Disorders of Peripheral and Central Auditory Processing
Handbook of Clinical Neurophysiology, Vol. 10
G.G. Celesia (Vol. Ed.)
# 2013 Elsevier B.V. All rights reserved
CHAPTER 9
Middle- and long-latency auditory evoked potentials:
what are they telling us on central auditory disorders?
Claude Alaina,b,*, Anja Royea and Stephen R. Arnotta
a
Rotman Research Institute, Baycrest Centre for Geriatric Care, Toronto, ON M6A 2E1, Canada
b
Department of Psychology, University of Toronto, Toronto, ON M8V 2S4, Canada
9.1. Introduction
Peripheral and central auditory processing disorders
are quite prevalent in noisy industrial societies, with
estimates of approximately 10% of the U.S. popula-
tion reporting a hearing difficulty in 2004 (Kochkin,
2005). Therefore, it is important to develop objective
measures that allow clinicians and researchers to
detect hearing impairments and assess the efficacy
of treatments. Scalp recording of neuroelectric (elec-
troencephalography (EEG)) brain activity has proven
to be a formidable tool in the arsenal available to hear-
ing scientists and clinicians interested in understand-
ing disorders of peripheral and central auditory
processes. This technique measures the dynamic pat-
tern of electrical fields at the scalp produced by the
coherent activity of large neuronal populations in
the brain. In hearing science, the measurement of
the neuroelectric activity generated by clicks, tone
pips or speech sounds allows for non-invasive
evaluation of hearing functions with high temporal
resolution. Moreover, scalp recording of auditory
event-related potentials (ERPs) makes it possible to
delineate normal or impaired system functioning at
different stages of processing. For instance, the
recording of auditory brainstem responses is now a
well accepted neurological test of auditory brainstem
function (see Celesia, Chapter 7, this volume).
In the last 20 years, there has been a great deal of
interest in developing new measures of central auditory
processing that assess hearing functions beyond the
mere sensation or simple registration of acoustic infor-
mation. In that regard, scientific interest has gradually
shifted toward the measurements of auditory ERPs as
*
Correspondence to: Dr. C. Alain, Rotman Research Insti-
tute, Baycrest Centre for Geriatric Care, 3560 Bathurst
Street, Toronto, ON M6A 2E1, Canada.
E-mail: calain@research.baycrest.org
177
potential biomarkers for more complex hearing func-
tions (for earlier discussion on the applicability of ERPs
in assessing central auditory disorders see, Alain and
Tremblay, 2007; Picton, 2010). In conjunction with
behavioral responses, ERPs provide a means to assess
perceptual and cognitive operations prior to and follow-
ing decision-related or response-related processes. One
important goal of ERP studies is to identify brain
responses that reflect psychologically meaningful pro-
cesses. This is done by characterizing the acoustic and
psychological parameters that modulate amplitudes
and/or latencies of the specific brain waves that com-
prise the auditory ERPs.
To explore the extent to which operations may occur
outside the focus of attention, neuroelectric recordings
can be evoked from sounds that are not task-relevant
(e.g., during reading or watching a muted movie, ter-
med the “passive” situation). Hence, ERPs indicating
automatic stimulus processing can be recorded without
behavioral measures, thereby allowing hearing assess-
ments in individuals who cannot easily comply with
task instructions (e.g., infants, patients with aphasia).
While this can be particularly important in clinical set-
tings, these measures can also enhance non-clinical
psychophysical methods by highlighting changes in
hearing functions that could be disguised by compensa-
tory effort in the behavioral measurements. However,
in order to separate brain responses related to task or
stimulus manipulations from those resulting from other
ongoing activity in the brain, the number of trials must
often be increased compared to studies recording only
behavioral measures.
Thanks to recent advances in brain electrical source
analysis techniques, scalp recordings of ERPs can now
serve as a bridge between various approaches used to
understand auditory perception. These advances allow
inferences regarding the neural generators that underlie
measured sensory (exogenous) and cognitive
178
(endogenous) evoked responses. Hence, when comple-
mented by source localization techniques, ERP record-
ing becomes an ideal tool for assessing auditory
functioning and the impact of training on functional
brain re-organization in sensory and/or cognitive sys-
tems (Alain and Ross, 2008). In several cases it may
even be the preferred method to more expensive imag-
ing techniques, such as functional magnetic resonance
imaging (fMRI).
In this chapter, we briefly review some of the contri-
butions that ERP research has made to our understand-
ing of auditory cognition and discuss their contribution
and potential application to our understanding of disor-
ders of peripheral and central auditory processing. Even
though they are not routinely utilized in clinical settings,
auditory ERPs are regularly used in research to deter-
mine how physical acoustic energy translates into pat-
terns of brain activity and how those patterns relate to
perception in normal and hearing-impaired listeners.
We begin with a review of some concepts relevant to
the generation, recording, and analysis of EEG data.
Work from Luck (2005) and Picton (2010) can be
consulted for more extensive reviews of EEG recording
and analysis.
9.2. Generation, recording, and analysis of
neuroelectric signals
EEG is a non-invasive technique for measuring brain
activity, which uses electrodes placed on the scalp.
In the brain, electrical currents travel through the con-
ductive brain tissue, cerebrospinal fluid, skull, and
skin, where they can be detected by the electrodes.
Activity picked up by the electrodes is dominated
by excitatory and inhibitory postsynaptic potentials
emitted from the apical dendrites of large numbers
of pyramidal neurons. These cells have a parallel, geo-
metric arrangement, which is conducive to a summa-
tion of electrical activity. Once it reaches the scalp,
however, the activity detected is weak (on the order
of a millionth of a volt (mV)) and thus needs to be
amplified by a magnitude of 10,000–1,000,000 times
in order to be useful. Once captured by the active
electrodes and amplified, the EEG voltage signal is
then converted from its continuous analog form
into discrete numerical voltage values by means of
an analog-to-digital converter.
The EEG response from a given (active) electrode
is expressed as a voltage difference between itself and
a reference electrode placed somewhere else on a rel-
atively inactive or “neutral” location(s) of the scalp.
C. ALAIN ET AL.
The search for a truly neutral reference location has
a long history, and the reader is directed to other
resources for a more in-depth discussion (Luck,
2005; Picton, 2010). One popular strategy is to take
the mean current from all electrodes as a reference site
(i.e., the average reference). Successful implementa-
tion of the average reference approach does, however,
require adequate sampling from all surfaces of the
brain (Bertrand et al., 1985).
EEG reveals rhythmic brain activity, classically
divided into frequency bands: delta (up to 4 Hz), theta
(4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz) and
gamma (10–100 Hz). The rate at which EEG record-
ings are acquired (i.e., the sampling rate) is governed
by Nyquist’s theorem, which dictates that the sampling
rate must be at least twice the value of the highest fre-
quency of interest in order to adequately replicate the
analog signal without losing information or introducing
any artificial low frequencies (i.e., aliasing). Typical
sampling rates range between 150 and 3000 Hz, with
higher sampling rates being needed for accurately mea-
suring early (high frequency) voltage fluctuations (i.e.,
deflections or waves). In addition, low-pass filters of
60–100 Hz are often applied to the EEG data in order
to reduce aliasing from the very high frequency activity
that is naturally present (e.g., muscle activity). Simi-
larly, high-pass filters in the order of 0.01 Hz can also
be implemented to remove large, slow voltage drifts
due to factors such as skin potentials.
To study normal as well as impaired auditory sys-
tem functioning, ERPs are usually obtained from the
raw EEG signal by averaging together multiple epochs
of brain waves that are time locked to either external
sensory events (e.g., presentation of a tone) or internal
events such as a perception or a decision-making pro-
cess. These ERPs comprise a sequence of several pos-
itive and negative deflections (i.e., waves), as shown
in Fig. 1. Each deflection reflects synchronous activity
from large neuronal ensembles time locked to the spe-
cific event. The latency of these brain waves refers to
the amount of time (measured in milliseconds (ms))
that is taken to generate the bioelectrical response fol-
lowing the onset of the event. The measured wave
amplitude is affected by the strength of the response,
the size of the responding neural population, how well
the neuronal activity is synchronized, and where these
neurons are located in the brain with respect to the point
of measurement. Based on the latency of the brain
waves, early brainstem responses, middle- and long-
latency evoked responses can be distinguished. Early
brainstem responses are elicited 1–10 ms after sound
METHODOLOGY AND TECHNIQUES 179

Fig. 1. The left side of the figure shows a schematic representation of the ascending auditory pathways. The right side shows a schematic of
auditory event-related potentials from the brainstem (wave V), middle- (Na, Pa, Pb) and long-latency auditory event-related potentials (P1, N1,
P2, ORN, MMN, N2, and P3). The colored arrow shows the progression from brainstem to long-latency evoked potentials along the ascending
auditory pathways. ORN ¼ object-related negativity; MMN ¼ mismatch negativity.

onset, followed by the first volley of cortical activity in
the primary auditory cortex (middle-latency responses
(MLRs), 10–50 ms) and on to later (“long-latency”,
>50 ms) waves that reflect higher-order auditory pro-
cesses associated with perception, memory, and other
cognitive processes (Fig. 1). Different conventions
exist for labeling the long-latency auditory evoked
potentials (LAEPs). First, the specific potential can
be named after its defining polarity (P, positive, N, neg-
ative) at the typical measurement location. The polarity
symbol is then followed by a number that either names
the actual peak latency (e.g., P300) or its serial position
within long-latency responses (e.g., P3). Further letters
refer to sub-types, such as P3b. Alternatively, an ERP
wave can be named after the functional characterization
of the response (e.g., ORN, object-related negativity).
Magnetic counterparts of the electrical ERP responses
(i.e., transient magnetic activity accompanying the
electric potential changes according to the laws of elec-
tromagnetic fields) are conventionally marked by the
letter “m” appended to the label of the corresponding
ERP (e.g., the magnetic counterpart of the N1 ERP is
often termed “N1m”).
Distinct brain waves are characterized by their dif-
ferent susceptibility to manipulations of acoustic
sound characteristics and psychological factors such
as task requirements, memory, or attention. While
the early brainstem and MLRs are elicited with every
sound that enters the auditory system, this is not the
case for every LAEP. The first LAEPs (P1, N1, and
P2 waves peaking at about 50, 100, and 180 ms after
sound onset respectively) are thought to be exogenous
(i.e., obligatory). That is P1, N1, and P2 occur
irrespective of the observer’s intention, reflecting
primarily the physical properties of the external events.
Subsequent LAEP deflections, such as the N2 and
the P3, are considered endogenous because they are
determined by psychological factors such as attention
and expectation (Fig. 1). However, a strict differentia-
tion between exogenous and endogenous needs to be
revised given that even early responses do not reveal
total independence from psychological factors (e.g.,
Hillyard et al., 1973; Woldorff and Hillyard, 1991;
Baess et al., 2009).
When EEG is recorded with a sufficient number of
scalp mounted electrodes, an evoked response cannot
only be characterized by its topographic distribution,
but inferences can also be made with respect to the
cortical sources underlying that activity. However,
identifying the precise neuronal sources of scalp-
recorded ERPs remains a challenge owing to the fact
that multiple source solutions can explain the same
observed signal pattern. This problem is referred to
as the bioelectromagnetic inverse problem.
The electrical activity recorded at the scalp is
often described in terms of equivalent current dipoles.
These representations closely approximate the parallel
organization of the pyramidal neurons with the
assumption that the synchronized activity of these
pyramidal neurons can be modeled by a point-like
180
electrical source (dipole). Radial dipoles are perpen-
dicular to the skull and are likely formed by activation
of postsynaptic potentials in the gyral cortex, whereas
tangential dipoles are parallel to the skull and reflect
postsynaptic potentials in sulci. In order to determine
the origin of scalp-recorded ERPs, the head is modeled
as a spherical volume (Sarvas, 1987), and a small num-
ber of dipole sources are assumed. For example, the
activity in auditory cortex is best modeled by both tan-
gential and radial sources along the superior temporal
plane near Heschl’s gyrus, which can typically explain
the electrical field distribution across the scalp
sufficiently (Celesia, 1976; Richer et al., 1989; Picton
et al., 1999). For estimation of dipole location, orien-
tation and strength, the difference between the mea-
sured electric field and the calculated field is
minimized by varying the dipole parameters. After
localizing the sources, a time series of brain activity
at the source location can be calculated to illustrate
the time course of neural activity. This source space
projection method transforms a large number of
ERP waveforms (e.g., 64 electrode montage) into a
small number of source waveforms (e.g., 2–10 source
waveforms) (Heinrich et al., 2004; McDonald and
Alain, 2005; Alain et al., 2009). This improves the
signal-to-noise ratio by reducing the overlap
from other possible sources and by filtering out the
effect of sensory noise (Tesche et al., 1995; Ross
et al., 2000). Therefore, when complemented with
source localization techniques, scalp recordings of
ERPs can serve as a bridge between various
approaches used to understand peripheral and central
auditory disorders.
To sum up, ERPs reflect time-locked neural
activity elicited by a physical stimulus or a psycho-
logical event. In particular, auditory ERPs are
elicited by sounds that enter the auditory system
and travel through the auditory pathway. Depending
on the latency which corresponds to the neural
sources along the ascending auditory pathway, early
brainstem responses, MLRs and LAEPs are differen-
tiated. The following two sections review prior
research on auditory MLRs and LAEPs. We will
focus on sound detection and sound discrimination
since these are of particular relevance for hearing
assessments and may provide more application in
the future. In each section, we will briefly discuss
methodological considerations and neural genera-
tors of the respective responses and will review
the relevance of these responses in present clinical
settings.
C. ALAIN ET AL.
9.3. Middle-latency responses (MLRs)
MLRs occur between 10 and 50 ms after sound onset
and comprise several negative and positive deflections
labeled as No, Po, Na, Pa, and Nb as shown in Fig. 2.
The No and Po responses immediately follow wave
V from the brainstem auditory evoked response and
are relatively small and difficult to distinguish from
the postauricular muscle reflex (Picton, 2010).
The subsequent Na, Pa and Nb waves are larger and
peak at about 20, 30 and 40 ms after sound onset,
respectively (Woods et al., 1993; Picton, 2010).
In some cases, the Nb is followed by a positive wave
referred to as Pb. However, when the focus is on
long-latency evoked responses, the same deflection
is referred to as P1 (Fig. 1).
MLRs can be generated by clicks or tone pips,
though clicks typically elicit larger responses with sig-
nificantly shorter latencies than do tone pips at the
same intensity in dB sensation level (Borgmann
et al., 2001). Thus, for good signal-to-noise ratio,
click stimuli are usually used and presented at high
rates of repetition (0.1–13.9 clicks/s) in order to get
a sufficient number of trials that can be averaged
together (about 1000–2000 trials). Even higher rates
of repetition (up to 80 clicks/s) seem to be applicable
if the so called maximum length sequence is used for
Na
No Nb
Po
-1 mV
Pa
0 20 40 60 ms
Fig. 2. Effects of cortical lesions on middle-latency auditory evoked
potentials. Relative to the neurologically intact brain (solid black
line), lesions to the prefrontal cortex (blue) increase the amplitude
of the Pa component (dotted blue line), whereas lesions to Heschl’s
gyrus and auditory cortex (red) decrease the Pa amplitude (dashed
red line). Adapted from Knight (1994).
METHODOLOGY AND TECHNIQUES
stimulation (Picton et al., 1992; Nagle and Musiek,
2009). However, the recovery cycle, which refers to
the minimum time needed to obtain a response at max-
imal amplitude, differs between the MLRs. While the
Pa amplitude is little affected by rates of stimulus pre-
sentation ranging from 0.5/s to 10/s, the amplitude of
the P1 wave is reduced in amplitude or absent at fast
rates. Pa latency, on the other hand, is delayed at faster
(e.g., 10/s) compared to slower (e.g., 1/s) presentation
rates (Erwin and Buchwald, 1986).
One of the potential strengths of using MLRs for
assessing central auditory disorders is their sensitivity
to sound features. For instance, MLR amplitudes
increase to a certain extent with stimulus intensity
(Thornton et al., 1977; Borgmann et al., 2001; Hesse
and Gerken, 2002). With increasing stimulus frequency,
the latency of MLRs (e.g., Na, Pa and Nb) has been
reported to decrease (Thornton et al., 1977; Woods
et al., 1993), although the amplitude distribution itself
does not differ for low- or high-frequency sounds
(Woods et al., 1995). Moreover, there is evidence that
the location of a sound modulates the amplitude and/
or the latency of MLRs (Woods and Clayworth, 1985).
9.3.1. Neuronal sources of MLRs
The usefulness of MLRs in audiology and speech and
hearing sciences has improved considerably, thanks to
basic research aimed at identifying the neural genera-
tors. Although the MLRs were originally thought to
reflect cortical activity (Geisler et al., 1958), subse-
quent research suggested that myogenic activity could
be a major confound. However, this controversy is
now resolved and it is well accepted that MLRs reflect
cortical activity. Evidence from intracerebral record-
ings in patients implanted with depth electrodes for
epilepsy suggests that the Pa wave is generated in pri-
mary auditory cortex (Liégeois-Chauvel et al., 1994).
The cortical origins of the Pa wave are further
supported by lesion studies showing that bilateral tem-
poral lobe lesions attenuate or even abolish the Pa
amplitude (Kraus et al., 1982; Özdamar et al., 1982;
Scherg and von Cramon, 1986; Kileny et al., 1987;
Shehata-Dieler et al., 1991). Conversely, cortical
lesions that spare the primary auditory cortex appear
to have little impact on MLR (Kileny et al., 1987;
Shehata-Dieler et al., 1991). There is also evidence
that unilateral prefrontal lesions that include the dor-
solateral regions enhance Pa amplitude (Knight
et al., 1989a). Together, these findings are consistent
with generators in or near the primary auditory cortex
181
(Kraus et al., 1982; Kileny et al., 1987) and further
suggest that prefrontal cortex modulates cortical activ-
ity in the auditory cortex.
9.3.2. Effects of aging
It is well documented that hearing abilities diminish
with age, and this is largely due to changes that take
place in the cochlea. However, there is increasing evi-
dence that changes in the peripheral system alone can-
not adequately account for all hearing problems
encountered by older adults and that deficits in central
auditory processing are likely playing an important
role. In that regard, scalp recordings of MLRs may
be important for differentiating a “central” from a
“peripheral” basis for the auditory deficits observed
in older adults as well as for helping to identify brain
areas that are more susceptible to the aging process.
In general, MLR amplitudes are positively corre-
lated with age (Chambers and Griffiths, 1991;
Chambers, 1992; Azumi et al., 1995; Amenedo and
Diaz, 1998a; Alain and McDonald, 2007). For
instance, Woods and Clayworth (1986) found an
age-related increase in Pa amplitude and latency that
remained even after controlling for age difference in
audiometric thresholds. No significant age-related
changes were found in Na amplitude or latency
(Woods and Clayworth, 1986; Alain and McDonald,
2007). In older adults with presbycusis, MLRs showed
large inter- and intra-subject variability and showed an
increase in latency (Lenzi et al., 1989). Several
accounts have been proposed for age-related changes
in Pa amplitude, including deficits in auditory
processing (Woods and Clayworth, 1986), impaired
inhibitory control mediated by the prefrontal cortex
(Chao and Knight, 1997), and/or deficits in inhibitory
functions in the ascending auditory pathways (Alain
and McDonald, 2007).
9.3.3. Clinical relevance
As mentioned earlier, MLR amplitudes and latencies
are sensitive to basic acoustic sound features and could
provide an alternative to behaviorally obtained pure
tone audiometry (Musiek and Geurkink, 1981;
Özdamar and Kraus, 1983; Nousak and Stapells,
2005), especially in situations where behavioral
responses are harder to obtain (e.g., neurologic and
psychiatric patients). There have been several
attempts to use MLRs to estimate hearing thresholds
and several studies have reported a relatively good
182
concordance between thresholds using MLR and pure
tone audiometry (e.g., Dauman et al., 1984; Szyfter
et al., 1984; Kankkunen and Rosenhall, 1985; Lenarz
et al., 1986), though MLR thresholds often tend to be
higher than those obtained using pure tone audiometry
(Kankkunen and Rosenhall, 1985). For adult patients
with sensorineural cochlear hearing loss, the sensitiv-
ity of MLRs for detecting a hearing loss reaches 100%
(Kankkunen and Rosenhall, 1985). Moreover, work-
related, noise-induced hearing loss has been found
to reduce MLR amplitude (Barrs et al., 1994). There
is also some evidence suggesting that high-frequency,
sensorineural hearing loss reduces the dynamic range
of the MLR for increments in sound intensity (Hesse
and Gerken, 2002).
Although MLRs could be used to assess hearing
sensitivity, which primarily relies on intact peripheral
processing, its true potential as a clinical tool rests on
the fact that MLRs are the earliest cortical responses
and as such provide a means with which to assess cen-
tral hearing disorders (Fig. 3). For instance, reduced
MLR amplitudes following a lesion to the acoustic
radiation or the right auditory cortex were paralleled
by impaired performance in a psychoacoustic discrim-
ination test (Scherg and Von Cramon, 1986).
In patients with tone deafness, which refers to the
inability to distinguish between musical notes or tones
of different frequency, the Pa wave is markedly
reduced (Özdamar et al., 1982) or even abolished
(Hayashi and Hayashi, 2007). Interestingly, the
brainstem responses often reveal normal functioning
Normal hearing
-1
Hearing loss
Na
Tinnitus
Amplitude (mV)
0
Pa
1 responses as they pertain to assessing central auditory
0 20 40
Time (ms)
Fig. 3. Schematic illustration of the middle-latency response to a
3 kHz pure tone in 11 normal hearing adults (black) as well as in
a single adult showing 45 dB HL hearing loss at 3 kHz (red).
Adapted from Gerken et al. (2001). The blue trace represents hypo-
thetical results for tinnitus patients with normal hearing based on
data from Gerken et al. (2001) and Singh et al. (2011).
C. ALAIN ET AL.
of the brainstem pathways (Özdamar et al., 1982).
This highlights the importance of measuring auditory
brainstem in conjunction with cortical evoked
responses in order to rule out potential contribution
from peripheral hearing loss and/or impairment in
the ascending auditory pathway. However, there are
instances of hearing disorders that are not necessarily
associated with changes in MLRs. Patients with verbal
auditory agnosia, for example, do not show differ-
ences in MLRs when compared with a control groups
of normal language development (Klein et al., 1995).
9.4. Long-latency auditory evoked potentials
(LAEPs)
LAEPs typically occur between 50 and 600 ms after
sound onset, but some deflections can also peak later
depending on the task. They are elicited by a wide
range of sounds including clicks, pure tones, noise
bursts, as well as musical, environmental sounds,
and speech sounds. LAEPs comprise several defle-
ctions or waves labeled P1, N1, P2 and N2, which
peak, respectively, at about 50, 100, 180 and 250 ms
after sound onset, as shown in Figs. 1 and 4. The N1
wave is by far the most studied, although there is an
increased interest in the P2 wave as an index of learn-
ing and sound object representations. In addition to the
P1–N1–P2 complex, three other brain responses are of
particular relevance to the present discussion on
LAEPs and their potential applicability in assessing
central auditory disorders. These LAEP responses
are the mismatch negativity (MMN), the object-
related negativity (ORN), and the P3b wave (also
referred to as P300 or P3). The MMN is elicited by
deviant stimuli in an ongoing stream of sounds be it
task-relevant or not (Näätänen et al., 1978; Picton
et al., 2000; Kujala et al., 2007). The ORN is generated
only in situations where more than one sound is heard
simultaneously (Alain et al., 2001a; Alain, 2007).
Finally, the P3b is an endogenous component that is
triggered by infrequent task-relevant oddball stimuli
(i.e., target) embedded in a stream of standard sounds.
We will discuss the relevance of each these brain
60
disorders in subsequent sections.
9.4.1. P1–N1–P2 complex
The P1-N1-P2 complex is sensitive to various stimu-
lus parameters such as frequency (Woods et al., 1993),
location (McEvoy et al., 1990, 1991), duration
METHODOLOGY AND TECHNIQUES 183

Fig. 4. Effects of age on long-latency auditory evoked potentials (LAEPs). A: butterfly plots showing group mean LAEPs (for 65 electrodes)
elicited by double vowel stimuli presented binaurally. The electrode Cz is shown in black. All other electrodes are shown in gray. B:
isopotential contour maps are shown for the P1, N1, P2, and slow wave (SW) recorded in young and older adults. The contour spacing
was set at 0.75 mV. The blue areas indicate negative voltage. The LAEPs were recorded while participants performed the double vowel task.
In the double vowel task, two vowels are presented simultaneously and participants indicated which vowels they heard by sequentially pressing
two buttons. The stimulus intensity was 80 dB SPL. Adapted from Alain and Snyder (2008).

(Alain et al., 1997; Ostroff et al., 2003), and/or inten-
sity (Taub and Raab, 1969). This sensitivity to varia-
tion in acoustic attributes makes it an ideal tool for
examining the physiological detection of important
acoustic cues contained within a signal. Among the
three waves, the N1 is often the largest, the most reli-
able and can easily be observed in a single individual.
The typical number of trials needed to observe reliable
LAEPs range from 20 to 100 depending on stimulus
intensity, duration and participant’s age. The recovery
cycle is longer than that reported for MLRs and there-
fore a lower rate of stimulus repetition (1–3 sounds/s)
is required to observe the response.
9.4.1.1. Neuronal sources of P1–N1–P2
The P1–N1–P2 responses are generated by multiple
sources, including thalamocortical projections as well
as primary and association areas of each auditory cor-
tex (Picton et al., 1999). Converging evidence from
lesion studies (Knight et al., 1980) and neuromagnetic
recordings (Ross and Tremblay, 2009; Arnott et al.,
2011) reveals distinct generators for the N1 and P2
waves, with the latter having sources anterior to
Heschl’s gyrus. Brain damage to the temporo-parietal
junction that extends to the auditory cortices along the
superior temporal gyrus decreases the N1 amplitude
but has little impact on the P2 wave (Knight et al.,
1980; Woods et al., 1987; Alain et al., 1998). Further-
more, there is evidence which suggests that lesions of
the anterior medial temporal lobe, the temporal poles,
and the orbital frontal cortex can also reduce N1
amplitude (O’Donnell et al., 1993). However, patients
with dorsolateral prefrontal cortex lesions show
enhanced P1 (Alho et al., 1994) and N1 (Knight
et al., 1980; Woods and Knight, 1986) amplitude rel-
ative to age-matched controls. This suggests that the
dorsolateral prefrontal cortex may play an important
role in gating sensory input to the auditory cortex.
Together, these results underline the critical role
played by the cortex of the posterior-superior temporal
plane and the adjacent cortex of the parietal lobe in the
production of the N1 wave.
9.4.1.2. Effects of aging
Aging has been shown to modulate the amplitude and
latency of LAEPs (Fig. 4). For instance, the amplitude
of the P1 wave is often larger for older than for youn-
ger adults (e.g., Pekkonen et al., 1995; Soros et al.,
2009; Ross et al., 2010; Lister et al., 2011). Some stud-
ies using pure tones or speech sounds during active or
passive listening have also reported a larger N1 wave
(e.g., Anderer et al., 1996; Chao and Knight, 1997;
Alain and Woods, 1999; Soros et al., 2009), while other
studies reported longer latencies (e.g., Iragui et al.,
1993; Anderer et al., 1996; Tremblay et al., 2003a).
For the P2 wave, studies using pure tone or speech
sounds have observed longer latencies for older than
for young adults during passive (e.g., Anderer et al.,
1996; Tremblay et al., 2003a; Lister et al., 2011)
and active listening tasks (Alain and Snyder, 2008;
184
Lister et al., 2011). These age-related changes in audi-
tory evoked responses are thought to reflect general
slowing in perceptual and cognitive processing
(Salthouse, 1996), and impaired inhibitory functions
(e.g., Chao and Knight, 1997; Alain and Woods,
1999; Soros et al., 2009), which could take place at var-
ious levels within the afferent and efferent auditory
pathways. Older adults may also have more difficulty
filtering task-irrelevant information, allocating more
attentional resources to the processing of auditory stim-
uli than young adults (Alain et al., 2004; Grady, 2008),
and this could account for the age-related increases in
the amplitude of auditory evoked responses.
9.4.1.3. Clinical relevance
There is growing interest in using LAEPs to determine
whether specific acoustic information is being detected
physiologically in normal or hearing-impaired individ-
uals. Because the P1, N1 and P2 waves are relatively
easy to record and show good test–retest reliability
(Walhovd and Fjell, 2002; Tremblay et al., 2003b), they
could make excellent metrics for assessing central audi-
tory processing and might eventually help audiologists
fit hearing aids and cochlear implants. This is important
given that the P1–N1–P2 complex can be recorded with-
out overt behavioral responses, as it allows for the
assessment of perceptual function in individuals that
cannot communicate or have difficulty understanding
task instructions (e.g., children, aphasic or patients with
dementia). For instance, abnormal speech-evoked N1
and P2 waves have been reported in various populations
with impaired speech–sound perception, including indi-
viduals with auditory neuropathy (Kraus and Cheour,
2000; Rance et al., 2008), children with auditory based
learning problems (Cunningham et al., 2000; Purdy
et al., 2002) and aging adults (Tremblay et al., 2003a,
2004; Harkrider et al., 2005). LAEPs have also been
recorded in people who wear cochlear implants
(Ponton et al., 1996b; Friesen and Tremblay, 2006;
Gordon et al., 2008, 2011) or hearing aids (Tremblay
et al., 2006), making it possible to examine the effects
of improved signal audibility on the physiological
detection of sound.
The physiological detection of sound and the
effects of decreased audibility have typically been
examined by either varying the signal-to-noise ratio
(Martin et al., 1997; Whiting et al., 1998; Martin
and Boothroyd, 1999; Martin and Stapells, 2005), or
testing individuals with sensorineural (Ponton et al.,
1996a; Oates et al., 2002; Tremblay et al., 2003a;
Bertoli et al., 2005) and conductive hearing losses
C. ALAIN ET AL.
(Vasama and Mäkelä, 1997). Martin and colleagues,
for example, examined the effects of competing sig-
nals by presenting speech signals embedded in noise
(Martin et al., 1997; Martin and Stapells, 2005). They
found that speech identification abilities decreased at
poorer signal-to-noise ratios and that the decrement in
performance was paralleled by both increased N1
latencies and decreased N1 amplitudes. Similar find-
ings have been reported in people with hearing loss.
The N1 peak latencies are typically delayed, and peak
amplitudes smaller, when stimulus audibility is com-
promised by the presence of conductive or sensorineu-
ral hearing loss (Fig. 5). Collectively, these results
demonstrate that the typical person with hearing loss,
or one who is trying to hear a signal in the presence
of competing noise, is at a disadvantage. The physio-
logical detection of sounds in these circumstances is
much slower and weaker than the detection perfor-
mance of a person with normal hearing, or when
0
10
Mean Threshold (dB)
20
30
40
50
60
70
250 500 1000 2000 4000 8000
Frequency (Hz)
N1
–
10 nAm
+ NH
BHL
P2
P1
0 200 400 ms
Fig. 5. Top: group means pure tone audiometric thresholds from six
older adults with normal hearing (NH, M = 70, sd = 5) and six older
adults with bilateral hearing loss (BHL, M = 72, sd = 8). Thresholds
were averaged from both ears. Error bars indicate 1 sd from the
mean. Bottom: group mean source waveforms from the left hemi-
sphere. We modeled the N1m from the magneto-encephalogram
(MEG) using dipoles in the left and right auditory cortices. Stimuli
were harmonic complex sounds presented at 85 sound pressure
level (SPL). Note the markedly reduced P1-N1 peak-to-peak ampli-
tude in older adults with BHL [C. Alain, unpublished data].
METHODOLOGY AND TECHNIQUES
listening in a quiet environment. More importantly, N1
amplitude and latency correlate significantly with
behavioral assessment of signal detectability (Martin
et al., 1997), with electrophysiological thresholds
closely approximating behavioral thresholds
(Lightfoot and Kennedy, 2006). These findings suggest
that LAEPs such as the N1 provide a sensitive measure
of signal audibility (see also Muller-Gass et al., 2008),
which may prove useful in evaluating hearing function
in those individuals that could not otherwise be tested
with conventional behavioral techniques.
LAEPs are also useful for predicting and/or assessing
neuropsychological disorders. For example, McArthur
et al. (2009) found that a subset of children diagnosed
with specific language impairment (SLI) or specific
reading disability (SRD) showed an atypical (i.e., “flat-
ter”) N1–P2 complex in response to rapidly as well as
slowly presented tonal and consonant–vowel sounds.
These results suggest that subgroups of SLI and SRD
children suffer from a generalized sound processing
deficit, as opposed to a speech-specific or a rate-specific
one. Moreover, the portion of the SLI group that dem-
onstrated atypical N1–P2 complexes was found to per-
form more poorly than those with typical N1–P2
complexes when reading and repeating non-words.
The authors proposed that such an N1–P2 auditory
processing impairment may represent a causal risk fac-
tor for both language and reading disorders. This exam-
ple illustrates how LAEPs may be a useful tool for
informing clinical practice.
9.4.2. Mismatch negativity (MMN)
Compared to the sensory evoked responses that are
elicited with every acoustic event, the MMN is evoked
only when a perceived stimulus deviates from previ-
ous stimuli and “mismatches” a more expected event
(for recent reviews see Kujala et al., 2007; May and
Tiitinen, 2010; Näätänen et al., 2011). Because the
MMN amplitude positively correlates with the magni-
tude of the acoustic change, the MMN is often viewed
as a discriminative response. It is usually obtained
using the so-called oddball paradigms in which a
frequently occurring “standard” stimulus (e.g., “ga”)
is occasionally replaced by an acoustically similar
but different “deviant” stimulus (e.g., “da”). Other
examples of stimulus contrasts include standard and
deviant stimuli that differ along a physical dimension
such as frequency, intensity, or spatial location
(Picton et al., 2000; Kujala et al., 2006). The MMN
can also be recorded from deviations in complex
185
sound sequences, such as sounds that alternate
regularly in pitch with an occasional repetition (e.g.,
Alain et al., 1994, 1999b).
The MMN appears as a negative displacement of
the LAEP that overlaps the N1 and P2 waves and
peaks at approximately 100–300 ms after deviant
onset (Fig. 6). The MMN is best illustrated by comput-
ing a difference wave between the LAEP elicited by
the standard and the deviant sounds. Amplitude max-
ima are measured at frontocentral electrodes, which
reverse polarity at the mastoids when the tip of the
nose is used as the point of electrical reference. Since
the MMN like other long-latency responses exhibits
frequencies around the alpha range, it is advised that
the digital filter should not cut off less than 20 Hz
and not more than 1 Hz (for more details on MMN
recording and analysis see Duncan et al., 2009).
The MMN is considered an attractive tool for
studying central auditory system functioning.
As already mentioned for the MLRs and P1–N1–P2
complex, the MMN can be elicited irrespective of
the ongoing task (e.g., Pettigrew et al., 2004;
Muller-Gass et al., 2005), although MMN amplitudes
may vary with highly focused attention (e.g.,Woldorff
et al., 1991; Alain and Woods, 1997; Arnott and Alain,
2002; Alain and Izenberg, 2003). Often, participants
are just instructed to watch a silent subtitled movie
or to read a book, making long recording sessions
Fig. 6. A: long-latency evoked potentials (LAEPs) elicited by stan-
dard (solid line) and frequency deviant (dashed line) stimuli in the
oddball paradigm. B: difference wave between the LAEPs elicited
by the standard and those elicited by the deviant stimuli.
186 C. ALAIN ET AL.

much more pleasant than demanding auditory or modulation may be due to long-term memory priming
visual tasks. In most cases, such a “passive” task might effects and was followed by a negativity at posterior
even be preferred over active listening (e.g., a target electrode positions around 200 ms. Furthermore, the
detection task) since the overlap of the MMN ampli- posterior negativity could be dissociated from the
tude with attention-related components such as the known MMN component, suggesting that every per-
N2b and P3b is highly reduced. A further aspect of ceived sound is automatically matched with existing
MMN is that the standard-deviant contrasts do not nec- memory schemata. The incoming sound that matches
essarily have to be very prominent to yield an MMN of long-term representations may trigger a switch of atten-
significant amplitude; near threshold stimuli can elicit tion even if it does not pop out due to its acoustic
reliable MMN responses in healthy young adults saliency in a highly varying acoustic environment.
(Alain et al., 2004). However, MMN amplitudes will
increase and latencies decrease as the standard-deviant
contrast gets larger and hence the deviant stimulus
becomes more discriminable (e.g., Sams et al., 1985;
Javitt et al., 1998; Alain et al., 2004). This relationship
between MMN and discrimination ability is also evi-
dent in effects of training or long-term auditory experi-
ence (for review see, Kujala and Näätänen, 2010).
Auditory events that find a matching representation
in memory, such as mother tongue phonemes, syllables,
or whole words, lead to enhanced MMN responses
compared to the same category of stimuli of a different
language (e.g., Dehaene-Lambertz, 1997; Näätänen
et al., 1997; Jacobsen et al., 2004), an effect that is even
suggested for second language acquisition in adulthood
(e.g., Winkler et al., 1999).
The effects of training on MMN as well as the real-
ization that the MMN occurs primarily for violations in
one’s own language suggest that MMN generation is
not only dependent on sensory memory (i.e., immediate
past), but is also sensitive to long-term representations.
This notion is further supported by research using
personally significant sounds (Fig. 7). In these studies,
participants’ own mobile phone ring tones have been
used as experimental stimuli which can be regarded
to be arbitrary without an associated individual experi- Fig. 7. Event-related potentials (ERPs) related to discrimination
ence. Within different experimental paradigms, the performance. The upper panel shows the mismatch negativity
own mobile phone ring tone was either presented as a (MMN) at a midline frontal electrode (Fz) and its topographic dis-
tribution over the scalp surface in a time window centered around its
rare stimulus among a repeating non-significant sound, peak latency (112–152 ms). Data were recorded within an auditory
that is within a classic MMN protocol (Roye et al., oddball paradigm in which a frequently presented standard stimulus
2007), or it was presented as a rare stimulus among was occasionally replaced by an acoustically distinct deviant stim-
several different non-significant sounds that occurred ulus. Later effects due to an attentional switch or further evaluation
with the same probability (Roye et al., 2010; Roye processes can follow the MMN component. The lower panel shows
ERPs at a midline posterior electrode (Pz) recorded within an odd-
et al., in press). Electrophysiological responses to the ball paradigm in which long-term memory representations of two
participant’s own ring tone could be compared with deviant stimuli were varied. When ERPs to a personally significant
responses to a non-significant sound (the ring tone of sound were compared with ERPs to a non-significant sound, a neg-
another participant). Analysis of the electrophysiologi- ative response was measured after around 200 ms with amplitude
cal data revealed that the brain differentiated between maxima at parietal and temporo-parietal electrode positions that
could be dissociated from the MMN component. The topographic
“own” and “other” ring tone within the first 100 ms map illustrates the amplitude distribution of this effect within a time
after sound onset, reflected in the evoked activity that window centered around its peak latency (184–224 ms). For a
oscillates with a frequency of about 40 Hz. This early detailed description of the effects see Roye et al. (2007).
METHODOLOGY AND TECHNIQUES
It remains to be investigated whether hearing-impaired
or older adults show benefits from individual long-term
memory schemata with certain sounds, especially in
noisy listening situations or in situations that are of
high cognitive demand. The present electrophysiologi-
cal indices of significant sound detection may provide
a tool that is independent from behavioral measures
to assess intact schema-driven central auditory
processing.
9.4.2.1. Neuronal sources of the MMN
Converging evidence from dipole source modeling of
scalp-recorded EEG and magnetoencephalography
(MEG) (for a review see, Alho, 1995), as well as from
lesion studies in humans (Alain et al., 1998; Deouell
et al., 2000; Ilvonen et al., 2001, 2004) are consistent
with generators located primarily in auditory cortices
(the supratemporal MMN generator; Fig. 8). Since
MMN amplitude distribution at the scalp surface var-
ies as a function of the deviating feature used within
different paradigms (Alho, 1995; Alain et al., 1999a;
Caclin et al., 2006), it is assumed that different audi-
tory fields within the auditory cortex contribute to the
scalp-recorded MMN. Results from a lesion study sup-
port the conclusion that sensory memory representa-
tions involved in change detection differ for distinct
types of feature comparisons (Aaltonen et al., 1993).
Patients with posterior damage of the left temporal
Fig. 8. Mismatch negativity (MMN) in patients with unilateral tem-
poral, frontal, or hippocampal lesions over the ipsilateral or contra-
lateral hemispheres. The traces reflect the difference wave between
the standard and the deviant stimuli. The red circles on the magnetic
resonance template highlight the areas that are damaged in most
patients, though the size of the areas may vary substantially between
individuals. Data were recorded within an auditory oddball para-
digm in which a frequently presented standard stimulus was occa-
sionally replaced by an acoustically distinct deviant stimulus. For
a detailed description of the effects see Alain et al. (1998).
187
lobe did not exhibit any MMN to vowel contrasts
while the MMN to frequency changes in simple tones
could be observed. There is also evidence suggesting
that the prefrontal cortex may play a role in modulat-
ing the MMN amplitude (Giard et al., 1990; Alho
et al., 1994; Alain et al., 1998). From a functional per-
spective, the sources in sensory cortices may be asso-
ciated with the change detection itself such as a
comparison process based on sensory memory repre-
sentations, while the frontal sources may play a role
in the initiation of an attentional switch to a change
in the auditory environment. Aside from frontal and
the temporal sources, other non-sensory structures
might contribute to the MMN. The involvement of
the thalamus is assumed based on data showing atten-
uated magnetic MMN amplitudes for patients with
unilateral lesions of anteromedial nuclei of the thala-
mus (Mäkelä et al., 1998). Although a contribution of
the hippocampus to change detection has been pro-
posed in animals (e.g., Ruusuvirta et al., 1995), hippo-
campal damage did not affect discrimination
performance and MMN elicitation in humans (Alain
et al., 1998).
9.4.2.2. Effects of aging
Several studies have reported that the MMN is reduced
in older compared to young adults (for a review see
Pekkonen, 2000). This age-related decrease in MMN
amplitude has been observed for frequency (Gaeta
et al., 1998; Alain and Woods, 1999; Cooper et al.,
2006; Schiff et al., 2008) as well as duration deviant
stimuli (Pekkonen et al., 1996; Cooper et al., 2006;
Ruzzoli et al., 2012) and appears to be greater at longer
ISIs (Pekkonen et al., 1995, 1996; Ruzzoli et al.,
2012). Older adults also show a reduced MMN to vio-
lations of complex tone sequences (Alain and Woods,
1999; Rimmele et al., 2012). The reduced MMN
amplitude with age may reflect an age-related decline
in discrimination abilities. However, Alain et al.
(2004) controlled for effects of behavioral discrimina-
tion acuity between young, middle-aged and older
adults and nevertheless found a decrease in MMN
amplitude during passive listening. Hence, the effects
of age on MMN appear to be related to deficits in
maintaining an accurate representation of sound attri-
butes as well as the temporal relations among succes-
sive sounds rather than a problem at discriminating the
standard and the deviant stimuli. The effects of age on
the MMN latency has been examined in many studies,
but the results are less consistent. This may be partly
188
related to the difficulty in accurately measuring
latency when the brain response is small.
9.4.2.3. Clinical relevance
In the last two decades there has been a surge of
research aimed to develop the MMN as a clinical tool
(for a discussion on clinical application of MMN see
Kurtzberg et al., 1995; Lang et al., 1995; Csepe and
Molnar, 1997; Näätänen, 2003). In order for the
MMN to be clinically relevant, the length of testing
time must be reduced, its sensitivity and specificity
delineated, and normative data need to be established.
Because these requirements have not yet been met, the
MMN is not routinely used in individual assessments.
However, researchers are beginning to develop new
recording paradigms that can profile different auditory
discrimination abilities over a shorter recording time
(Näätänen et al., 2004). A variety of studies have
employed MMN paradigms to investigate biological
processes underlying auditory perception in different
clinical groups such as older adults with cognitive
impairments (Kazmerski et al., 1997), stroke patients
(Alho et al., 1994; Alain et al., 1998; Deouell et al.,
2000; Ilvonen et al., 2004), aphasic patients (Becker
and Reinvang, 2007), or children with attention, learn-
ing, and language disabilities (Kurtzberg et al., 1995;
Kraus et al., 1996). Although the MMN seems to be a
sensitive measure to explore functional auditory
processing deficits in children, it should be noted that
children show a considerable amount of heterogeneity
within groups, with the MMN being affected for
instance by age, maturation, and stimulus-related
characteristics (Ahmmed et al., 2008). Children may
even reveal change-related responses with positive
polarities (Ruhnau et al., 2010) that can vary between
different subgroups (Ahmmed et al., 2008), making
comparisons of grand-average MMNs between groups
more complicated.
Several studies have examined the effectiveness of
MMN to assess the functional status of the auditory
system in clinical populations such as people with
hearing loss as well as clients who received cochlear
implants (CIs) (e.g., Singh et al., 2004; Kelly et al.,
2005; Roman et al., 2005). Perceptual abilities, espe-
cially the ability to process speech sound contrasts can
vary in adults or children with CI and this variability
is reflected in MMN elicitation. Indeed, CI users
with good speech perception abilities have revealed
normal MMN responses to speech sound contrasts,
while the MMN is reduced or absent in bad performers
(Groenen et al., 1996; Kelly et al., 2005; Rahne et al.,
C. ALAIN ET AL.
2010). Other studies have reported correlations of
speech perception or discrimination abilities with
MMN latency (Roman et al., 2005) and overall dura-
tion of the mismatch response (Singh et al., 2004).
These effects suggest that the MMN may be a useful
tool to monitor progress in auditory perception after
implantation.
While the MMN amplitude is mainly used as a
measure of sensory memory and discrimination per-
formance, it is also affected by sensory encoding of
each perceived stimulus. As was shown for the N1
and P2 waves, reducing stimulus audibility through
the use of masking increases MMN latency and
decreases MMN amplitude (Martin et al., 1999).
These findings suggest that decreased hearing sensi-
tivity interferes with the ability to discriminate
between standard and deviant stimuli. For this reason,
when testing older adults, it is not only critical to
adjust sound intensity based on individual hearing
thresholds, but also to use low-frequency stimulus
contrasts to minimize the confounding effects of
age-related high-frequency hearing loss. Furthermore,
as mentioned in the previous section on the P1–N1–P2
complex, sensory electrophysiological responses of
the single LAEPs can exhibit age-related amplifica-
tion or reduction. Due to the fact that MMN is com-
puted as the difference wave between deviant and
standard LAEPs, this can lead to reduced or amplified
MMN amplitudes. In a study by Alain and Woods
(1999), for example, the impaired inhibitory control
of sensory input reflected in increased N1 amplitudes
in older participants helped partially explain the
observed MMN reduction.
In summary, the MMN reflects the remarkable abil-
ity of the central auditory system to register small occa-
sional changes in the perceptual stream. Our review of
the literature shows that MMN amplitude is highly sen-
sitive to discrimination deficits in different clinical
populations including individuals suffering from learn-
ing disabilities and/or hearing impairment. For these
reasons, there is hope that the MMN can be used as a
clinical tool for assessing central auditory discrimina-
tion. Compared to MLRs and the P1–N1–P2 complex,
which basically indicate acoustic stimulus detection, the
MMN-eliciting mechanism is a more complex percep-
tual process, making it harder to determine the specific-
ity of the response. MMN elicitation requires not only
intact sensory processing but also relies on auditory sen-
sory memory to model regularities within acoustic envi-
ronments which in turn allow “mismatch” detection
(Näätänen and Winkler, 1999). It is important to note
METHODOLOGY AND TECHNIQUES 189

that the different aspects that contribute to the measured
MMN amplitude (sensory processing, auditory sensory
memory, discrimination) can be affected by impair-
ments associated with aging or by other cognitive def-
icits (e.g., working memory) not directly related to
hearing. That is, when the MMN is aimed to be used
as a tool to study discrimination performance, factors
which may confound the intended measure, such as a
general decline in sensory sensation levels or impaired
sensory memory performance, should be reduced by
choosing appropriate experimental setups (e.g., short
ISIs, intensities above hearing threshold, appropriate
frequency range). Furthermore, it is important to
develop new ways to generate and to reliably measure
MMNs at an individual level. Given that MMN cannot
always be observed in every individual even with
normal hearing and given that the amplitude can vary
considerably with inner-subject factors like alertness,
more research is necessary before MMN can be rou-
tinely used in clinical settings.
9.4.3. Object related negativity (ORN)
The ORN is a relatively newly discovered component
of the LAEP that appears to be particularly sensitive to
the process of parsing multiple sound objects that
occur simultaneously (Alain et al., 2001a; for a review
see Alain, 2007). In the laboratory, this component can
be evoked using the mistuned harmonic paradigm
(Moore et al., 1986; Alain et al., 2001a). When lis-
teners are presented with a harmonic complex in
which the tonal elements are all integer multiples of
the fundamental frequency ( f0), they report hearing
a single “buzz-like” sound whose pitch corresponds
to that of the f0. When one of the (typically lower) har-
monics is mistuned sufficiently (by 10–16% of its
original value) such that it is no longer an integer mul-
tiple of the f0, listeners often report hearing the mis-
tuned harmonic “pop-out” such that two sounds are
perceived: a buzz-like sound corresponding to the har-
monic complex, as well as a sound corresponding to
the pitch of the mistuned harmonic (Moore et al.,
1986; Alain et al., 2001a). Subtracting the LAEPs of
this mistuned complex from that of the harmonic com-
plex reveals the ORN, a negative wave that overlaps
with the N1 and P2 deflections, peaking around
180 ms post-stimulus onset (Fig. 9). The ORN ampli-
tude correlates with perceptual judgment, increasing
when the listener reports hearing two sounds rather
than one. That said, the ORN is present even when
the participant is not attending to the stimuli,
suggesting that the component is sensitive to concur-
rent sound segregation independent of the listeners’
attention. However, when the listener is actively
attending to the sound, a later positive wave peaking
at 400 ms post-stimulus onset is also observed.
Because it is only present during active listening con-
ditions, this positive component most likely reflects
the conscious cognitive decision-making aspect of
sound segregation.
The ORN generation is not limited to the detection
of mistuned harmonics; it can also be recorded when
concurrent sounds (e.g., harmonic complex tones or
vowels) are segregated based on location cues (e.g.,

Fig. 9. Event-related potentials elicited by harmonic complex tones. The left panel shows the ERPs elicited by a 4% mistuned harmonic when
participants reported hearing a single sound object (solid black) and when the same participants reported hearing two concurrent sound objects
(i.e., a buzz plus another sound with a pure tone quality; dotted red). The perception of two concurrent sound objects coincided with an object-
related negativity (ORN) and a positive wave peaking at about 400 ms after sound onset, which are best illustrated in the difference wave (solid
gold). The right panel shows isocontour maps for the ORN and the P400 wave. In both cases, the amplitude distribution is consistent with
generators located in the auditory cortex in the superior temporal plane. Data from Alain et al. (2001a).
190
Johnson et al., 2003; McDonald and Alain, 2005) or
when there is difference in onset asynchrony (e.g., Lipp
et al., 2010). Research has shown that improvement in
vowel identification with increment in frequency and/
or location separation correlated with ORN amplitude
(Alain et al., 2005a; Du et al., 2011). Moreover, there
is evidence that ORN for concurrent vowel separation
is not under volitional control. That is, it was present
even when participants were not actively engaged in
the vowel identification task (Alain et al., 2005a).
Taken together these findings suggest that the ORN
indexes the automatic registration of ƒ0 and location
separations and plays an important role in concurrent
sound segregation and identification.
9.4.3.1. Neuronal sources of ORN
Compared to MLRs and other LAEP components dis-
cussed so far, our understanding of the neural mecha-
nisms and generators underlying the ORN is still in its
infancy. The detection of a mistuned harmonic in an
otherwise periodic signal may involve neurons sensi-
tive to equal spacing (i.e., period) between tonal ele-
ments (Roberts, 1998; Roberts and Brunstrom, 1998)
which, in turn, could be used to build a harmonic sieve
or template (Moore et al., 1986; Hartmann et al., 1990;
Lin and Hartmann, 1998). That is, neurons sensitive to
frequency periodicity could act as a series of filters that
allow harmonically related partials to group together
with the ƒ0 and mistuned partials to form separate rep-
resentations. Evidence from dipole source modeling
(Alain et al., 2001a) and neuromagnetic recording
(Arnott et al., 2011) suggests that the ORN depends
on generators distinct from those of the N1 wave, which
are enlisted by stimulus onset. Finally, a functional
magnetic resonance imaging study has shown that
identifying two vowels simultaneously is associated
with activation of a thalamocortical network (Alain
et al., 2005b) and is paralleled by an ORN and N2b
components that index the automatic registration of
ƒ0 separation and vowel identification, respectively
(Alain et al., 2005a).
9.4.3.2. Effects of aging
Age-related declines in concurrent sound segregation
may have dramatic consequences for the perception
and identification of speech in complex environments
such as everyday social situations. This proposal has
received some support from recent studies showing
that older adults have higher thresholds for detecting
a mistuned harmonic than young adults (Alain et al.,
2001b; Grube et al., 2003). This age-related increase
C. ALAIN ET AL.
in mistuning thresholds remains significant even after
statistically controlling for differences in audiometric
threshold between age groups (Alain et al., 2001b) and
coincides with lower performance in the speech-
in-noise (SPIN) test, which requires identifying the
last word of a sentence embedded in multi-talker bab-
ble. Increased SPIN thresholds in individuals who also
showed deficits in detecting a mistuned harmonic is
consistent with the hypothesis that age-related
changes in primitive sound segregation contribute to
the speech perception problems found in older adults.
In addition to age-related increases in thresholds
for detecting a mistuned harmonic, older adults have
difficulty identifying two different vowels presented
simultaneously (Snyder and Alain, 2005; Vongpaisal
and Pichora-Fuller, 2007), and this coincides with
reduced neural activity reflecting a difference in ƒ0
between the two vowels (Snyder and Alain, 2005).
These age-related changes in concurrent sound
perception may be related to a broadening of auditory
filters as well as a decrease in phase-locked activity.
Older adults are also less likely to report hearing a
mistuned harmonic as a separate sound than young
adults, especially if the harmonic complex tone is
short in duration (i.e., 40 ms). This age-related differ-
ence in perception coincided with a reduced ORN
amplitude in older adults (Alain and McDonald,
2007). For longer duration (e.g., 200 ms), the likeli-
hood of reporting hearing two concurrent sound
objects as a function of mistuning was comparable
for young and older adults as was the amplitude of
the ORN (Alain et al., 2012). Together, these findings
suggest that older adults need longer signal durations
than young adults before they can perceive the mis-
tuned harmonic as a separate sound. The greater age
difference for short compared to long duration sounds
may be related to a general slowing of acoustic infor-
mation processing (Salthouse, 1996; Finkel et al.,
2007), which could cause a broadening of the temporal
integration window. In the present context, the tempo-
ral integration window of an auditory evoked response
is defined as the minimal stimulus duration that
produces the maximal amplitude. Alternatively, audi-
tory processing may become less efficient with
advancing age because of age-related changes in inter-
nal neuronal noise (Garrett et al., 2011), independent
of general slowing. That is, for shorter stimulus dura-
tions there is less information upon which to base sub-
sequent processing thereby increasing uncertainty in
signal detection and analysis. However, it might be
difficult to distinguish between the two as both would
METHODOLOGY AND TECHNIQUES
arguably contribute to lengthening the temporal inte-
gration window.
9.4.3.3. Clinical relevance
For effective speech perception to take place, listeners
must rely on the perceptual mechanisms that group
together those sound elements coming from one
source (i.e., one speaker) and segregate those arising
from other sources (another speaker). Attending to a
particular conversation in the midst of multiple talkers
is one example, which highlights the importance of
concurrent sound segregation in everyday listening
situations. The fact that we can focus our attention
on one person speaking in the presence of other talkers
indicates that our perceptual system is generally suc-
cessful at grouping sound elements from one source
and segregating them from others. However, there
are instances where one may fail to successfully sep-
arate concurrent speech sounds (e.g., noisy surround-
ing, hearing impairment). Moreover, there are several
factors that may contribute to difficulty in understand-
ing speech in noisy situations including conductive
hearing loss, central auditory disorders, deficits in
attention and memory. In that regard, the ORN may
provide a means to assess whether listeners can suc-
cessfully take advantages of perceptual cues in parsing
the incoming acoustic data.
To our knowledge, no ORN studies have been done
with clinical populations. However, given that the
response is relatively small, further research is needed
to optimize the current paradigm such that the ORN
can be recorded and measured reliably from each indi-
vidual. There is also a need to assess the test–retest
reliability and validity of the measure before it can
be used in clinical research and practice.
9.4.4. P3b (P300)
The P3b, also referred to as P300, is a positive deflec-
tion at midline parietal site that is most commonly
elicited using an oddball paradigm in which a partic-
ipant is asked to detect an occasional “target” stimulus
in a regular train of standard stimuli (for reviews see
Picton, 1992; Polich, 2007). Although the P3b wave
is likely the most studied ERP deflection, its potential
role for assessing central auditory disorders has
received scant attention. This is likely due to the fact
that P3b generation is under volitional control and
depends on the listener’s ability to attend and respond
to the pre-defined target stimuli. Consequently, the
P3b suffers from the same limitations related to
191
behavioral assessment of hearing functions in cogni-
tively challenge individuals. Nonetheless, coupled
with behavioral techniques, the P3b wave may provide
converging and additional information regarding the
nature of some hearing disorders. For instance, the
P3b can be substantially larger than the sensory
evoked responses (e.g., N1) and is observable for stim-
uli presented at or near behavioral thresholds (Musiek
et al., 2005). Accordingly, the P3b provides a means
with which to assess discrimination thresholds in
patients who can perform the simple oddball task.
The typical number of trials needed to observe a reli-
able P3b range from 10 to 100, depending on target
discriminability and the participant’s age. The P3b
recovery cycle is less than 1 s (Woods et al., 1980),
significantly shorter than the recovery cycle for the
N1 and P2 waves, which remain attenuated with stim-
ulus repetition at longer ISIs (e.g., 5 s).
9.4.2.1. Neuronal sources of P3b
The P3b wave receives contributions from a widely
distributed network of brain regions including the
medial temporal lobe, the parietal cortex, and the pre-
frontal cortex (for reviews see Picton, 1992; Polich,
2007). For instance, lesions in the prefrontal cortex
and the temporal-parietal cortex (Knight et al.,
1989b) reduce P3b amplitude. Moreover, intracerebral
recordings in epileptic patients implanted with depth
electrodes for presurgical investigation suggest neuro-
nal sources in the medial temporal lobe (Halgren et al.,
1980, 1995b) as well as in parietal (Smith et al., 1990;
Halgren et al., 1995a) and prefrontal (Smith et al.,
1990; Baudena et al., 1995) cortices. However, there
is still no conclusive evidence regarding the functional
role of the various sources of the P3b. Future research
combining transcranial magnetic stimulation with
EEG and fMRI might help identify the core regions
as well as their function during the generation of the
auditory P3b.
9.4.1.2. Effects of aging
Earlier studies investigating the effects of age on the
P3b have consistently reported decreased amplitudes
and increased latencies (e.g., Goodin et al., 1978;
Pfefferbaum et al., 1980; Verleger et al., 1991; Iragui
et al., 1993; Karayanidis et al., 1995; Anderer et al.,
1996; Amenedo and Diaz, 1998b; Gaeta et al., 1998).
However, the effect of age on the P3b may be partly
confounded with age-related decline in perceptual acu-
ity with older adults having more difficulty discriminat-
ing between targets and non-targets. When young and
192
older adults are matched in terms of discriminability by
using targets that are equally difficult to detect, the age-
related difference in P3b amplitude can become mark-
edly reduced or even abolished (Alain et al., 2004).
However, the age-related increase in P3b latency
remains even after controlling for differences in target
discriminability, suggesting that the P3b may provide a
neural metric to assess how quickly listeners can distin-
guish between two different stimuli.
9.4.1.3. Clinical relevance
The P3b has been investigated in a wide range of neu-
rological diseases and more recently has attracted con-
siderable attention in assessing mild cognitive
impairment (Golob et al., 2001, 2009). However, fewer
studies have assessed the potential application of P3b to
assess hearing disorders. In healthy listeners, the mild
and moderate threshold elevations produced by a
broadband noise masker decreases the listener’s ability
to discriminate speech stimuli, which coincide with a
reduced P3b amplitude (Whiting et al., 1998).
Studies that have investigated the effects of hearing
loss on the P3b have shown that listeners with moderate
to severe hearing loss have an increased P3b latency
(Polen, 1984; Oates et al., 2002), while those with
mild or moderate hearing loss either show no changes
in P3b latency (Polen, 1984) or an increase in latency
(Oates et al., 2002). Thus, the P3b could be useful
for informing scientists and clinicians that specific
acoustic information is being detected physiologically
in normal or hearing-impaired individuals. The
P3b wave may also be useful for investigating auditory
disorders that involve higher level processes such as
verbal agnosia, congenital amusia, or language
impairment. For example, congenital amusia is associ-
ated with abnormal N2 and P3b responses (Peretz
et al., 2005).
9.5. Concluding remarks
In the preceding sections, we selectively reviewed the
literature on MLRs and LAEPs as they relate to central
auditory disorders. An exhaustive review was beyond
the scope of this chapter, and each section could easily
be expanded due to the great progress made over the
last two decades within the field. Hearing disorders
and decreased audibility due to hearing loss or induced
by masking noise have different effects on auditory
evoked responses. The MLRs and N1 appear to index
C. ALAIN ET AL.
audibility with the responses being present as long as
the sound is registered by the auditory system. The P2,
MMN, ORN and P3b are primarily affected by condi-
tions that affect discriminability and as such may help
assess the impact of hearing disorders on the discrim-
ination and identification of complex stimuli such as
speech sounds. Hence, MLRs and LAEPs provide a
means to evaluate how hearing disorders (e.g., sensory
neural hearing loss) alter the brain processes that
underlie auditory detection and discrimination. How-
ever, there are many challenges ahead. Among the
most important issues is the need to develop new,
and refine current, paradigms that can quickly and
reliably record MLRs and LAEPs in individual partic-
ipants. It will also be important to develop new metrics
and norms against which the results obtained from a
single subject can be compared. Studying evoked
responses in patients with circumscribed lesions
may also help us understand the neural architecture
supporting MLRs and LAEPs. Finally, it will be
important to differentiate between disease-specific
as opposed to disease-general changes in evoked
responses. In other words, can MLRs and/or LAEPs
help differentiate between possible etymologies in
hearing disorders? With the advent of new statistical
and analytical techniques, the next decade promises
to further bridge the current gap between basic audi-
tory evoked response research and its application to
clinical populations.
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