Long latency responses (Niraj)

Auditory
Long Latency Evoked
Potentials

Presenter: Niraj Kumar
Moderator: Ms Rashmi Bhat 1

CONTENTS
1. Introduction
2. Generators
3. Recording parameters
4. Factors affecting
5. Protocol
6. Clinical utility
7. References

2

INTRODUCTION
• It is event-related potentials (ERPs) occurring 50 to
300 ms following stimulus onset; namely, the P1-N1-
P2 complex.

• These auditory evoked potentials are brain
responses that are evoked by the presentation of
auditory stimuli and processed in or near the auditory
cortex, and they are therefore referred to as cortical
auditory evoked potentials (CAEPs).

3

• the P1-N1-P2 complex is traditionally considered to be
comprised of slow components (50-300 ms).

• ERPs can also be classified as sensory evoked,
processing contingent or movement related.

• Sensory-evoked components are obligatory, exogenous
potentials, meaning their amplitudes and latencies are
primarily determined by physical and temporal
characteristics of the stimulus, such as intensity or
frequency.

4

• P1, N1 and P2 are considered to be sensory-evoked
potentials.

• The P1-N1-P2 complex while composed of sensory-
evoked components is not purely sensory. It is
affected by attention and can be modified by auditory
training.

5

Historical Overview:
• The LLR was actually the first auditory electrical
response to be recorded from CNS.

• P1-N1-P2 complex was discovered in 1939 by P.A.
Davis, who described changes in the
electroencephalogram (EEG) in response to sound in
EEG as ‘K-complex.

• As electric computers and signal averaging become
available in some of the premiere auditory research
labs in the early 1960s, a proliferation of studies of
ALLR as “an accurate obj. method of evaluating
auditory acuity in man” 8

• By the second half of the 1960s development of
instrumentation of specifically for clinical
measurement of late auditory potentials was reported
in the scientific literature.

• Davis designed a device called HAVOC (histogram,
average, and ogive computer) and coupled it to
GATES (generators of acoustic transients) and a
system of amplifying and filtering the incoming EEG.

• With the help of these combination of equipment high
quality waveform were recorded.

9

• Historically, brief stimuli such as clicks and tone
bursts have been used to evoked the P1-N1-P2
complex.

• However these responses can also be elicited by
changes in an ongoing sound such as intensity and
frequency modulation of a sustained tone or in
response to acoustic changes in ongoing, more
complex sounds, such as speech (Martin, Lee, and
Kurtzberg)

10

COMPONENTS AND
GENERATORS OF LLR

11

Components:
The P1-N1-P2 Complex:

12

• P1, N1 and P2 are typically recorded together, at
least in adults; When elicited together, the response
is referred to as the P1-N1-P2 complex.

• N2 might or might not be present even in Normal's,
so not much importance is given for that.

• The specific latencies and amplitudes of each peak
depend on the acoustic characteristics of the
incoming sound and on subject factors.

13

• P1, the first major component of the P1-N1-P2
complex, is a vertex-positive voltage deflection that
often occurs between 55 to 80 ms. after sound onset.

• P1 is usually small in amplitude in adults (typically <2
uv) but is large in young children and may dominate
their response.

• Generators of P1 have traditionally been identified in
the primary auditory cortex and specifically Heschl’s
gyrus.

• P1 is typically largest when measured by electrodes
over midline central to lateral central scalp regions. 14

• Generation of P1 may actually be more
complex than early studies suggest, and
additional regions that may contribute to this
response, including the hippocampus,
planum temporale, and lateral temporal
cortex have been identified.

• Recent work has also focused attention on
the importance of neocortical areas to P1.

15

• N1 appears as a negative peak that often occurs
between 90 to 110 ms after sound onset.

• N1 latency can be longer in some cases, depending
on the duration and complexity of the signals used to
evoke the response.

• N1 follows P1 and precedes P2.

• Compared to P1, N1 is relatively large in amplitude in
adults (typically 2-5 uv, depending on stimulus
parameters).
16

• In young children, however, N1 generators may be
immature and therefore the response absent, particularly
if stimuli are presented rapidly.

• N1 is known to have multiple generations in the primary
and secondary auditory cortex and is therefore described
as having at least three components.

• The first is fronto-central negativity (N11) that is
generated by bilateral vertical dipoles in or near the
auditory cortex in the superior portion of the temporal
lobe and is largest when measured by electrodes near
the vertex.
17

• It is thought that this component may reflect attention
to sound arrival, the reading out of sensory
information from the auditory cortex, or the formation
of a sensory memory of the sound stimulus in the
auditory cortex

• The second component is known as the T complex.

• It is a positive wave occurring approximately 100 ms
after sound onset, followed by a negative wave
occurring approximately 150 ms after sound onset.

18

• The T complex is generated by a radial
source in the secondary auditory cortex
within the superior temporal gyrus and
is therefore largest when measured by
electrodes over mid temporal scalp
regions.

• While it has been proposed that the T
complex may involve a simple inversion
of the N11 component.

19

• The third component is a negativity occurring
approximately 100 ms after sound onset that is best
recorded near the vertex using long inter-stimulus
intervals.

• The generator of the component is unknown, and it
may not be specific to sound.

• In general recorded from electrodes in midline central
scalp locations.

• For this reason, it is wise to include electrodes over
lateral temporal sites to optimally pick up contributions
from the secondary auditory cortex.
20

• P2 is a positive waveform that occurs approximately
180 ms after sound onset.

• It is relatively large in amplitude in adults (approx. 2-5
uv or more) but may be absent in young children.

• P2 is not as well understood as the P1 and N1
components, but it appears to have generators in
multiple auditory areas including the primary auditory
cortex, the secondary cortex and the mescencephalic
reticular activating system.

• It has been hypothesized that P2 (or at least the
magnetic version P2m) is generated from multiple
sources, with a center of activity near Heschl’s gyrus. 21

• P2 is best recorded using electrodes over midline
central scalp regions.

• As with N1, P2 does not appear to be a unitary
potential, meaning that it is likely that there are
several component generation processes occurring in
the time-frame of P2, these components may be
different for different age groups and subject states.

• P2 latencies are consistently reported to be delayed
in older adults.

22

Component Classification Generators

LLR P60 (a) Exogenous - Late thalamic projections into Auditory cortex
(P1) (b) Late potential - Specific sensory system
(c) Long latency evoked
potential

N 100 (N1) (a) Exogenous -Supra temporal auditory cortex
(b) Late potential -Non specific poly sensory system
(c) Long latency RESP

P160 (P2) (a) Exogenous -Lateral-frontal supra temporal auditory cortex
(b) Late potential

P200 (N2) (a) endogenous -Supra temporal auditory cortex
(b) Late potential
(c) Long latency
24

P300 - Endogenous -Hippocampus & Frontal lobe
- Cognitive response

N400 Endogenous -Multiple parallel and sequential generators in the
cortex

P500 Endogenous -Multiple parallel and sequential generators in the
cortex

T-Complex Exogenous -Posterior temporal lobe

CNV Endogenous -Thalamic nuclei midbrain (Redicular formation)

Processing Endogenous -Auditory cortex
negativity

25

RECORDING PARAMETER
USED for THRESHOLD
ESTIMATION

26

Recording parameters for
supra threshold applications

29

Summary of recording parameters for supra threshold
applications

30

Recording Factors:
• The P1-N1-P2 complex and threshold estimation.

• Clinical judgment should be used to determine the
most efficient response testing, it is often wise first to
obtain thresholds for a high frequency in each ear
and a low frequency in each ear and subsequently to
fill in other frequencies provided the patient remains
quiet, alert, and cooperative.

• It is not always necessary to begin testing at high
intensities (e.g. 80 dBpeSPL), and it may be more
efficient to begin with stimuli of low to moderate
intensity (e.g. 20-40 dB peSPL).

• If a response is present at low intensities, it is not
necessary to test at higher intensities. 32

Factor Affecting

33

FACTORS AFFECTING
Stimulus Factors
•While it is possible to obtain P1-N1-P2 using a variety
of stimuli, including clicks, tone bursts, complex sounds,
and speech, much of the parametric literature has
focused on click and/or tone burst stimuli.

•It is likely that many of the same principles will hold for
complex stimuli such as speech, however, there might
also be complex interactions among the various
acoustic parameters contained within the speech signal
that affect the neural detection and processing of the
speech signal differently than simple stimuli.

34

Type of stimulus:

•Tonal stimulus: tonal stimulus have been typically
used to elicit ALR (Davis, Bowers, &Hirsh,1968)

•Amplitudes for the N1 and P2 components of the ALR
are larger, and latencies longer for low frequency tonal
signal in comparison to high frequency signal (Alain,
Woods, & Covarrubias, 1997; Jacobson et al., 1992;
Sugg & Polich,1995)

•Some components of ALR (e.g., p100 & N250) show
larger amplitudes and shorter latency for complex tones
than for single frequency tonal stimuli.

35

Speech:

• Speech stimulus are quiet efficient in eliciting the
ALR.

• Amplitude of the N1 to P2 complex is larger speech
sounds than for single freq. tonal stimuli, but latency
values for the N1 and P1 are usually earlier for tonal
versus speech stimuli (Ceponiene et al., 2001)

• Natural vowel sounds generate ALR components (N1
and later waves) that are detected with considerably
larger amplitude from the left hemisphere, whereas
tonal stimuli produce symmetrical brain activity 36
(Szymanski., 1999)

Intensity:

•P1-N1-P2 amplitude increases with stimulus intensity in
an essentially linear manner, though the amplitude-
intensity function may saturate at intensities exceeding
approximately 70 dB normal hearing level (nHL),
particularly when short ISIs are used.

•Amplitude of the N1 and P2 wave does increase in
parallel for low and moderate levels.

•For higher signal levels, how ever, P2 amplitude
continues to increase while amplitude of N1
decreases( Adler & Adler., 1989)

37

• Frequency:

• As stimulus frequencies increases, amplitude of the
complex decreases even when loudness is
controlled. Latencies increase as frequency
decreases particularly when high stimulus intensities
are used.

39

• Rate and ISI:
• P1-N1-P2 amplitude increases as the rate of stimulus
presentation decreases until the ISI is approximately
10 seconds.

• At low stimulus intensities, amplitudes asymptote or
level off at shorter ISIs, while at high stimulus
intensities, amplitude increases continue to occur
even beyond ISIs of 10 seconds.

• The most pronounced effect of longer ISI times is
within 1 to 6 seconds.

• There is little change in latency as stimulus rate
changes. 40

• Stimulus Duration:

• Amplitude increase as stimulus duration increases up
to approximately 30 to 50 ms but decreases when
rise and fall times exceed 50 ms

42

• Ears:

• Amplitudes are larger for binaural than monaural
stimuli. Latencies are similar for monaural and
binaural stimuli however, N1 shows shorter latency
when recorded contra laterally than ipsilaterally.

43

Number of Stimuli:

•Response amplitude decreases as the number of
stimuli presented increases.

•This effect is maximal over approximately the first five
stimuli presented and is most likely due to neural
refractoriness.

•This effect is stimulus specific, because if a new sound
is introduced. N1 amplitude increases by an amount
proportional to the magnitude of stimulus change.

44

Subject Factors:
Subject State:
•Unlike the auditory brainstem response, the P1-N1-P2 complex
can be affected by subject state. For example, attending or
ignoring a competing audio signal can increase N1 and P2
amplitudes, particularly for low intensity sounds.

•Morphology is also dramatically affected by sleep, but in a
complex manner.

•The N1 component may be attenuated in sleep, and an
additional negativity emerges at approximately 300 ms.
Changes in morphology vary as a function of sleep state.

•These sleep-related changes in morphology can significantly
increase the variability of the response. For this reason, P1-N1-
P2 is typically recorded while subjects are awake. 45

Maturation and Aging:

•The morphology of the P1-N1-P2 complex is affected
by maturation. The complex changes dramatically over
the first 2 years of life.

•The complex begins as a large P1 wave is followed by
a broad, slow negativity occurring near 200 to 250 ms
after the onset of the sound.

•A P1-N1-P2 complex similar to that of adults is not
seen until approximately 9 to 10 years of age unless
stimuli are presented at a very slow rate.

•Refractory changes occurring between the ages of 6
and 18 years of age can affect waveform morphology. 46

• Responses recorded at midline central electrode
sites, reflecting contributions from primary auditory
cortex, mature more rapidly than those from lateral
temporal sites, which reflect maturation of secondary
auditory cortex.

• These potentials continue to mature until the second
decade of life and then change again with old age.
Prolonged N1 and P2 latencies and amplitude
changes have been reported in aging adults.

47

• ALR latency decreases and amplitude increases as a
function of age during childhood, up until about age 10
years (Weitman, Fishbin & Graziani, 1965; Whiteman & Graziani, 1968).

• Some investigators have described the latency increase
and also amplitude decrease, with advanced age
(Callaway, Halliday, 1973; Goodlin et al. 1978; Roth & Kopell, 1980).

• James et al. (1997) examined maturational changes in
spectro-temporal features of central and lateral N1
components of the auditory evoked potential to tone
stimuli presented with a long stimulus onset
asynchrony.
 Peak latencies of both components decreased with
age.
 Peak amplitude also decreased with age consequently, 50
the difference between the lateral N1 and the central
N1 amplitude also decreased with age.

• Deepa (1997) studied the age related change
in ALLR. The LLR waveforms achieved at
70, 50 and 30 dBnHL.
 was significant difference between children and adults for all the
peak latency and for amplitude.

 There was no significant difference between males and females
for adult and children.

 There was a significant difference only in N1 peak latency 7-8
years group, P2 latency between 8-9 years group and P2
latency between 7-9 years of age group.

51

Gender:

•There is some evidence that N1 latencies are shorter
and amplitudes larger in women than in men.

•Additionally, amplitude-intensity functions have been
reported to be steeper for females than males.

52

Handedness:
•There was no handedness effect seen for the N1
amplitude, latency of N1 component was shorter for left
handed versus right handed subjects.

•P2 amplitude values were smaller in left hand users.

•Handedness was not a factor in N2 amplitude.

53

State of arousal and sleep:
•Sleep has pronounced effect on LLR

•There are significant but differential changes in the
major ALR waves as the person becomes drowsy and
falls asleep.

•Progressively diminished amplitude of N1 is seen from
wake to sleep state.( Campbell & Colrain, 2002)

54

• During the transition to deep sleep P2
amplitude increases (Campbell et al.,1992).

• The over all amplitude of N1 and P2 may
remain reasonably stable across sleep stages
(de Lugt, Loewy, & Campbell, 1996)

55

Attention:
•N1 and P2 waves of ALR are altered differentially when
the subject is paying close attention to the stimulus or
listening for a change in some aspect of the stimulus.

•N1 wave, an increase in attention causes greater
amplitude.

•The P2, appears to diminish with increased attention
by the subject on the signals (Michie et al., 1993)

57

Drugs:
•Sedatives: ALR variability is increased.

•Measurement of ALR and P300 responses
under sedation is ill advised as validity of the
findings may be compromised.

•Opioid analgesic like Morphine, has no
apparent effect on ALR or ABR.

•Droperidol produces prolongation of P1 and N1
components by about 10ms and also reduction
in amplitude seen. 58

• Anesthetic agent: the results across studies are
varying greatly.
• Generally concluded that there is little effect on the
latency of ALR components, but there might be
amplitude reduction seen as anesthesia is given.

• Alcohol: amplitude of ALR is reduced by acute
alcohol intoxication.
• Latency of N1 component was seen to be prolonged
after alcohol ingestion, where as P2 latency was
unchanged( Teo & Ferguson, 1986)

59

Applications of CAEPs:

• P1-N1-P2 complex signals the cortical detection of an
auditory event, can be reliably recorded in groups
and individuals, and is highly sensitive to disorders
affecting the central processing of sound.

• Therefore, P1-N1-P2 response are typically used by
audiologists to estimate threshold sensitivity,
especially in adults; to index changes in neural
processing with hearing loss and aural rehabilitation,
and to identify underlying biological processing
disorders in people with impaired speech
understanding.

60

• Estimation of hearing threshold
• Neurodiagnosis
• Selection of amplification
• Efficacy of amplification
• Neural maturation

61

Estimation of Hearing Threshold:
• The P1-N1-P2 complex is highly sensitive to hearing
loss and P1-N1-P2 and behavioral thresholds
typically fall within approximately 10 dB of each other.
Larger discrepancies have been reported, however,
this is most likely due to lack of control over subject
state.

• The N1 is used in some clinical settings for the
assessment of threshold in adult compensation cases
and medico-legal patients.

• Similar to the intensity functions for the ABR, N1
latency increases and amplitude decreases as the
intensity of the stimulating signal approaches 62
threshold.

The P1-N1-P2 complex has several advantages over
ABR for threshold estimation:

1.It can be elicited by longer-duration, more frequency-specific
stimuli than the ABR and thus provides a better estimate of the
audiogram.

2.It involves less data collection time because cortical responses
are larger in amplitude and thus easier to identify than the ABR.

3.It is mores resistant to electrophysiological noise.

4.It provides a measure of the integrity of the auditory system
beyond the brainstem.

5.It can be evoked by complex stimuli, such as speech, and can
therefore be used to assess cortical speech detection.
64

• It is for these reasons that the P1-N1-P2 complex is
considered to be superior to the ABR for threshold
estimation.

• Yet in the United States the P1-N1-P2 is rarely used
for this purpose, and for the most part has been
replaced by the ABR.

• This is likely because the largest population of
patients requiring physiological estimates of hearing
sensitivity is infants and young children, who need to
be sleeping and/or sedated during testing.

65

Changes in neural processing with Hg loss
and rehabilitation
• One of the more recent applications of CAEPs is
monitoring experience-related changes in neural
activity.

• Because the central auditory system is plastic, that is,
capable of reorganization as a function of deprivation
and stimulation, CAEPs have been used to monitor
changes in the neural processing of speech in
patients with hearing loss and various forms of
auditory rehabilitation, such as use of hearing aids,
cochlear implants, and auditory training.
66

Hearing Loss:
• CAEPs have been used to examine changes in the
neural processing of speech in simulated and actual
hearing loss.

• Martin and colleagues examined N1, MMN (along
with P3), and behavioral measures in response to the
stimuli /ba/ and /da/ in normally hearing listeners
when audibility was reduced using high-pass, low-
pass, or broadband noise masking, partially
simulating the effects of high-frequency, low
frequency, and flat hearing loss, respectively.

• In general, N1 amplitude decreased and latency
increased systematically as audibility was reduced.
67

• This finding is consistent with the role of N1 in the
cortical detection of sound.

• In contrast, the MMN showed decreasing amplitude
and increasing latency changes beginning only when
the masking noise affected audibility in the 1000- to
2000- Hz region, which is the spectral region
containing the acoustic cues differentiating /ba/
and /da/.

• This finding is consistent with the role of MMN in the
cortical discrimination of sound.

68

• Similar results have been obtained in
individuals with sensorineural hearing
loss.

• That is P1-N1-P2 latencies increase
and amplitudes decrease in the
presence of hearing loss, and MMN
latencies increase and amplitudes
decrease as behavioral speech
discrimination becomes more difficult.

69

Hearing Aids:
• ERPs can be reliably recorded in individuals, even
when the sound is processed through a hearing aid.
Yet to date only a few studies have examined ERPs
in patients using hearing aids. In earlier studies,
cortical ERPs were recorded in aided versus un-
aided conditions in children with varying degrees of
hearing loss. These studies showed good agreement
with the neural detection and audibility of sound.

• That is, in unaided conditions (subthreshold) the
equivalent of the P1-N1-P2 was a clear obligatory P1
response, followed by a prominent negativity (N200-
250).

70

• Korezak, Kurzberg and Stapells also demonstrated
that hearing aids improve the detectability of CAEPs
(as well as improving behavioral discrimination
performance), particularly for individuals with severe
to profound hearing loss.

• Even though most of the subjects with hearing loss
showed increased amplitudes, decreased latencies,
and improved waveform morphology in the aided
conditions, the amount of response change was quite
variable across individuals.

71

• This variability may be related to the fact that a
hearing aid alters the acoustics of a signal, which in
turn affects the evoked response pattern.

• Therefore, when sound is processed through a
hearing aid, it is necessary to understand what the
hearing aid is doing to the signal. Otherwise
erroneous conclusions can be drawn from waveform
morphology.

• Despite the latency and amplitude changes that can
occur with amplification, most subjects with hearing
loss tested by Korezak and colleagues still showed
longer peak latencies and reduced amplitudes than a
normally hearing group.
72

Cochlear Implants:
• CAEPs can be recorded from individuals with
cochlear implants (Friesen and Tremblay, in press).

• Latencies and amplitudes of N1 and P2 in “good”
implant users are similar to those seen in normally
hearing adults but are abnormal in “poor” implant
users and P2 in particular may be prognostic in terms
of separating “good” from “poor” users.

• CAEPs can be recorded in implant users in response
to sound presented either electrically (directly to the
speech processor) or acoustically (presented via
loud-speaker to the implant microphone), however,
stimulus-related cochlear implant artifact can
sometimes interfere (Martin, in press; Friesen and
Tremblay, submitted). 73

Auditory training:
• Even if the central auditory system is capable of
processing the signal, the individual’s ability to
integrate these new neural response patterns into
meaningful perceptual events may vary. For this
reason, CAEPs have been used to examine the brain
and behavior changes associated with auditory
training.

• The objective of auditory training is to improve the
perception of acoustic contrasts. In other words,
patients are taught to make new perceptual
distinctions. When individuals are trained to perceive
different sounds, changes in the N1-P2 complex and
the MMN have been reported.

74

Other Applications:
• In addition to hearing loss, CAEPs are being used to
explore the biological processes underlying impaired
speech understanding in response to various types of
sound and in various populations with communication
disorders. In some cases, the motivation is to learn more
about the relationship between the brain and behavior.
• Abnormal neural response patterns have been recorded
in children with various types of learning problems.
• Older adults with and without hearing loss and individuals
with auditory neuropathy or dyssynchrony also show
abnormal neural response patterns.
• Because CAEPs reflect experience-related change in
neural activity, CAEPs are now being used to examine
children with learning problems undergoing speech sound
training and other forms of learning such as speech sound
segregation and music training.
75

Conclusion:
• Cortical auditory evoked potentials (CAEPs) are brain
responses generated in or near the auditory cortex
that are evoked by the presentation of auditory
stimuli.
• The P1-N1-P2 complex signals the arrival of stimulus
information to the auditory cortex and the initiation of
cortical sound processing.
• Taken together, these CAEPs provide a tool for
tapping different stages of neural processing of
sound within the auditory system, and current
research is exploring exciting applications for the
assessment and remediation of hearing loss.

76

• A woman born in 1929. In 1999, she noticed hearing
problems when using the telephone and an articulation
disorder, which worsened rapidly over 2 years.

• Neurologically, except for the hearing and articulation
problems, she exhibited no dysfunction of the motor
or sensory system. Her speech and hearing had
deteriorated to the point that she could not
communicate orally, although she could
communicate with family members and others by
exchanging written messages.

77

Long latency responses (Niraj)

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