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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: 10.1597/11-014 137 138 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 140 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. 142 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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