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Deficient auditory interhemispheric transfer in patients with PAX6 mutations.

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Deficient Auditory Interhemispheric Transfer
in Patients with PAX6 Mutations
Doris-Eva Bamiou, MD, MSc,1 Frank E. Musiek, PhD,2 Sanjay M. Sisodiya, FRCP, PhD,3
Samantha L. Free, PhD,3 Rosalyn A. Davies, FRCP, PhD,1 Anthony Moore, FRCOpth,4
Veronica van Heyningen, DPhil, FRSE, FMedSci, MRC,5 Linda M. Luxon, BSc (Hons), MB, BS, FRCP1,6
PAX6 mutations are associated with absence/hypoplasia of the anterior commissure and reduction in the callosal area in
humans. Both of these structures contain auditory interhemispheric fibers. The aim of this study was to characterize
central auditory function in patients with a PAX6 mutation. We conducted central auditory tests (dichotic speech,
pattern, and gaps in noise tests) on eight subjects with a PAX6 mutation and eight age- and sex-matched controls. Brain
magnetic resonance imaging showed absent/hypoplastic anterior commissure in six and a hypoplastic corpus callosum in
three PAX6 subjects. The control group gave normal central auditory tests results. All the PAX6 subjects gave abnormal
results in at least two tests that require interhemispheric transfer, and all but one gave normal results in a test not
requiring interhemispheric transfer. The left ear scores in the dichotic speech tests was significantly lower in the PAX6
than in the control group. These results are consistent with deficient auditory interhemispheric transfer in patients with
a PAX6 mutation, which may be attributable to structural and/or functional abnormalities of the anterior commisure and
corpus callosum, although the exact contribution of these two formations to our findings remains unclear. Our unique
findings broaden the possible functions of PAX6 to include neurodevelopmental roles in higher order auditory processing.
Ann Neurol 2004;56:503–509
The PAX6 gene encodes a highly conserved transcriptional regulator.1 Phenotypic manifestations of heterozygous PAX6 mutations include panocular maldevelopment with aniridia1 and structural brain
abnormalities, with absent or hypoplastic anterior commissure and with present, but in some cases hypoplastic, corpus callosum.2–5 The functional significance of
these brain abnormalities is not well understood.
The anterior commissure is implicated in olfactory
interhemispheric transfer,6 and abnormal olfaction was
identified in PAX6 heterozygotes.2 In addition, our recent report found impaired auditory interhemispheric
transfer in a patient with PAX6 haploinsufficiency.7
This deficit may be attributable to structural and/or
functional abnormalities of the anterior commissure
and corpus callosum, because these structures contain
auditory interhemispheric fibers.8 Subjects with callosal
agenesis, with or without an anterior commissure, may
suffer from central auditory deficits in phonological
processing,9 sound localization,10 and interhemispheric
transfer,11,12 with characteristic ear asymmetries to verbal stimuli in dichotic speech tasks, that is, tasks in
which the two ears are in competition.13 These auditory deficits, which do not correlate with the IQ,14 are
associated with educational difficulties.15,16 The profile
in callosal agenesis is subtler than in the case of the
“split brain” patient who had surgical section of the
corpus callosum. In “split brain” cases, left ear performance in dichotic speech tasks is reduced to near extinction17; performance in both ears for monaural tasks
requiring interhemispheric transfer is severely reduced,17,18 but performance in auditory tasks not requiring such transfer is normal.17 It is not clear
whether the presence of an intact anterior commisure
in callosotomy cases is associated with milder auditory
deficits19 or not,20 or whether hypertrophy of the anterior commisure in cases with corpus callosum agenesis enables functional compensation.21
The purpose of this study was to assess auditory interhemispheric transfer in patients with PAX6 muta-
From the 1Neuro-otology Department, National Hospital for
Neurology and Neurosurgery, London, United Kingdom; 2Communication Sciences, University of Connecticut, Storrs, CT; 3Department of Clinical and Experimental Epilepsy Institute of Neurology;
National Hospital for Neurology and Neurosurgery, London; 4Division of Inherited Eye Disease, Institute of Opthalmology, and
Moorfields Eye Hospital, London; 5Human Genetics Unit, Edinburgh; and 6Institute of Child Health, University College London.
Received Mar 15, 2004, and in revised form May 20. Accepted for
publication Jun 10, 2004.
Published online Sep 9, 2004, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20227
Address correspondence to Dr Bamiou, Neuro-otology Department,
National Hospital for Neurology and Neurosurgery, Queen Square,
London WC1N 3BG, UK. E-mail: doris-eva.bamiou@uclh.org
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
503
tions, by means of a central auditory test battery, to
characterize the genotype–phenotype relationship and
to gain insight into the functional significance of the
abnormalities in the auditory interhemispheric pathway. We hypothesized that (1) patients with PAX6 mutations would have deficient auditory interhemispheric
transfer and (2) auditory interhemispheric transfer
would be more severely impaired in patients who had
both absent anterior commissure and hypoplastic corpus callosum.
Subjects and Methods
Subjects
We recruited adult subjects with a known PAX6 mutation
who attended Moorfields Eye Hospital for their visual difficulties and an equal number of normal controls, who were
matched to the subjects for age, sex, and handedness.
Procedures
All the subjects had undergone brain magnetic resonance imaging (MRI). Subjects and controls had standard baseline
and central auditory tests. The study was approved by the
ethics committee. Written informed consent was obtained
from subjects and controls.
Brain Magnetic Resonance Imaging
Subjects had a high-resolution brain MRI. This was a T1weighted three-dimensional coronal inversion recovery prepared fast spoiled gradient-recalled (SPGR) sequence. Corpus
callosum cross-sectional area was measured on the midsagittal slice of the MRI SPGR data as previously reported.21
Standard Baseline Audiometric Tests
We conducted pure-tone audiometry, tympanometry, and
otoacoustic emissions.
Standardized pure-tone audiometry was performed with a
GSI 61 audiometer with TDH-49 earphones in a soundproof room.22 Tympanometry was obtained with a continuous probe signal tone of 226Hz at 85dB SPL using a GSI-33
Middle Ear Analyser (Grason Stadler, Madison, WI). Tympanograms were considered normal if middle ear pressure
was greater than ⫺150mm H2O and compliance was greater
than 0.3cm3.
Transient otoacoustic emissions tests were conducted in
both ears using the ILO88/92 Otodynamic Analyser (Otodynamics, Hatfield, Herts, UK), with a standard default setup.23 The presence of normal OAEs across 500 to 4,000Hz
was determined by overall response amplitude signal to noise
ratio of at least 6dB and waveform reproducibility of greater
than 70% in at least three adjacent octave bands.24
Central Auditory Tests
We conducted dichotic speech tests (digits, consonant-vowels
[CVs], and fused rhymed words), pattern tests (frequency
and duration), and a temporal resolution (gaps in noise
[GiN]) test. Normative values were available for the dichotic
digits, frequency pattern, duration pattern, and gaps in noise
test. Results for the dichotic rhyme and dichotic CVs tests
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were judged as abnormal when they exceeded the minimummaximum range of results in the group of normal controls.
All the tests were available on CD, which was played with a
Sony CD player and routed through the speech circuit of the
GSI 61 audiometer.
The Dichotic Digits test25 is composed of digits from 1 to
9, excluding 7. A different pair of digits is given simultaneously to each ear at 50dBSL. The outcome measure is the
percentage of correct responses for each ear. Normal scores
are 90% or better. A list of 40 paired digits was administered
in each ear.
The Dichotic CVs test26 is composed of six CV syllables
formed by a stop plosive (b, p, t, d, g, k) and the vowel /a/.
A different CV syllable is presented to each ear, at 50dBSL.
The outcome measure is the percentage of correct responses
in the right and in left ear. One 30-trial block was administered.
The Dichotic Rhyme test27 is composed of 15 dichotic
pairs of words that are presented twice in a 30-trial block.
The words consist of monosyllabic consonant-vowelconsonant words that begin with one of the six stop consonants (b, p, t, d, g, k). The only difference for the two words
in each pair is in the initial consonant. The listener reports
only one word. The outcome measure is the percentage of
correct responses in each ear. Three 30-trial blocks were administered.
The Frequency pattern test28 consists of three tone-burst
sequences, which are a combination of a low (880Hz) and a
high frequency (1,122Hz) tone. Each sequence is composed
of two bursts of the same and one burst of a different frequency. The listener is required to name the sequence (eg,
high-high-low). The outcome measure is the percentage of
correct responses. Normal scores are 80% or better. A total
of 30 patterns were presented monaurally to each ear at
50dBSL after a brief practice session.
The Duration pattern test29 consists of three tone-burst
sequences, which are a combination of a long (500 milliseconds) and a brief duration (250 milliseconds) tone of
1,000Hz. Each sequence is composed of two bursts of the
same and one burst of a different duration at 300millisecond interstimulus intervals. The listener is required to
name the sequence (eg, short-long-short). The outcome measure is the percentage of correct responses. Normal scores are
70% correct or better. A total of 30 patterns were presented
monaurally to each ear at 50dBSL after a brief practice session.
In the Gaps in Noise test (F. E. Musiek, personal observations), the patient is monaurally presented with a 6-second
burst of white noise with 0 to 3 embedded gaps of 2 to
20-millisecond duration. The patient has to identify the
number of gaps in each noise burst. This test provides two
scores, the correct detection score (percentage of correct answers) and the gap detection threshold, that is, the shortest
gap duration t correctly identified in 50% (three of six) of
the trials for each gap duration. Normal results are a threshold of 6 milliseconds or better and a correct score of 50% or
better (own normative data).
Statistical Analysis
The results were analyzed with the SPSS version 11.5. We
used Mann–Whitney nonparametric tests. We applied the
Table. Brain MRI Abnormalities and Central Auditory Test Findings in the PAX6 Group
Case
No.
Age
(yr)
4
30
8
39
5
2
1
6
3
44
40
53
35
57
7
43
Mutation
Premature truncation
probably haploinsufficiency
In-frame deletion
(predicted nonfunctional protein)
C-terminal extension
C-terminal extension
C-terminal extension
Haploinsufficiency
Premature truncationprobably haploinsufficiency
C terminal extension
Anterior
Commissure
Corpus
Callosum
Absent
Drhya
DCVa
Normal
Abnormal
Abnormal
Abnormal
Abnormal
Normal
Normal
Normal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Abnormal
Normal
Normal
Abnormal
Normal
?b
Normal
Abnormal
Normal
Abnormal
?b
Abnormal
Abnormal
Abnormal
Normal
Abnormal
Abnormal
Abnormal
Abnormal
Normal
Abnormal
Abnormal
Abnormal
DDT
FPT
DPT
Normal
Normal
Normal
Absent
Normal
Normal
Present
Present
Absent
Small
Absent
Normal
Small
Normal
Normal
Small
Absent
Small
a
The CV test results are given as abnormal when the left ear score was lower than the minimum left ear score in the normal control group.
Results in the Dichotic Rhyme test are given as abnormal when the right ear score is higher than the maximum right ear score in the normal
control group.
b
Test not done.
MRI ⫽ magnetic resonance imaging; DDT ⫽ dichotic digits test; DCV ⫽ dichotic CVs test, DPT ⫽ duration pattern tests, Drhy ⫽ dichotic
rhyme test, FPT ⫽ frequency pattern test.
Bonferroni correction to control for multiple comparisons,
and we accepted a p value of 0.006 as significant.
Results
We recruited eight right-handed subjects with a PAX6
mutation (two men and six women; age range, 30 –57
years) and an equal number of age- and sex-matched
right-handed controls. All subjects were of normal intelligence.30
Brain Magnetic Resonance Imaging
The anterior commissure was absent in five and hypoplastic in one subject. The corpus callosum midsagittal
cross-sectional area was reduced in size in three subjects
(Table).
Standard Baseline Audiometric Tests
Pure-tone audiometry, tympanometry, and otoacoustic
emissions were bilaterally normal in all subjects and
controls.
Central Auditory Tests
Central auditory tests were normal in all controls. The
results in subjects are summarized in the Table.
Dichotic Digits Test
All the PAX6 subjects gave normal results in the right
ear, whereas five gave abnormal results in the left ear.
The left ear scores were significantly lower in the PAX6
group (median, 83%) than in the normal group (median, 97%) at p value 0.002 (Fig 1), and this result
remains significant after applying the Bonferroni correction.
Dichotic Consonant-Vowels Test
The right ear scores were comparable in the two groups
(PAX6 median, 44%; normal median, 43.5%). The left
ear scores were significantly lower in the PAX6 group
(median, 22%) than in the normal group (median,
31.5%) at p value 0.005 (Fig 2), and this result remains significant after applying the Bonferroni correction. Five of the eight PAX6 subjects had left ear scores
below the minimum value of the control group.
Dichotic Rhyme Test (Drhy)
The right ear mean score was significantly higher in
the PAX6 group (median, 56%) than in the normal
group (median, 47%) at p value 0.021; however, this
result does not remain significant after applying the
Bonferroni correction. The left ear scores were slightly
lower in the PAX6 group (median, 42%) than in the
normal group (median, 47%) but this did not reach
significance (Fig 3). Five of the eight PAX6 subjects
had right ear scores exceeding the maximum value of
the control group.
Frequency Pattern and Duration Pattern Tests
Frequency Pattern (FPT) scores were abnormal in five
of eight subjects and normal in all controls. DPT
scores were abnormal in four of eight subjects and normal in all controls.
Bamiou et al: PAX6 Aniridia
505
Fig 1. Boxplot of dichotic digits right and left ear scores in
normal and in PAX6 subjects.
Gaps in Noise Test
Only one subject gave abnormal thresholds and scores
for the GiN Test in both ears (Case 2). There was no
difference in GiN thresholds or scores in either ear between the PAX6 and the normal control group ( p ⬎
0.05).
The Table shows the MRI and central auditory test
results in the PAX6 group. All the PAX6 patients gave
abnormal results in two or more of the central auditory
tests.
Fig 2. Boxplot of dichotic consonant-vowels (CVs) right and
left ear scores in normal and in PAX6 subjects.
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Fig 3. Boxplot of dichotic rhyme right and left ear scores in
normal and in PAX6 subjects.
Discussion
Both as a group and on an individual patient basis, the
PAX6 patients were found to have a specific constellation of results in a central auditory test battery. This
study expands on our previous case report, which
showed central auditory deficits in one subject with
PAX6 haploinsufficiency.7
PAX6 mutations are associated with the absence or
hypoplasia of the anterior commissure (AC) with a
present but in some cases smaller corpus callosum
(CC).2 Both the AC and CC contain auditory interhemispheric fibers. The CC consists of heavily myelinated fibers connecting the two hemispheres. Its caudal
portion and splenium contain fibers that originate
from the primary and second auditory cortices8 and
from other auditory responsive areas.31 The AC in humans has an average area that is 1% of the total callosal
area32 and contains interhemispheric fibers from the
midportion of the superior temporal gyrus and the adjacent superior sulcus,8 two areas that are activated by
auditory words, environmental sounds, and music.33–35
Fibers from cortices with more differentiated lamination patterns travel in the CC, and fibers from less differentiated cortices travel in the AC.36
The functional role of these interhemispheric connections has been examined in patients who had these
pathways sectioned. Although results in monaural
speech tests remain normal,16 these subjects typically
will show reduced to near extinct left ear performance
in dichotic digits16 and CVs, with increased right ear
performance in dichotic rhyme tests.37 These findings
have been explained on the basis of the “callosal relay
model”,38 which proposes that language perception
takes place in the left hemisphere, and that in the di-
chotic situation, the contralateral pathway, which dominates in auditory signal transmission, takes over. Thus,
in dichotic tests, speech stimuli from the left ear will be
transmitted to the right (nonlanguage) hemisphere and
will require transfer via the interhemispheric commissures to the left hemisphere for linguistic processing.38,39 In addition, after complete callosotomy, scores
in the frequency16 and duration pattern tests17 are bilaterally reduced, as for a sequence of sounds, and the
pattern of the sequence is determined in the right
hemisphere as a gestalt, but the labeling happens in the
left (language) hemisphere.40 All these findings are specific for section of the posterior part of the corpus callosum and splenium,16,41 which contain auditory fibers,8 whereas anterior section of the corpus callosum
causes no such effects.42
We observed similar abnormalities to the “split
brain” in the PAX6 group, albeit to a less severe degree.
We explain these auditory deficits according to the
“callosal relay model.”38 This model is supported by
positron emission tomography studies, which show bilateral temporal cortex activation for pitch and duration pattern analysis,43 as well as by psychoacoustic experiments,44 functional MRI studies of dichotic
tasks,45 and functional connectivity studies.46 However, the “direct-access model”38 proposes that speech
stimuli from the left ear will be directly analyzed in the
right auditory cortex, albeit less efficiently than in the
left cortex. In addition, complex dichotic speech tasks
activate a wider network in each hemisphere than simpler tasks, and the dichotic test results may well reflect
both the effects of interhemispheric transfer and of
asymmetries in processing efficiency because of other
“top-down” processes.44,45,47 In either case, it becomes
evident that although deficient interhemispheric transfer may not be the sole culprit, it is a significant component underlying these findings. Other alternative explanations for our findings would include the presence
of auditory cortex or subcortical abnormalities. The
PAX6 gene is essential for differentiation and maintenance of cerebellar granule cells,48 and PAX6 mutations are associated with MRI-documented gray matter
changes in the cerebellum and occipital lobe, which
are, however, nonauditory areas, whereas the brainstem, including the inferior colliculi and posterior
commissure, appears normal on MRI.21 Polymicrogyria of the temporal cortex also has been reported in 2
of 24 patients with PAX6 mutations.49 However, none
of our eight subjects had either polymicrogyria or any
other auditory cortical or subcortical or brainstem abnormalities on MRI, and, furthermore, the presence of
normal results in the gaps in noise test and the lateralization of the test findings (with left ear deficit on the
dichotic tasks) would also argue against these possibilities. Abnormal results in the gaps in noise test were
observed only in Case 2, and in this case the presence
of other subtle abnormalities of the auditory pathway,
not detectable by MRI, could not be entirely excluded.
With this exception, the constellation of test results in
the other seven patients provides strong evidence for
deficient auditory interhemispheric transfer, which
could be attributed to structural and/or functional abnormalities of the AC and CC, although the exact contribution of these two formations to our findings remains unclear.
There are no previous reports on auditory interhemispheric transfer function in cases of congenital absence
of the AC with a present CC, because this brain malformation is newly reported.2 Callosal agenesis causes
mild impairment of auditory interhemispheric transfer,
probably because of development of alternative pathways resulting from brain plasticity.11,12 There is anecdotal evidence that hypertrophy of the AC may be associated with better functional compensation,20 due to
rerouting of some of the neuronal axons through the
AC.50,51 However, the AC is found to be enlarged in
only 10% of cases with callosal agenesis, and it is entirely absent in another 10%.50 In callosotomy cases, it
is unclear whether presence of an intact AC is associated with milder deficits,18 or not.19 On this basis, it
would have been expected that the PAX6 patients
would exhibit only mild auditory abnormalities, as the
CC was present (reduced in size in only three patients)
and the AC would be expected to be of lesser importance in auditory interhemispheric transfer, because of
its significantly smaller size,7 but also because it contains fibers originating from less differentiated cortical
areas.36 In addition, because these structural abnormalities are developmental, functional compensation may
be expected to occur, because of brain plasticity. However, the PAX6 patients showed abnormalities that varied from severe, with abnormal results in four of five
tests (eg, Cases 3 and 7) to mild, with abnormal results
in two of five tests (Cases 4 and 8). Cases 3 and 7 had
the most severe structural abnormalities in the group,
with both an absent AC and a hypoplastic CC, and it
is possible that the brain’s potential for plasticity or
compensation was reduced. In Case 4, the youngest in
the group, the milder deficits could be attributed to the
normal callosal area. The sample was too small to differentially assess the effects of severity of each malformation on the results. In addition, the presence of deficits in Case 5 could indicate the presence of
abnormalities on a functional as opposed to structural
level, because the AC was present and the callosal area
was also normal. Also, PAX6 mutation might lead to
cortical reorganization that has no obvious MRI appearance.21 Other factors, such as individual strategies
and top-down processes, or age,52 may have influenced
the central auditory test results.
In conclusion, we found a specific constellation of
central auditory findings in a group of patients with
Bamiou et al: PAX6 Aniridia
507
PAX6 mutations, which provide evidence for decreased
auditory interhemispheric transfer. This decrease could
be attributed to the presence of congenital structural,
and possibly, functional abnormalities of the auditory
interhemispheric pathways and to reduced capacity for
plasticity or compensation of the brain. Further studies
of these patients would add to our understanding of
the function of the commissural pathways of the brain
and of the profile resulting from commissural pathway
dysgenesis. Our unique findings broaden the possible
role of PAX6 to include higher order roles not only in
visual and olfactory sensory domains, but also in auditory processing, and may have implications for education in these subjects.
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