Differential habituation to repeated sounds in infants at high risk for autism.

Abstract

It has been suggested that poor habituation to stimuli might explain atypical sensory behaviours in autism. We investigated habituation to repeated sounds using an oddball paradigm in 9-month-old infants with an older sibling with autism and hence at high risk for developing autism. Auditory-evoked responses to repeated sounds in control infants (at low risk of developing autism) decreased over time, demonstrating habituation, and their responses to deviant sounds were larger than responses to standard sounds, indicating discrimination. In contrast, neural responses in infants at high risk showed less habituation and a reduced sensitivity to changes in frequency. Reduced sensory habituation may be present at a younger age than the emergence of autistic behaviour in some individuals, and we propose that this could play a role in the over responsiveness to some stimuli and undersensitivity to others observed in autism.

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Differential habituation to repeated sounds in infants at high
risk for autism
Jeanne A. Guirauda, Elena Kushnerenkob, Przemyslaw Tomalskib, Kim Daviesa,
Helena Ribeiroa, Mark H. Johnsonaand The BASIS Team
It has been suggested that poor habituation to stimuli
might explain atypical sensory behaviours in autism. We
investigated habituation to repeated sounds using an
oddball paradigm in 9-month-old infants with an older
sibling with autism and hence at high risk for developing
autism. Auditory-evoked responses to repeated sounds in
control infants (at low risk of developing autism) decreased
over time, demonstrating habituation, and their responses
to deviant sounds were larger than responses to standard
sounds, indicating discrimination. In contrast, neural
responses in infants at high risk showed less habituation
and a reduced sensitivity to changes in frequency.
Reduced sensory habituation may be present at a
younger age than the emergence of autistic behaviour
in some individuals, and we propose that this could
play a role in the over responsiveness to some
stimuli and undersensitivity to others observed in
autism. NeuroReport 00:000–000 ? c 2011 Wolters Kluwer
Health | Lippincott Williams & Wilkins.
NeuroReport 2011, 00:000–000
Keywords: auditory, autism, event-related potentials, habituation, infants,
mismatch negativity
aDepartment of Psychological Science, Centre for Brain and Cognitive
Development, Birkbeck, University of London andbInstitute for Research in Child
Development, School of Psychology, University of East London, London, UK
Correspondence to Jeanne A. Guiraud, PhD, Department of Psychological
Science, Centre for Brain and Cognitive Development, Birkbeck, University of
London, The Henry Wellcome Building, London WC1E 7HX, UK
Tel: + 44 7846115332; fax:+ 44 2076316587;
e-mail: jeanne_guiraud@hotmail.com
Received 8 August 2011 accepted 15 August 2011
Introduction
Autism is a neurodevelopmental disorder typically diag-
nosed from around 3 years, which is characterized by
impaired communication and social skills and repetitive or
stereotypical behaviours [1]. It is highly associated with
genetic risk; although the prevalence of broader-defined
autism spectrum disorder (ASD) is approximately 1% in
the general population, about 20% of those infants who
have an older sibling diagnosed will go on to receive the
diagnosis themselves [2]. Children and adults with autism
often present with abnormal sensory behaviours, being
easily distressed or preoccupied by innocuous sights,
sounds, odours and textures and under responsive to other
stimuli leading to atypicalities such as a high-pain thresh-
old [3]. Distortions in sensory input in early infancy could
lead to a failure to develop more complex cognitive
abilities and sensory abnormalities at 14 months of age
might be early indicators of later autism [4]. Infants later
diagnosed with ASD and toddlers with autism between the
ages of 6 and 35 months display unusual behaviours in
response to changes in sensory stimuli [5]. This is
particularly the case in the auditory modality, in which
unusual responses to sounds; both hyporeactivity and
hyperreactivity are reported [6]. Although hypersensitivity
is a trait that autistic children share with developmentally
delayed children, and correlates with their mental age,
hyposensitivity appears to be a characteristic specific to
autism [7]. Furthermore, a review by Rogers and Ozonoff
(2005) [8] highlights the fact that there is more evidence
that children with autism, as a group, are hyporeactive
rather than hyper-responsive to sensory stimuli. It is
possible that some behaviours observed in autism are an
expression of compensatory responses to cope with
hyposensitivity, which may therefore play a role in the
emergence of autistic characteristics. The reasons why
individuals with autism are hyposensitive, however, are as
yet poorly understood.
Reduced habituation to sensory stimulation could explain
both hyposensitivity and hypersensitivity in autism.
Neural habituation is a process by which the neural
response decreases over time during repeated stimula-
tion [9]. A reduced habituation could lead to an inability
to discriminate novel from repeated sounds and therefore
to a form of hyposensitivity to changes in the auditory
environment. At the same time, failure to habituate could
foster an experience of sensory overload, which in turn
could lead to hypersensitivity. Several studies have
suggested that habituation is reduced in individuals with
autism. An event-related potential (ERP) study showed
that children with autism may have reduced habitua-
tion [10]. In this study, the amplitude of the P50 com-
ponent did not decrease in response to a click after another
click in 12 7–13-year-old high-functioning children with
autism. This was in contrast to typically developing
children, whose diminished electrophysiological response
The BASIS team members are: Simon Baron-Cohen, Patrick Bolton, Susie
Chandler, Tony Charman, Mayada Elsabbagh, Janice Fernandes, Teodora Gliga,
Greg Pasco and Leslie Tucker
Developmental neuroscience1
0959-4965 ? c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
DOI: 10.1097/WNR.0b013e32834c0bec

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to repeated stimuli reflected habituation. Other studies
have shown that severity of autistic symptoms in adults
correlates with poor behavioural habituation to faces
(e.g., [11]) and a reduced functional MRI-adaptation
effect in the amygdala due to repeated exposure to
faces [12]. The fact that habituation is reduced in
children with autism and that symptom severity corre-
lates with poor habituation in adults suggest that poor
habituation may play a role in the emergence of autistic
symptoms, including atypical sensory responses.
Little is known about the underlying causes of autism
or the process through which symptoms emerge (for a
review [13]). Researchers, until recently, have relied on
limited retrospective data on infants younger than 2 years
of age before diagnosis. Infants at high risk, by virtue of
being genetic relatives of children with autism, might
share some characteristics with affected individuals; even
if they do not themselves go on to receive a diagnosis. In
adults, the broader autism phenotype refers to clinical,
behavioural and brain characteristics associated with
autism found not only in affected individuals but also in
their relatives [14]. It is not known whether reduced
habituation is a feature of the broader autism phenotype
and/or is involved in the emergence of the sensory
characteristics of autism.
In this study, we used an oddball paradigm to investigate
habituation and its role in auditory discrimination in 9-
month-old infants at high risk of developing autism to
determine whether poor habituation is present before the
onset of autism in some individuals. In oddball paradigms,
neuronal adaptation [15] to repetitive standard sounds is
necessary in order for infrequent deviant sounds to
generate the mismatch neural response called mismatch
negativity (for review see [16]). We recorded the P150,
an evoked potential component thought to reflect
auditory sensory processes [17], in response to standard
and deviant auditory tones. In low-risk infants with an
older sibling without autism, we expected to find a
decrease in P150 amplitude with repetitions of the
standard tone, demonstrating habituation and an en-
hanced electrophysiological response to pitch deviants
compared with standards reflecting discrimination [18].
In the group of infants at high risk, we predicted a
reduced decrease in neural responses to repeated
standards, and no enhanced responses to deviants
indicating poor habituation that might underlie their
atypical behavioural responses to changes in sounds.
Materials and methods
Participants
We tested 35 infants (14 females) from the British
Autism Study of Infant Siblings (BASIS; www.basisnetwork.
org), all of whom had an older full sibling (of which four
were females) with a community clinical diagnosis of
ASD. We also recruited 21 low-risk infants (11 females)
with no reported family history (first-degree relative) of
autism from a volunteer database at the Birkbeck Centre
for Brain and Cognitive Development. All low-risk infants
had at least one older full sibling. Infants were tested at
around 9 months and 9 days of age (±27 days in the high-
risk group, ±23 days in the control group).
Stimuli
Sounds were presented in an oddball paradigm adapted
from Kushnerenko et al. [17]: two different types of
infrequent sounds (11.5% probability each) occurred at
random positions within a sequence of 500-Hz pure tones
(standards), with the restriction that these sounds were
always followed by at least two standards. One infrequent
sound was a pure tone of 650Hz (the deviant), and the
other infrequent sound was white noise. To rule out that
poor habituation and encoding of deviant pitch was due
to the auditory processing difficulties often reported in
children with autism [19], the white-noise deviants were
used to assess the integrity of central auditory processing
in high-risk infants as reflected by ERP responses to a
spectrally rich stimulus known to elicit the most reliable
and invariant across individual infants response compared
with all other types of deviants [17]. The duration of the
sounds was 100ms, including 5-ms rise and 5-ms fall
times, with an inter-stimulus (offset to onset) interval of
700ms. The intensity of the sounds was 70dB SPL. We
presented the stimuli until the infants became restless,
that is, on average 472 events were presented to low-risk
infants and 507 events to high-risk infants.
Procedure
Infants were seated on their caregiver’s lap within a
sound attenuated room, whereas sounds were presented
through two speakers, 1m apart and located 1m in front
of the infant. An experimenter blew bubbles during the
presentation of the sounds to direct the infant’s attention
away from the sounds, as is usual practice in mismatch
negativity studies [11]. Parents gave their consent for
their infant to participate in the study. The study was
approved by London National Health Service Research
Ethical Committee (reference number: 06/MRE02/73)
and conducted in accordance with the Declaration of
Helsinki (1964).
Data acquisition and analysis
Brain electrical activity was measured using an EGI 128-
channel Hydrocel Sensor Net. We could not record
electroencephalographic data from three low-risk infants
who did not like having the net on their head. The
reference electrode at recording was the vertex (Cz in the
conventional 10/20 system). The electrical potential was
filtered with 0.1–200-Hz bandpass, and digitized at 500-
Hz sampling rate. Continuous data were filtered offline
with a 15-Hz low-pass filter. Epochs of 800-ms duration,
including 100-ms prestimulus interval, were extracted for
each stimulus. Furthermore, the first three epochs and
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2011, Vol 00 No 00

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those exceeding 150mV at any signal channel were
excluded from averaging. The average amount of trials
per condition was 284 standards (±76), 44 tone deviants
(±12) and 41 noises (±11) in the 35 high-risk infants
and 243 standards (±56), 34 tone deviants (±9) and 38
noises (±11) in the 18 controls from whom we collected
data. Epochs were separately averaged for the different
conditions (standards, deviants and noise) and rerefer-
enced to average reference. Responses to standards were
further processed by averaging separately the responses
to the first, second and third standards after a deviant or
noise to look at habituation. We looked at ERPs generated
over the right hemisphere, consistent with the previous
literature on tone processing in infants (e.g., [20]).
Amplitude measurements were extracted from seven
electrodes around the C4 area, where mismatch responses
are commonly studied (e.g., [17]), and baseline corrected
using a 100-ms long prestimulus baseline. For each
analysis, we selected time windows for amplitude
measurement spanning 50% of the peak amplitude of
the grand averaged waveforms across groups in both
directions, that is, from 110ms to 250ms for P150 in
response to the first three standards after a deviant/noise
for the habituation analysis within and across groups, from
90 to 170ms for P150 in response to all the standards and
deviants for the sensitivity to deviant analysis across
groups, and from 120 to 320ms for the comparison of
P150 amplitudes in response to noise across groups.
Amplitudes were calculated as the mean voltage within
each latency window.
Results
Poor habituation in high-risk infants
As shown in Fig. 1, low-risk infants habituated to
standards, with the amplitude in response to third
standards after a tone deviant/noise decreasing signifi-
cantly when compared with first standards [repeated
analysis of variance: F(1,87)=4.804, P=0.043], whereas
as a group, high-risk infants did not [repeated analysis of
variance: F(1,147)=1.029, P=0.318]. Further evidence
that low-risk infants habituated more than high-risk
infants was provided by the fact that while the amplitude
in response to first standards after a deviant/noise did not
differ across groups [two-tailed independent sample t-
test: t(51)=0.406, P=0.687], the amplitude in response
to third standards was significantly smaller in controls
compared with high-risk infants [two-tailed independent
sample t-test: t(51)=2.005, P=0.050].
Hyposensitivity to deviants in high-risk infants
There was a significant increase in the amplitude of
responses to deviants compared with standards in low-risk
infants [one-tailed paired t-test: t(17)=2.102, P=0.025],
but not in high-risk infants [one-tailed paired t-test:
t(34)=0.427, P=0.336]. Lack of differential response to
deviants compared with standards could not be due to
impaired auditory processing in the infants at high risk, as
there was no significant difference in amplitude of the
responses to noise in high-risk infants compared with low-
risk infants [two-tailed independent t-test: t(51)=0.406,
P=0.686]. Figure 2 shows the ERPs in response to the
various stimuli in both groups.
Discussion
In this study, we show that low-risk infants typically have
a bigger P150 in response to deviants compared with
standards, reflecting better discrimination of the devi-
ants, whereas the electrophysiological activity of infants
at high risk of developing autism is similar in response to
deviants and standards. This finding is in line with
previous studies, which have failed to show a typical
mismatch response to tones deviant in frequency in
children with autism (e.g., [21]). A recent theory
proposes that the mismatch response to deviants in an
oddball paradigm arises from neuronal adaptation in
auditory cortex [15]. It is suggested that repetition of
auditory standards leads to frequency-specific inhibition
of the tonotopic representation of the standard, and in
parallel, release from inhibition of all other (nonadapted)
frequency representations. Absence of a mismatch
response in infants at high risk could thus be a result of
the reduced habituation effect that we observe here.
Stimulus-specific adaptation can be shown by a gradual
decrease in auditory ERP amplitude in response to
repetitive tones during passive listening [22]. Unlike
low-risk infants, our group of high-risk infants does not
show a decrement in P150 amplitude to standards,
confirming our prediction that they have reduced
habituation to repeated sounds. The effect of reduced
habituation on performance has been studied in adults
with autism in a tactile task, where, in contrast with
controls, earlier history of tactile stimulation failed to
Fig. 1
P150 amplitude (µV)
ST1ST2ST3
∗
∗
Low-risk infants
High-risk infants
2
1.5
1
0.5
0
−0.5
−1
Amplitude of P150 on right central electrodes (see bottom right corner
for the region selected) in response to the first, second and third
standards after a deviant/noise (ST1, ST2 and ST3, respectively). Bars
are standard errors of the mean. *P<0.05.
Poor auditory habituation in infants at risk Guiraud et al.
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alter tactile spatial localization [23]. Hence, reduced
neural habituation in infants at high risk may prevent
them from discriminating deviant sounds.
According to the ‘over-arousal theory’, poor habituation to
stimuli in the environment in children with autism
contributes to general levels of over arousal followed by
heightened arousal in response to specific stimulation
(for a review [8]). However, there is also accumulating
evidence that supports the opposite hypothesis of under
arousal, which states that impairment of a child with
autism’s ability to connect previous experiences with
current ones prevents learning and generalization, and
contributes to nontypical reactions and/or under reactiv-
ity to stimuli [8]. Our results show how habituation, a
neuronal mechanism thought to reflect plasticity and
learning [24], has the capacity to explain both theories.
Reduced habituation leads to hyposensitivity to a
stimulus change and at the same time an over-reactivity
to repeated stimulation. Reduced habituation could also
result in other characteristics of autism, such as
restrictive and repetitive behaviours [25].
Conclusion
This study shows that reduced neural habituation is
present in infants at high risk for autism, and results in
reduced neural responses to tone frequency changes. We
speculate that reduced habituation may generate hypo-
sensitivity to subtle changes in auditory environment, at
the same time resulting in over reactivity to repeated,
irrelevant information and play a role in the emergence of
other autistic characteristics in some children.
Acknowledgements
The authors thank the BASIS families for the generous
contribution they have made toward this study.
Authors contributions to the study: the first author
designed the study, analysed and interpreted the data and
wrote the article; the second and third authors con-
tributed to designing and setting up the study and
editing the article; the fourth and fifth authors helped
set up the study, collected the data, and edited the
article; the sixth author directed the BASIS programme,
interpreted the data and contributed to writing the
article; the BASIS team contributed to establishing and
running the programme, provided advice on the study,
recruited and scheduled families and edited the article.
Sources of any support: BASIS is supported by a con-
sortium of funders led by Autistica (see www.basisnetwork.org).
This project is additionally supported by Medical
Research Council Grant G0701484 to M.H. Johnson.
Conflicts of interest
None declared.
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