Diffusion tensor imaging analysis of the corpus callosum in children with high-risk autism spectrum disorder

Abstract

BACKGROUND:

OBJECTIVE:

The purpose of this study was to examine the development of the corpus callosum and its relationship to neurobehavior in young children with high-risk (HR) ASD using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI).

METHODS:

Twenty-one children with HR-ASD who visited Anhui Children’s Hospital between January 2020 and December 2021 were selected as the study group, while 19 matched children with normal development during the same time were adopted as the control group. Cranial MRI $+$ DTI were performed for all of the enrolled children and fractional anisotropy (FA) measurements were taken in each region of the corpus callosum.

RESULTS:

The FA values in all regions of the corpus callosum were higher in the study group than in the control group (0.417 $\pm$ 0.016 vs. 0.412 $\pm$ 0.02 in the corpus callosum knee, 0.439 $\pm$ 0.018 vs. 0.431 $\pm$ 0.023 in the corpus callosum body, and 0.446 $\pm$ 0.017 vs. 0.434 $\pm$ 0.019 in the splenium of corpus callosum [SCC]), where the difference in the FA in the SCC was statistically significant between the two groups ( $P<$ 0.05). There was a positive correlation between the FA in the corpus callosum knee and speech scores in the neuropsychological development of the study group ( $P<$ 0.05).

CONCLUSION:

There was a premature development tendency for corpus callosum myelination in young children with HR-ASD, and the developmental tendency was visible in the SCC. There was also a positive relationship between corpus callosum knee development and language function.

Keywords

Autism spectrum disorder diffusion tensor imaging corpus callosum fractional anisotropy developmental quotients

1. Introduction

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that begins in early infancy and childhood and is characterized by impaired social communication and repetitive stereotyped behaviors, among which social communication disorders are the core symptoms [1]. ASD was first reported by Kanner in 1943; currently, the incidence of ASD is approximately 2%, with an increasing annual trend [2]. There are no biologically based diagnostic criteria for ASD, and most of its early clinical manifestations are atypical; as such, there is a lack of screening and early warning mechanisms for detecting these indicators. A symptom-based diagnosis is difficult, a behavior-based diagnosis is inevitably subjective, and most diagnoses are confirmed at ages older than 3 years, resulting in missed opportunities for early and timely intervention for these children [3].

In recent years, science and technology has been continuously developed and applied on ASD [4, 5]. The value of neuroimaging in early diagnosis of ASD is gradually being recognized by domestic and international researchers [6]. In the present study, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) was applied to investigate the characteristics of the fiber development of the corpus callosum in children with high-risk (HR) ASD, and the correlation with neurobehavioral development was analyzed to provide an evidence-based approach for early clinical diagnosis and treatment.

2. Materials and method

2.1 Case presentation

Twenty-one children who had been diagnosed with HR-ASD, and who visited the Rehabilitation Department of Anhui Children’s Hospital from January 2020 to December 2021 were enrolled as the study group. The group included 17 males and 4 females, aged 1.5–3-years old, with an average age of 1.96 $\pm$ 0.34 years. During the same period, 19 sex-and-age-matched children with normal development attending Anhui Children’s Hospital were selected as the control group; they included 13 males and 6 females, aged 1–3 years, with an average age of 1.73 $\pm$ 0.57 years.

The inclusion criteria for HR-ASD were: (1) Patients who screened positive on the Modified Checklist for Autism in Toddlers (M-CHAT); (2) patients who met the core symptoms of the diagnostic criteria for ASD in the Diagnostic and Statistical Manual of Mental Disorders; (3) patients aged 1–3-years old.

The exclusion criteria were: (1) Patients with inherited metabolic diseases; (2) patients with a history of encephalitis and cranial trauma; (3) patients who were unable to cooperate in completing the appropriate tests.

The parents of all enrolled children signed the informed consent form for inclusion in the research. The study was conducted in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of Anhui Children’s Hospital.

2.2 Method

Cranial MRI scanning and DTI were performed for all enrolled cases using a Philips Achieva 1.5T MRI scanner at the imaging center. For children who could not cooperate at the time, a 10% chloral hydrate solution was administered orally or by enema at a dose of 0.3–0.5 ml/kg before conducting the scanning, and the scanning was completed after the patient fell asleep. The head was fixed with a sponge pad during scanning. All scanning data were processed by the Service Pack 9 software (affiliated with the workstation) to form the fractional anisotropy (FA) images, including measurement of the FA in the white matter fiber bundles. In the present study, the region of interest (ROI) was primarily the white matter fiber bundles in the corpus callosum, including the corpus callosum knee, body, and the splenium of corpus callosum (SCC). Between 2–3 ROIs were drawn for each region, each with an area of 35–45 mm ${}^{2}$ , and the average FA value was calculated.

The M-CHAT is a revised version of the CHAT, which is one of the most commonly used international screening scales for children aged 16–30 months.

Gesell development schedules were adopted for participants younger than 3 years. The neurological development of the children was assessed according to the following five dimensions: gross motor skills, fine motor skills, language development, personal–social behaviors, and adaptive behavior.

Excel 2007 and SPSS Statistics version 19.0 software programs were adopted to record and analyze the data. The measurement data that satisfied the normal distribution were expressed as means $\pm$ standard deviation ( $\bar{x}\pm s$ ). The differences in the FA in different regions of the corpus callosum between the normal children and children with HR-ASD were analyzed using an independent samples $t$ -test. Spearman correlation analysis was conducted to investigate the correlation between FA in different regions of the corpus callosum and various behavioral abilities.

3. Results

3.1 A comparison of the FA values that were measured in different regions of the corpus callosum between the two groups of children

The FA values in different regions of the corpus callosum in the HR-ASD group were all greater than those in the control group, and the differences in FA in the SCC were statistically significant ( $P<$ 0.05; see Table 1).

Table 1
Comparison of the FA values in different regions of the corpus callosum between the two groups of children

ROI	FA		$P$
	HR-ASD	Control group
Corpus callosum knee	0.417 $\pm$ 0.016	0.412 $\pm$ 0.021	0.553
Corpus callosum body	0.439 $\pm$ 0.018	0.431 $\pm$ 0.023	0.471
Splenium of the corpus callosum	0.446 $\pm$ 0.017	0.434 $\pm$ 0.019	0.036

3.2 Correlation analysis of the FA values in different regions of the corpus callosum and each dimension in the developmental scale in the HR-ASD group

The FA values measured in different regions of the corpus callosum were positively correlated with each dimension in the developmental scale, and the correlation between the FA in the corpus callosum knee and the language function was statistically significant ( $r=$ 0.56, $P<$ 0.05), as shown in Table 2.

Table 2
The correlation coefficients r between the FA values in each region of the corpus callosum and the developmental scale scores in the HR-ASD group

Region	Gross motor	Fine motor	Language	Personal-social behaviors	Adaptive behavior
Corpus callosum knee	0.16	0.12	0.56	0.25	0.23
Corpus callosum body	0.11	0.10	0.29	0.24	0.16
Splenium of the corpus callosum	0.14	0.15	0.26	0.27	0.19

4. Discussion

ASD is mainly characterized by social interaction disorders, verbal communication disorders, narrow interests, and repetitive stereotyped behaviors. However, the early clinical manifestations in children with ASD are atypical, making a symptom-based diagnosis difficult. Most patients with ASD are diagnosed at an age older than 3 years, thereby missing the best time for early intervention [7]. In recent years, with the continued development of imaging technology, the application of functional MRI for children with ASD as a means for analyzing the changes of the functional and structural characteristics in the brain has been a particular focus of research and has improved the early warning and screening rates of ASD [8].

Studies have shown that children with ASD have abnormal white matter connectivity in multiple parts of the brain, which can manifest as short-range over-connectivity and long-range under-connectivity [9]. The corpus callosum is part of the long-range connection and is the largest connecting fiber in the brain; 70%–80% of the information in the cerebral cortex is connected through the corpus callosum, which plays an important role in the integration of information transfer and processing between the two cerebral hemispheres. The investigation of these structural features will help to further gain a better understanding of the pathological basis of neurodevelopment in children with ASD.

DTI can reflect the maturation process of individual white matter fiber bundles and is currently the only new technique that can non-invasively display the integrity and directionality of cerebral fiber bundles in vivo. Additionally, DTI is one of the most effective tools for investigating the structural connectivity of the cerebral white matter, primarily using the diffusion anisotropy of water molecules for imaging and reflecting the diffusion changes of water molecules in the brain to show the major white matter fiber bundles, as well as any changes during the development. In the present study, the FA data in young children with HR-ASD were analyzed by DTI, based on a region of interest (ROI) analysis. The results showed that the FA values in the corpus callosum knee, body, and the SCC were higher than those in the normal controls of the same age, and the differences in the SCC were statistically significant ( $P<$ 0.05).

The above results suggest that the development of different regions of the corpus callosum in early childhood in children with ASD may not be synchronized with those in normal children, and may also be particularly pronounced in the SCC. This was consistent with a study conducted by Chang et al. [6], but contradicted the results of other studies [10]. The similarities and differences in the results of these studies may be associated with factors such as the study population and the age group of the study subjects. The FA values primarily correlated with the degree of myelination and the integrity of axonal cell membranes [11]. The higher the cell membrane integrity, and the more mature the myelination, the higher the FA value tended to be. Myelin formation and the maturation of nerve cells are important processes of brain development in normal children, and FA values at this stage are positively correlated with an increase in age, whereas children with ASD tend to show abnormal development of the brain white matter fibers due to various abnormal factors.

The results of the present study support the etiological hypothesis that children with autism have abnormal neurofibrillary “connectivity” during brain development [12]. A longitudinal study [13] suggested that this high FA value in the corpus callosum was predominant in a younger age group, while there existed a decrease in the FA values in an older age group, with a crossover point of this increase in the early stage and a decrease in the later stage compared with normal children at approximately 7–8-years of age. The results of a similar study showed that the crossover point for this change was at approximately 12-years of age [14]. The high FA values in the present group of children may be correlated with their younger age and the tendency for premature overdevelopment of corpus callosum myelination during this period. This is consistent with studies of brain volume in cases of ASD, where a large head circumference was observed in early infancy and a significant increase in brain volume was measured during the same period, supporting the presence of early overdevelopment [15].

To investigate the relationship between the developmental characteristics of the corpus callosum and the clinical phenotype of children with HR-ASD, Pearson correlation analysis was adopted in the present study to explore the correlation between the FA values in different regions of the corpus callosum and pediatric neuropsychological development (i.e., developmental quotients [DQ]) in children with ASD. The results showed that the FA values of the corpus callosum in children with HR-ASD were positively correlated with neuropsychological development, and the positive correlation between the FA in the corpus callosum knee and the language development score was statistically significant ( $P<$ 0.05). The corpus callosum mainly comprises fibers that connect the neocortex of both hemispheres, connecting the corresponding cortex of both hemispheres. The fibers in the corpus callosum knee connect the large anterior part of the frontal brain lobes on both sides. The fibers in the corpus callosum body connect the posterior premotor area, precentral gyrus, and the parietal lobe of the frontal lobes of both hemispheres. The fibers in the posterior part of the body and the SCC connect the temporal and occipital lobes on both sides [16]. The frontal lobe is involved in the complex regulation of cognitive behavior, personality expression, and executive function, while the fibers of the frontal cortical neurons on both sides are interconnected mainly through the corpus callosum knee for functional expression and integration. In the present study, all instances of the early callosum development in early childhood proceeded earlier than in normal children of the same age, and the development of the corpus callosum knee was significantly and positively correlated with language function, enabling them to have better speech skills in early childhood. However, this language function was mostly manifested in stereotyped repetitive expressions and poor comprehension, the so-called language separation phenomenon [17]. This early separation of uneven language development is rarely taken seriously by parents and most of these patients often visit hospital for late developmental lag or even loss or regression in overall language function. The mechanism of this language regression remains unclear; studies suggest that it is correlated with the inappropriate shaping and cutting of early overgrown joint structures and that it chiefly begins in the second year of life [18].

The current study is not without limitations. Because this study had a small enrollment sample size, it is anticipated that follow-up studies will be conducted using larger sample sizes. In addition, the present study had a cross-sectional nature; additional longitudinal follow-up studies involving the same individuals are needed to render the results more representative. Moreover, a comparative analysis of the whole-brain white matter, as well as a comparison between the left and right sides of brain white matter were not conducted and requires in-depth focus in future studies.

5. Conclusion

DTI may be able to reflect the characteristics of the white matter development of the corpus callosum in children with HR-ASD. There indeed existed a tendency toward premature overdevelopment of the myelination process of the white matter of the corpus callosum in young children with ASD, which may be relatively obvious in the SCC, suggesting the overdevelopment of the association of distant white matter fiber bundles in the early stages, where the uneven development of each region will affect the ability of information transmission and integration processing. The FA value in each region of the corpus callosum was positively correlated with each behavior score on the DQ scale, and there was a significant positive correlation with language development in the corpus callosum knee, indicating that the more developed this region was, the higher the language value was on the DQ scale. However, the mechanisms underlying this uneven development of language function, which is mostly exhibited as stereotyped repetitive speech and lags within comprehensible speech development, require further investigation.

Footnotes

Conflict of interest

The authors declare no conflict of interest.

Funding

This study was supported by the Scientific Research Fund of Anhui Medical University (No. 2019xkj183).

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