierences among studies preclude any confident conclusions. A study conducted on children with ADHD
looking at the eect of medication on the P300 found that a
higher percentage of medicated children showed evidence of
P300 (57%), whereas only 28% of nonmedicated children had
a P300.72 Also, Yamamuro et al73 found that P300 latency was
significantly shorter after 2 months of medication, but there was
no significant improvement in amplitude. Finally, Johnstone et
al74 conducted a study examining the developmental changes
relating to topographic distribution of the P300 activity. These
researchers consistently found amplitude reduction of the P300
at posterior sites in conjunction with an increased amplitude at
the anterior site compared to normal control group. The abnormal P300 patterns were more prevalent among the combined
type as compared to the inattentive type. The variations were
also age dependent, as this shift in neuronal activity seemed to
reverse with increasing age. It may therefore be valuable to conduct topographic analysis on children with ADHD to distinguish
between those two subtypes.
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Cochlear Implantation
Early P300 research in pediatric CI users show evidence of sig-
nificantly delayed but present P300 response.75 These findings
generated curiosity among other researcher to understand
better the variability observed in auditory and linguistic tasks
among CI recipients, including studies comparing CI users with
poor speech recognition as measured behaviorally to CI users
with good speech recognition.
76
The results from both groups
were then compared with those of normal-hearing children.
Dierences in the P300 when tonal stimuli were used were
nonsignificant. When speech stimuli were used, however, the
poor-performance CI group demonstrated either abnormally
delayed or absent P300, whereas the good-performance CI group
had P300 results similar to the control group. The results are
suggestive that P300 may be reective of auditory and phonetic
discrimination cognitive processes.76 In an attempt to under-
stand the eect of noise on auditory attention in CI users, Soshi
et al77 conducted a study on adult patients and concluded that
CI patients with good linguistic performance showed evidence
of P300, indicating conscious attention to distinguish speech
in noise. They also found that better speech performance was
correlated with larger P300 amplitude. As such, the P300 could
be used as objective evaluative test for improvement of CI users’
speech performance in noise.
Autism Spectrum Disorders
A recent meta-analysis by Cui et al78 revealed 32 studies on
autistic children and adults. Findings provide general agreement
among examined studies of reduced P3b amplitude. There was,
however, no statistical dierence with regards to P3b latency nor
to latency or amplitude of P3a. These findings suggest that the
abnormality mostly occurs at the level of stimuli discrimination
when attention is required.
14.7 Conclusion
Cortical auditory evoked response tests applied in clinical
assessment of children with suspected or confirmed hearing
impairment most often include the auditory late response
(AMLR), the auditory late response (ALR), and the auditory P300
response. Importantly, cortical auditory evoked responses now
contribute to the diagnosis and management of children with
a wide variety of disorders. Indeed, cortical auditory evoked
responses are now among the objective procedures within the
modern test battery that serve in the implementation of the
cross-check principle in pediatric hearing assessment. We provide a practical review of techniques and protocols for recording
cortical auditory evoked responses for assessment of auditory
function of children in the audiology clinic. Special attention
is paid to the responses in infants and young children. We also
review selected clinical applications of these three cortical
auditory responses with ample citations from the peer-reviewed
literature.
Discussion Questions
1. Where in the central auditory system are the generators for
the AMLR?
2. Describe briey the “electrode eect” in AMLR ndings.
3. What kind of stimuli can be used to evoke the ALR?
4. How can the ALR contribute to documenting eective man-
agement of children with the diagnosis of ANSD?
5. What is the main dierence in the protocol for recording the
ALR versus P300 response?
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