Download Structural Abnormalities of the Central Auditory Pathway in Infants

Structural Abnormalities of the Central Auditory Pathway in Infants With
Nonsyndromic Cleft Lip and/or Palate
Frank F. Yang, M.D.S., Bradley McPherson, Ph.D., Huang Shu, M.D.S., Na Xie, M.D., Kui Xiang, B.D.S.
Objective: To investigate possible structural abnormalities of the central
auditory pathway in infants with nonsyndromic cleft lip and/or palate (NSCL/P).
Participants: Twenty-seven Chinese infants with NSCL/P, aged from 6 to
24 months.
Intervention: Morphological magnetic resonance imaging (MRI) measurements
of the central auditory nervous system (CANS) in infants with NSCL/P were
analyzed and compared with those of age- and sex-matched normal controls.
Results: No significant group differences were found in general brain
measurements, including volumes of the brain stem and right hemisphere.
However, infants with NSCL/P had statistically significantly smaller volumes of
the left thalamus and left auditory cortex and notably decreased thickness of
the left auditory cortex.
Conclusion: Cortical abnormalities were more marked compared with other
MRI measurements. Structural CANS abnormalities in infants with NSCL/P may
be located mainly in the left cerebral hemisphere. The development and
maturation of the auditory cortex in infants with NSCL/P may be abnormal
when compared with those of normal children.
KEY WORDS:
central auditory nervous system, cleft lip and palate, hearing
impairment, magnetic resonance imaging
Recently, (central) auditory processing disorders in
children with craniofacial cleft disorders have drawn the
attention of researchers (Minardi et al., 2004; Yang and
McPherson, 2007; Boscariol et al., 2009). Such a hearing
impairment may be a secondary outcome derived from
factors such as long-term conductive hearing impairment,
mechanical speech problems, or even the social and/or
emotional manifestations of living with facial anomalies
(Gould, 1990; Broen et al., 1996). However, there is some
evidence to suggest that the cognitive dysfunction noted in
some individuals with nonsyndromic cleft lip and/or palate
(NSCL/P) may be related to brain pathology and cortical
dysfunction (Kapp-Simon and Krueckeberg, 2000; Nopoulos et al., 2002b, 2007b; Laasonen et al., 2004; Nopoulos
et al., 2007). Possibly the cognitive impairment found in some
individuals with NSCL/P is not secondary to external factors
but primary to brain malformation and/or dysfunction.
Nopoulos and colleagues (2000, 2001) conducted a series
of studies to investigate cortical anatomical structures in
persons with craniofacial clefts, including individuals with
nonsyndromic clefts or NSCL/P, using brain magnetic
resonance imaging (MRI) scanning and image processing.
They reported the presence of a specific midline brain
anomaly (enlarged cavum septi pellucidi) and other brain
abnormalities in adult men with NSCL/P. The research
group believed that the etiology of these cognitive deficits
was primarily a problem of abnormal brain development.
Interestingly, the research group found that the most
severely affected region of the brain in adult men with
NSCL/P was the temporal lobe (Nopoulos et al., 2002a).
Because the auditory cortex is located in this cortical area,
these structural abnormalities may lead directly to auditory
dysfunction. They also investigated the brain structures in
children with NSCL/P (aged 7 to 17 years) and found that
children with NSCL/P had abnormally small cortical volume
and different tissue distribution compared with their normal
peers (Nopoulos et al., 2007a), suggesting that cortical
development might be abnormal in children with NSCL/P.
However, the existing research literature has mainly
described brain anomalies in older children or adolescents
and adults. For infants and young children with NSCL/P,
our understanding of the central auditory nervous system
(CANS) or auditory pathways remains incomplete and
requires more investigation. It is unclear whether the
abnormal brain structures noted in older groups are
congenital or developmental, and the developmental
Mr. Yang and Prof. McPherson are with the Center for Communication Disorders, University of Hong Kong, Hong Kong, China. Mr. Shu is
with the Cleft Lip and Palate Centre and Dr. Xie and Ms. Xiang are with
the Department of Radiology, Shenzhen Children’s Hospital, Shenzhen,
China. Prof. McPherson is Director, Center for Communication Disorders,
University of Hong Kong, Hong Kong, China.
Submitted February 2011; Accepted July 2011.
Address correspondence to: Mr. Frank Feng Yang, Center for
Communication Disorders, the University of Hong Kong, 5F, Prince
Philip Dental Hospital, 34 Hospital Road, Hong Kong, China. E-mail
[email protected].
DOI: 10.1597/11-014
137
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Cleft Palate–Craniofacial Journal, March 2012, Vol. 49 No. 2
features of the CANS in infants with NSCL/P have not
been investigated. Further research to assess and characterize the structures and development style of the CANS in
infants with NSCL/P is necessary. Improved understanding
of this issue may provide important information that can be
used in clinical treatment and/or rehabilitation of auditory
disorders associated with craniofacial clefts and in the
development of comprehensive prognostic markers.
In the present study, structural analysis of the CANS in a
group of infants with NSC/LP was conducted using a brain
MRI scanning and image-processing approach, and the
results were compared to those of age- and sex-matched
normal control participants.
It has been reported that MRI processing software,
including SPM, Brainvoyager, FreeSurfer, Caret, BrainSuite,
and BrainVisa, might have bias when analyzing brain images
of young children or infants (Leroy et al., 2011). However, the
purpose of the current study was not to provide the exact
anatomic values of the brain structures in infants who
participated in this study, but rather to determine whether
there were any significant differences between infants with
NSCL/P and their normal control infants with regard to the
overall anatomical structure of the CANS.
METHODS
The present study was approved by the Institutional
Review Board of the University of Hong Kong/Hospital
Authority West Cluster (HKU/HA IRB, protocol
number UW 07-250). This study was conducted in
collaboration with the Cleft Lip and/or Palate Center, the
Hearing Center, and the Department of Radiology in
Shenzhen Children’s Hospital, Shenzhen, China.
Participants
From September 2007 to August 2008, a total of 81 infants
with NSCL/P, aged from 6 to 24 months, were recruited to
participate in the present program from the Cleft Lip and/
or Palate Center, Shenzhen Children’s Hospital, using a
convenience sampling method. Clinical history questionnaires
were completed by a certified medical clinician for all infants
who participated in the study through interview of the parents
or caregivers. The selection criteria were as follows: Full-term
birth and uncomplicated delivery (with normal birth history);
nonsyndromic cleft (no other disorders, e.g., known genetic
syndromes, ventricular septum defect, perinatal asphyxia);
and no other chronic health disorders. Following application
of the inclusion criteria, six infants with cleft-related
syndromes, three infants with abnormal delivery histories,
and 12 infants with acute or chronic respiratory infections
were excluded from the present investigation. In addition,
because this study aimed to investigate the central auditory
status of the subjects, an assessment of peripheral hearing
status was first conducted using middle ear examination
(otoscopy plus tympanometry), transient evoked otoacoustic
TABLE 1
Subject Characteristics of the NSCL/P Group
Gender
Type of
Cleft*
LUCP6L
RUCP6L
BCP6L
CP
CL6A
Total
Cleft Status
Male
Female
Unrepaired
6
5
6
5
2
24 (88.9%)
1
1
0
1
0
3 (11.1%)
1
1
0
3
0
5 (18.5%)
Repaired
Total
6
7
5
6
6
6
3
6
2
2
22 (81.5%) 27 (100.0%)
* LUCP6L 5 left unilateral complete cleft palate with or without cleft lip; RUCP6L 5
right unilateral complete cleft palate with or without cleft lip; BCP6L 5 bilateral complete
cleft palate with or without cleft lip; CP 5 cleft palate only; CL6A5 cleft lip with or
without cleft alveolus.
emission (TEOAE) screening, and air conduction auditory
brain stem–evoked response (ABR) hearing threshold acquisition with click stimuli. Thirty-three infants with active
middle ear disease (diagnosed otitis media or abnormal
tympanograms in one or both ears) or with a history of
recurrent (three times within 6 months or four or more
episodes within 1 year) or chronic (exceeding 3 months)
middle ear disorder (Paradise, 1980) in one or both ears, as
well as those with an abnormal hearing level (ABR air
conduction threshold above 30 dB nHL bilaterally or
unilaterally), were excluded from the study.
Twenty-seven NSCL/P infants with normal middle and
inner ear function and normal bilateral hearing levels were
therefore included in this study. The mean age of the
NSCL/P group was 15.6 months (standard deviation
5.7 months). Next, 27 noncleft infants from the Health
Care Center, Shenzhen Children’s Hospital, were recruited
as normal control subjects during routine checkups of their
growth and development. The normal infants were
matched with each infant with NSCL/P for both age and
gender. There were 24 male and three female infants in the
control group, aged from 6 to 24 months, and the mean age
was 15.6 months (standard deviation 5.7 months).
The purpose of the study was explained to parents, and
informed consent was obtained from all parents or
caregivers of the study participants before testing. Demographic data, including age, gender, cleft type, and cleft
repair status, were recorded. All participants were Han
Chinese from southern mainland China, and 86% of infants
were from families with low socioeconomic status residing
in rural areas. Almost 90% of the cleft subjects were male;
this gender imbalance might relate to a preference for male
offspring in Chinese families with low socioeconomic status
(Liang et al., 2000). The characteristics of the subjects in the
NSCL/P group are summarized in Table 1.
Procedures
Audiological Assessment
All hearing assessments were conducted by a certified and
experienced audiometry technician in the Hearing Center
of Shenzhen Children’s Hospital at one appointment. The
Yang et al., AUDITORY PATHWAY MALFORMATIONS IN CLEFT INFANTS
infant subjects were kept in a natural sleep state as much as
possible throughout the hearing examinations, and breaks
were given when necessary. All tests were supervised by a
researcher from the Division of Speech and Hearing
Sciences, University of Hong Kong. Infant subjects with
normal otoscopic findings (Chu and McPherson, 2005), type
A tympanogram (Jerger, 1970), TEOAE pass (Anteunis et
al., 1998), and ABR air conduction thresholds under 30 dB
nHL (Sininger, 1993) were considered to have normal
peripheral hearing function and were sent to the Radiology
Department of Shenzhen Children’s Hospital for brain MRI
scanning. Patients who failed the hearing assessments were
referred to the Otolaryngology Department of Shenzhen
Children’s Hospital for audiological and otological intervention.
Brain MRI Scanning
Brain MRI scans were conducted with a 1.5-Tesla
General Electric EXCITE System (GE Medical Systems
Corp., WI) with an eight-channel pediatric head coil
employed as the MR signal receiver to improve the
signal-to-noise ratio. Axial three-dimensional T1-weighted
images of the subjects were acquired using a fast spoiled
gradient-echo sequence (Ax 3D-FSPGR). The standard
structural scanning protocol was applied according to the
manufacturer’s instructions with two sequences (Ax 3DFSPGR T1), and images were obtained for each subject for
structural analysis. Conventional MRI scans were also
performed on all the subjects (T1WI spin echo images and
T2WI fast spin echo images) for clinical diagnosis by two
experienced radiologists to exclude other brain pathology.
The T1WI sequences used a 1.5-mm slice thickness, 40u flip
angle, TR/TE 5 24/5 ms, NEX 5 2, field of view 260 3
260 mm2, and matrix 256 3 192 pixels; and the T2WI
sequences used a 3.0-mm slice thickness, TE 36 ms (for
PD), 96 ms (for T2), TR 3000 ms, NEX 5 1, field of view
260 3 260 mm2, and matrix 256 3 192 pixels. During the
MRI brain scanning, all subjects were sedated with 10%
chloral hydrate solution to keep the infants in deep sleep to
prevent head movement in the MRI scanning environment.
Brain MRI Image Processing
High-resolution three-dimensional T1 images were obtained as the original files (raw data in digital imaging and
communication in medicine [DICOM] format). The raw data
files were identified and processed with the FreeSurfer
software package developed by the Athinoula A. Martinos
Center for Biomedical Imaging (http://www.nmr.mgh.
harvard.edu/martinos). FreeSurfer, a freely distributed software package (version 3.5) for the Linux platform (CentOS,
version 4.5) (http://www.martinos.org/freesurfer), is a set of
automated tools for reconstruction of human brain structures
from structural MRI data; it includes tool sets for subdividing
the subcortical brain structures (Dale et al., 1999), labeling the
139
cerebral cortex into anatomically based regions of interest
(Fischl et al., 1999), and measuring the thickness of the
cerebral cortex from MRIs (Fischl and Dale, 2000).
Statistical Analysis
Statistical analysis was performed using the SPSS version
16.0 software package, and a covariate-adjusted multivariate analysis of variance (MANCOVA) approach was
applied. For measurements of both body height and head
circumference, age (in months) was used as the covariant.
For brain size and brain stem measurements, head
circumference was selected as the covariant. For cerebrum
measurements, brain size was used as the covariant. In the
analysis of superior temporal plane (STP, left and right),
the volume of the corresponding hemisphere was applied as
the covariant. Wilks’ lambda test was used for group
comparisons, with an alpha level of .05 (two-tailed) set to
indicate statistical significance.
RESULTS
General Brain Measurements
No differences between groups were found in body
growth measurements, including height and head circumference. General brain measurements also showed no
significant differences between infants with NSCL/P and
normal controls. Table 2 shows the descriptive data and the
results of MANCOVA.
For the general volume measurements (including cerebrum, cerebellum, and brain stem) of brain size, there was
no significant group difference found between infants with
NSCL/P and normal controls. Similarly, for the brain stem,
no statistically significant difference was found between
groups. Figure 1 shows the group comparisons of brain size
and brain stem volume.
Structural Analysis of the Cerebrum
Table 3 shows the descriptive data and MANCOVA results
for the structural analysis of the cerebrum. No significant
group difference was found in the right cerebral measurements between infants with NSCL/P and normal controls.
For the left cerebrum, there were no statistically significant
differences for general volume and white matter volume
between groups. However, the volumes of the cerebral cortex
and thalamus of the left cerebrum in infants with NSCL/P
were found to be significantly smaller than those of their
normal peers (p , 0.001). Figure 2 shows the group
comparisons of the left cerebral cortex and thalamus volumes.
Structural Analysis of the Superior Temporal Plane
Table 4 shows the descriptive data and MANCOVA
results for the STP measures. No significant abnormalities
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Cleft Palate–Craniofacial Journal, March 2012, Vol. 49 No. 2
TABLE 2
Body Growth and General Brain Measurements in NSCL/P and Normal Infants
NSCL/P (n 5 27)
Measure
Body height*
Head circumference*
Brain size (cm3){
Brain stem (cm3){
Normal (n 5 27)
Mean
SD{
Adjusted Mean
Mean
SD{
Adjusted Mean
F (1, 51)
p
80.08
46.79
1201.30
11.45
6.15
1.32
267.95
2.09
80.09
46.80
1217.64
11.58
80.53
46.98
1216.22
11.47
6.45
1.42
262.61
2.11
80.53
46.98
1199.88
11.34
1.269
1.972
0.444
1.483
.265
.166
.508
.229
* covariate 5 age (mo).
{ covariate 5 head circumference (in cm).
{ SD 5 standard deviation; adjusted mean is controlled by covariate.
of the right STP in the NSCL/P group were observed for
any of the three indices applied in the present study.
However, infants with NSCL/P were found to have
significant structural abnormalities in the left STP, with
smaller volume and reduced thickness versus their normal
peers. Figure 3 shows the group comparisons of the volume
and thickness of the left STP.
with age, from no distinct difference at the age of 6 months
to an average difference of nearly 13.2% in thickness and
21.3% in volume by the time infants reached 2 years of age,
indicating that the development of the left STP may be
inhibited in infants with NSCL/P.
Development of Left STP in Infants With NSCL/P
No Significant General Brain Malformation in Infants
With NSCL/P
As shown in the scatterplot graph of the volume and
thickness of the left STP with the age of infants (in month)
in the two participating groups (Fig. 4), the difference
between the measures noted in the two groups increased
FIGURE 1 Group comparisons of brain size and brain stem volume for
infants with NSCL/P and normal controls. A: Brain size. B: Brain stem volume.
DISCUSSION
The present study found no significant differences in
body growth between infants with NSCL/P and normal
FIGURE 2 Group comparisons of left cerebral cortex and thalamus
volume in infants with NSCL/P and normal controls. A: Left cerebral cortex
volume. B: Left thalamus volume.
Yang et al., AUDITORY PATHWAY MALFORMATIONS IN CLEFT INFANTS
TABLE 3
141
Cerebrum Measurements in NSCL/P and Normal Infants
NSCL/P (n 5 27)
Normal (n 5 27)
Mean
SD{
Adjusted Mean
Mean
Left cerebrum
Volume (cm3)
Gray matter (cm3)
White matter (cm3)
Thalamus (cm3)
379.53
276.18
103.35
4.98
73.53
52.15
21.73
0.66
381.63
277.69
103.94
5.00
Right cerebrum
Volume (cm3)
Gray matter (cm3)
White matter (cm3)
Thalamus (cm3)
380.92
270.02
110.90
5.65
62.01
39.18
23.57
1.04
382.65
271.20
111.54
5.68
Measure{
SD{
Adjusted Mean
F (1, 51)
p
393.03
287.33
105.70
5.59
31.08
1.06
390.92
285.82
1.5.10
5.57
1.719
4.796
0.066
51.653
.196
.033*
.799
.000*
383.46
272.75
110.71
5.65
63.56
40.36
23.71
1.14
381.72
271.65
110.07
5.62
0.078
0.055
0.652
1.069
.781
.815
.423
.306
* P , 0.05.
{ covariate 5 brain size (in cm3).
{ SD 5 standard deviation; adjusted mean is controlled by covariate.
controls, both for body height and for general brain
measurements. This finding is in contrast with the findings
of Nopoulos et al., who reported that body growth in
children from 7 to 17 years old with NSCL/P was less than
that in control subjects (Nopoulos et al., 2007a). However,
other studies have also reported that although general body
growth in subjects with CL/P during childhood is less than
that in normal children, most eventually reach normal
height (Cunningham and Jerome, 1997). There is evidence
for the existence of growth hormone deficiency in children
with CL/P during early childhood. For example, Ranalli
and Mazaheri (1975) investigated the growth of 279
children with CL/P from birth to 6 years and found that,
despite an early ‘‘lag and catch-up’’ period, the height of
children with CL/P did not differ significantly from that of
normal controls. It has also been suggested that children
with CL/P may have delayed growth because of surgical
cleft repair operations, as well as an increased risk of
feeding difficulties and airway infections, but that these
factors would not affect the ultimate development of
children (Felix-Schollaart et al., 1992).
General brain structures, including brain size, volume of
the brain stem, gray/white matter distribution in each
hemisphere, and the volume of the thalamus, were analyzed
in the present investigation. No major brain malformations
TABLE 4
were found, as there were no significant differences in most
of the observed indices between the two groups, except for
the volume of the left cerebral cortex and left thalamus.
This finding was also different from those of Nopoulos
et al., who reported that older children with NSCL/P had
abnormally smaller brain size, including the cerebrum and
cerebellum. The distribution of cerebral cortical gray
matter and white matter was also reported to be abnormal
in boys with NSCL/P (larger cortical volume, smaller
volume of white matter) (Nopoulos et al., 2007a). The same
research group also reported no significant differences
between adult men with NSCL/P and controls in intracranial volume, general brain tissue distribution, and total
volume of the cerebrum, but a significantly lower volume of
the cerebral cortex in bilateral temporal lobes was noted
(Nopoulos et al., 2000). It is very interesting that the
present study found that the brain malformation status in
infants with NSCL/P was more similar to that previously
reported in adults with NSCL/P rather than children. In
our observations, the cerebral structural malformation in
infants with NSCL/P was located mainly in the left
hemisphere, with reduced volume of the gray matter
(cerebral cortex), and the most abnormal involvement
was the reduced volume and decreased thickness of the left
STP versus that of healthy infants. Conversely, in another
STP Measurements in NSCL/P and Normal Infants
NSCL/P (n 5 27)
Normal (n 5 27)
Measure
Mean
SD1
Adjusted Mean
Mean
SD1
Adjusted Mean
F (1, 51)
p
Left STP
Volume (cm3){
Thickness (mm){
Area (cm2){
7.42
2.73
26.42
2.91
0.28
8.58
7.68
2.77
27.08
8.77
2.98
28.39
3.38
0.40
8.53
8.52
2.95
27.73
8.188
33.953
0.570
.006*
.000*
.454
Right STP
Volume (cm3){
Thickness (mm){
Area (cm2){
8.69
3.18
26.31
3.20
0.54
6.39
8.76
3.20
26.43
8.70
3.24
25.87
3.17
0.57
6.01
8.64
3.23
25.75
0.496
2.941
2.150
.485
.092
.149
*
{
{
1
P , 0.05.
covariate 5 volume of left hemisphere (in cm3).
covariate 5 volume of right hemisphere (in cm3).
SD 5 standard deviation; adjusted mean is controlled by covariate.
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Cleft Palate–Craniofacial Journal, March 2012, Vol. 49 No. 2
FIGURE 3 Group comparisons of volume and thickness of the left STP in
infants with NSCL/P and normal controls. A: Left STP volume comparison.
B: Left STP thickness comparison.
published work in the MRI study series (Shriver et al.,
2006), the STP was reported to be disproportionately larger
in adult men with NSCL/P compared to control subjects.
Shriver et al. (2006) further reported that the gray matter
volume of STP was inversely correlated with all measures
of intelligence quotient (including full scale and performance and verbal subscales) and language test scores in
NSCL/P subjects. They also examined the incidence of
hearing deficits in subjects during their infancy and
childhood and did not find a significant correlation with
the STP malformations. Thus, the authors suggested that
the structural abnormalities and dysfunction of the STP in
adult men with NSCL/P could be a pathologic enlargement
with no relationship to childhood hearing deficits. The
differences between the present results and previous reports
need to be discussed and further explored. The differences
in target population (including ethnicity and age range of
the subjects), the equipment and protocol used in brain
MRI scanning, and the methodology applied for imaging
processing may have contributed to these differences. On
the other hand, the growth and development of the human
brain itself is very complex and prolonged. Genetic
elements and environmental factors always play roles in
this process. Although the cerebral volume in 5-year-old
FIGURE 4 Scatterplot of volume and thickness of left STP with
increasing age (in months) in infants with NSCL/P and normal controls.
A: Left STP volume. B: Left STP thickness.
children can reach 95% of that in adults, the distribution of
cerebral gray and white matter changes substantially,
especially during puberty, and is continually modified,
even up to 30 years of age (Pienaar et al., 2008). The
volume of the cerebrum in children with NSCL/P could
eventually reach normality, but abnormal distribution of
the cerebral tissue in infants, children, and adults has been
noted consistently in all studies. This may suggest that
different stages of cortical growth and development, from
young childhood to school age and into adulthood, might
have different trajectories in subjects with NSCL/P
compared with normal individuals. Longitudinal assessment of subjects with and without NSCL/P would provide
a better understanding of the pattern of brain growth and
development in NSCL/P and how it differs from that of
healthy controls.
Structural Abnormalities of the CANS in Infants
With NSCL/P
From auditory nerve to auditory cortex following the
ascending pathway, the human CANS comprises mainly
Yang et al., AUDITORY PATHWAY MALFORMATIONS IN CLEFT INFANTS
the following structures: the auditory nerve; the auditory
structures of the brain stem (including cochlear nuclei,
trapezoid body, superior olivary complex, and lateral
lemniscus); the inferior colliculus (in midbrain); the
auditory part of the thalamus (medial geniculate nucleus);
and the primary auditory cortex, which is located in the
temporal lobe. Because of the limited resolution of the 1.5Tesla MRI scanning system used in the present study, it
was difficult to analyze all structures of the CANS in
infants under 2 years of age. Based on the available
techniques, image processing could only approximately
identify CANS structures, such as the brain stem, thalamus,
and STP, in which the major cortical auditory structures
are located. At the brain stem level, the auditory structures
consist mainly of the cochlear nuclei, the trapezoid body,
and the lateral lemniscus (Musiek et al., 2005). The acoustic
signal is transferred into neural information from the
auditory nerve, follows along the ascending auditory
pathway in the brain stem bilaterally, and reaches the
thalamus, which is the major connection between the
cerebral cortex and midbrain. The thalamus has many
functions. In general, it plays a transporting role between
the subcortical structures and cerebral cortical corresponding areas (Demanez and Demanez, 2003). Almost every
sensory system (visual, auditory, and somatosensory
systems) has its connecting nucleus in the thalamus and
sends the neural information to the associated primary
cortical area (Demanez and Demanez, 2003). For the
auditory system, the medial geniculate nucleus acts as a
key relay between the lower auditory structures and the
primary auditory cortex (Zaehle et al., 2008).
The STP is the dorsal portion of the superior temporal
gyrus. It is located within the sylvian fissure and can be
divided into the transverse temporal gyri (Heschl’s gyrus
[HG]), the planum temporale (PT), and the planum polare
(PP). HG comprises one or two small gyri on the dorsal
surface of the superior temporal gyrus, and it is considered
to be the primary auditory cortex (Brodmann areas 41 and
42) (Hall et al., 2003). The PP and PT are located directly
anterior and posterior to HG, respectively, and these
regions are considered to be the auditory-associated cortex
(Karabanov et al., 2009). These structures are believed to
govern auditory processing abilities and some aspects of
language function. It is thought that HG may be involved
in the processing of basic sound features, such as frequency
and intensity level, while the PP and PT may be responsible
for processing more complex acoustic signals (Hall et al.,
2003). Therefore, the STP was selected as one of the target
structures for the present investigation.
The results of the present study did not show significant
group differences in the volume of the brain stem and right
thalamus or for measurements of the right STP, indicating
no significant abnormalities for these structures in infants
with NSCL/P. However, it was observed that infants of the
cleft group had significantly smaller volumes of the left
thalamus and left STP and, notably, decreased thickness of
143
the left STP. Since these structures are believed to have
crucial auditory functions, it could be assumed that
patients in this group might be at risk of auditory
dysfunction at the subcortical and/or cortical levels.
However, it should be clarified that the auditory pathway
has bilateral transactions at these levels, and therefore
unilateral lesions may not lead to observable auditory
dysfunction (Demanez and Demanez, 2003). Further
investigations based on the functional evaluation of the
auditory pathways could provide more evidence regarding
the central auditory status of this group.
Abnormal Development of the Auditory Cortex in Infants
With NSCL/P
It has been assumed that any structural malformations of
brain components in subjects with NSCL/P would be
congenital; however, this hypothesis was not supported by
the results of the present study. With respect to the
development of the CANS in infants, the results showed
significant differences only in the volume of the left
thalamus and left cerebral cortex and in measurements of
the left STP between the cleft group and normal control
participants. The most distinct structural abnormality was
the left STP, in which the primary and associated auditory
cortices are located. However, it appears that this difference
becomes more marked with increasing age—from almost
no difference at 6 months of age to a difference in volume
of more than 20% by the time infants reached age 2 years.
This finding indicates that the development of the auditory
cortex in infants with NSCL/P might be inhibited during
early childhood.
The different maturation stages and development styles
of the brain stem, subcortical structures, and auditory
cortex in the human CANS during early childhood might
provide an explanation for the present findings. The
development and maturation of the brain stem are
completed at a very early age. It has been reported that
an ABR can first be recorded in a premature infant of
27 weeks’ gestation (Amin et al., 1999). The development of
the auditory brain stem continues throughout the first
2 years of life, particularly in the first 12 months after birth,
and during this time the auditory structures of the thalamus
are just beginning to connect to the auditory cortex (Ohl
et al., 2009). The maturation of the auditory cortex occurs
much later than that of the brain stem, and the thickness is
only half of that in adults, while the laminar pattern of
cytoarchitecture in infants is indistinct as well, and changes
can be observed in the cortical auditory structures
throughout puberty (Hall et al., 2003).
If auditory sensory input is inhibited, especially during
early childhood, the morphological and functional development of neurons in the CANS could also be inhibited.
Hearing impairments in infants can go undetected until
2 years of age if no specialized tests are performed. For
children with NSCL/P, otitis media occurs frequently
144
Cleft Palate–Craniofacial Journal, March 2012, Vol. 49 No. 2
during early childhood, and the prevalence of conductive
hearing loss is rather high. Although the subjects in the
present study had passed their peripheral hearing examinations, the effects of a history of middle ear disorders on
the development of the CANS in infants with clefts in this
study could not be ruled out. In some cases, the parents or
caregivers might have no recollection of middle ear
disorders in their children, especially when the symptoms
were mild. Daly et al. (1994) compared parental reports
with medical records for 157 children with chronic otitis
media with effusion. In parental reports, there was a
substantial proportion of missing data for age at first
episode of otitis media, occurrence of otitis media the
previous summer, and number of episodes in the previous
18 months. The accuracy and completeness of parental
report of the child’s hearing history seemed to be affected
by the timing and/or seriousness of middle ear disorders
and the duration prior to recall (Broen et al., 1996). Almost
all research on neural development of the CANS in children
supports the principle that early assessments and interventions are crucial for maximizing the development of
communicative abilities in young children (Moore, 2006).
The results of the present study could also provide evidence
to support this consensus, implying that it is important to
monitor the neurological development of the auditory
pathway in children with CL/P, which was not a focus of
previous studies.
The Relationship between Brain Malformations and NSCL/P
There are two important research questions to be
answered in this area. First, is there any relationship
between brain malformation and NSCL/P? A definitive
statement cannot yet be made, based on the limited
evidence to date. Structural abnormalities of the brain
were found in the series of studies of Nopoulos et al. and in
the present study, which used MRI brain scanning and
image analysis. Different results were reported for abnormalities of brain general development, regional analysis,
and structural distribution, perhaps because of differences
in the target subject groups selected, MRI instruments,
scanning protocols, and image-processing techniques.
However, the collective results of these studies indicate
that patients with NSCL/P may be at risk of developmental
brain abnormalities. Nevertheless, longitudinal observation
and larger sample size investigations are necessary, and
further analysis across racial and gender factors on brain
development in patients with craniofacial clefts should be
conducted.
Second, what is the basis for the relationship between
structural brain abnormalities and NSCL/P? One possible
answer might be that direct relationship is unlikely. A claim
that observed brain abnormalities are directly related to the
craniofacial cleft would never be appropriate. The relationship between the two could only be interpreted based
on the fact that development of the face and brain occurs
under the same biologic environment—either normal or
pathologic. On the other hand, craniofacial clefts are
malformations of both facial appearance and the basal
portion of the skull, which may lead to structural brain
malformations. Furthermore, the etiology of craniofacial
clefts including NSCL/P is very complex, with genetic and
environmental factors interacting throughout embryonic
development. Because brain and facial development are
intimately related, it seems likely that both the genetic and
the biologic elements involved in NSCL/P may also play
roles in the formation of brain structure abnormalities in
this group.
SUMMARY
The present study investigated structural abnormalities
of the CANS in infants with NSCL/P using brain MRI
scanning and image processing. The results showed no
significant abnormalities in general brain development in
infants with NSCL/P compared with normal controls.
Significant group differences were found in measurements
of the left hemisphere, including the volume of the
thalamus and cerebral cortex. In particular, in comparison
with their normal counterparts, infants with NSCL/P were
found to have significantly lower volume and decreased
thickness of the left STP, in which the auditory cortex is
located. Furthermore, the pattern of increasing difference
with increasing age of the brain structures suggests a
developmental rather than a congenital abnormality in the
infants with NSCL/P who participated in the present study.
Further investigations of the central auditory status in
subjects with NSCL/P using functional and behavioral
assessment techniques are needed.
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