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自闭症谱系障碍（ASD）是一种儿童神经发育障碍。早期诊断和干预可以重塑大脑的神经结构并提高生活质量，但如果仅基于临床症状和评估量表可能不准确。功能性 MRI 显示与 ASD 核心症状相关的功能网络破坏、灌注异常和神经血管解耦。质子磁共振波谱显示不同时期神经元代谢物的异常变化。沿着血管周围间隙指数的弥散张量成像信号减少反映了自闭症谱系障碍儿童的类淋巴系统功能受损。自闭症谱系障碍儿童的年龄、亚型、脑损伤程度和重塑程度的差异导致了研究结果的异质性。
- autism spectrum disorder
- early diagnosis
- magnetic resonance imaging
- glymphatic system
一、简介
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社交沟通和互动障碍，以及受限的重复刻板行为[ 1 ]。根据美国教育部的数据，患自闭症谱系障碍的风险每年增加10%至17%[ 2 ]。在美国，每 36 名儿童中就有 1 名被诊断患有 ASD，男孩的患病率是女孩的 3.8 倍[ 3 ]；这种疾病给家庭和社会带来沉重的经济和情感负担[ 4 , 5 ]。自闭症谱系障碍通常在 4 岁时被诊断出来，磁共振成像 (MRI) 可以帮助及早发现大脑的异常变化 [ 6]，包括脑容量增加、白质纤维束完整性受损以及大脑结构和功能网络连接、组织灌注和神经元代谢异常[7,8,9 ]。通过早期诊断自闭症谱系障碍，科学有效的干预措施可能有助于重塑大脑的神经连接，提高自闭症谱系障碍儿童的生活质量[ 10 ]。目前，广泛使用的MRI技术包括结构MRI（sMRI）、扩散张量成像（DTI）、功能MRI（fMRI）、三维动脉自旋标记（3D-ASL）和质子磁共振波谱（ 1 H-MRS ）。
2. 自闭症谱系障碍中的结构 MRI
In sMRI, changes in brain volume in children with ASD are shown using voxel-based morphometry. Changes in the surface area and thickness of the cerebral cortex can be studied using surface-based morphometry. The brain volume of children with ASD begins to increase at the age of 12–24 months, rapidly increases at 2.5 years, and increases by approximately 10% compared with the brain of typically developing (TD) children at the age of 2–4 years; the brain volume then increases slowly during late childhood and adolescence [6,13,14,15]. Excessive early brain growth may be associated with an increased number of neurons, which in turn results in an excess of axons, dendrites, synapses, and myelin, leading to increase in both gray- and white-matter volumes in the brain [16]. In addition, the symmetric amplification of germinal cells around the ventricles in individuals with ASD may lead to an increase in minicolumns, which could contribute to the expansion of the cortical surface area. This increased surface area is primarily located in the middle occipital gyrus, cuneus, and lingual gyrus areas, further promoting early brain overgrowth [15,17,18]. Compared with TD children, the volumes of the bilateral superior frontal gyrus, left precuneus, left inferior occipital gyrus, right angular gyrus, bilateral superior temporal gyrus, and left inferior parietal lobule of the brain are increased in children with ASD [6,19,20,21], whereas the right inferior temporal gyrus decreases in volume, thereby reflecting the atypical nature of the brain structure in children with ASD [22]. As the angular and superior frontal gyri are located in the cognitively relevant default mode network (DMN), their volume changes are closely associated with social and cognitive deficits [15]. Children with ASD have increased hippocampal volume compared with that of TD children [23,24,25]. Specifically, the left hippocampal white-matter volume increases [26] while bilateral gray-matter volume decreases [27] or increases compared with TD children [28]. The increase in hippocampal volume may be associated with an increase in pyramidal neurons during the birth process [29]. Due to the involvement of the hippocampus in the core functions of the “social brain,” changes in its volume can lead to language and cognitive impairments [26,27]. Previous studies have shown that histopathological changes in the cerebellum, such as the reduction of granule cells, hypertrophy, and atrophy of cerebellar nuclei can be observed in the postmortem brains of individuals with ASD [30]. Increased cerebellar volume at 4–6 months of age in children with ASD can predict the emergence of restricted and repetitive behaviors in early childhood [31]. Increased cerebellar volume during infancy and childhood in individuals with ASD may be related to early brain overgrowth [30], while the decreased cerebellar volume in adolescents and adults with ASD is positively correlated with the severity of motor restrictions [32,33].
In addition to changes in volume, children with ASD also exhibit abnormalities in cortical thickness. Children with ASD have significant cortical thickening in early childhood, accelerated thinning in late childhood and adolescence, and gradual cortical thinning with age in adulthood. These cortical changes in the inferior frontal, inferior temporal, and posterior cingulate gyri are the most pronounced. These changes are associated with social cognitive deficits, verbal communication deficits, and stereotypical movements [36,37,38,39,40,41,42,43]. Normally, brain regions maintain structural and functional laterality. Cortical thickness asymmetry of the medial frontal, orbitofrontal, inferior temporal, and cingulate gyri is reduced in children with ASD, reflecting disruption of lateralized neurodevelopment [44,45]. Orbitofrontal cortical abnormalities are strongly associated with self-regulation and social–emotional–behavioral deficits in children with ASD [46]. As the cerebral cortex expands within the limited space in the skull, it gradually increases the number of cortical folds [47]. In children with ASD, the gyrification index, which reflects the degree of cortical folding, increases atypically in childhood and then decreases in adolescence and adulthood, primarily in the frontal and parietal regions [48,49,50]. In children with ASD, the cortical gyrification index is significantly higher in the bilateral temporal lobes, left isthmus cingulate, and left frontal lobe and lower in the right precuneus compared with that in TD children, thereby reflecting the presence of atypical rotational patterns in children with ASD [49,51,52,53].
3. Studying Brain Network Changes in Children with ASD Using DTI
Diffusion tensor imaging is a non-invasive technique for assessing the orientation and connectivity of cerebral white-matter fiber bundles, thereby allowing for qualitative and quantitative analyses of water-molecule diffusion characteristics within three-dimensional spaces [51]. Commonly used parameters include fractional anisotropy (FA) and mean diffusion (MD), which reflect microstructural changes in the white matter [55]. FA increases in children with ASD before the age of 4 years, which may be associated with excess prenatal neurons, leading to frontal axonal overconnectivity [56]. This excessive axonal growth leads to signal delays and metabolic inefficiencies in connecting different regions of the brain, thus affecting myelin development [56]. After the age of 4 years, the rate of myelination development slows down, resulting in a decrease in the integrity of white-matter fiber bundles throughout the brain and a gradual decline in FA [57,58]. Compared with TD children, children with ASD show increased FA during early childhood, primarily observed in the corpus callosum, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, posterior cingulate cortex, and limbic lobe. A higher FA in the corpus callosum is associated with impaired social and communicative functions, and that in the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus is associated with difficulty in recognizing emotions and facial expressions [11,59]. During the childhood phase in ASD individuals, there is a decline in FA, primarily observed in the sagittal stratum, corpus callosum, superior cerebellar peduncle, superior longitudinal fasciculus, cingulum, and uncinate fasciculus, which are associated with motor functions, language, and social impairments [57,58,60,61,62,63,64,65]. However, Weinstein et al. [66] found increased FA values in the corpus callosum and superior longitudinal fasciculus in children with ASD aged 1.5–6 years old. This inconsistency in research findings may be attributable to variations in the age range of the study samples [67]. In comparison with TD children, children with ASD show decreased MD values in the left corpus callosum, posterior cingulate cortex, limbic lobe, and insular cortex during early childhood, which are associated with cognitive impairments [11].
Furthermore, graph theory analysis based on DTI can reflect the whole-brain connectivity characteristics of individuals with ASD. Network properties include the clustering coefficient, local efficiency, shortest path length, global efficiency, and small-worldness coefficient. Based on DTI brain network connectivity, the node efficiency of the left pallidum, right caudate nucleus, left precuneus, thalamus, and bilateral superior parietal cortex increased in children with ASD aged 2–6 years compared with TD children [73,74]. Increased node efficiency reflects the presence of hyperconnectivity in the brain structures of preschool-going children with ASD, which may be related to early brain overgrowth. The nodal efficiency of the precuneus is correlated with the severity of ASD [73]. The increased nodal efficiency primarily occurs in the left hemisphere of the brain, specifically in regions associated with language and social communication functions. Therefore, the enhanced network efficiency in the left hemisphere may contribute to language and social impairments in children with ASD [73]. However, reduced nodal efficiency in adolescents and adults with ASD compared with TD individuals suggests that impaired integrity of white-matter fiber tracts may disrupt the topological properties of nodal connectivity fibers. The regions with reduced nodal efficiency are mainly located in the left inferior frontal gyrus, left precentral gyrus, right cingulate gyrus, right precuneus, and right amygdala, which are associated with impaired language and social communication [75,76].
In addition, edge density (ED) can further elucidate the brain connectome by examining the potential fiber bundles between cortical nodes. Changes in connectivity around the ventricles are associated with ASD, where ED increases during early childhood. However, during adolescence, there is a widespread reduction in ED within white-matter fiber bundles except for the internal capsule. In adults with ASD, the regions exhibiting decreased ED are mainly located in the posterior commissural and paraventricular white-matter tracts [8].
4. Functional MRI–Based Functional Brain Network Alterations in ASD
Resting-state fMRI (rs-fMRI) reflects neural activity and functional changes in the functional areas of the brain by studying the temporal correlation of blood oxygen-level-dependent signals in different brain regions [81]. Based on rs-fMRI, abnormal functional connectivity (FC) was found in the brains of children with ASD, most notably located in the DMN, salience network (SN), central executive control network (ECN), ventral attention networks (VAN), and dorsal attention networks (DAN) [82,83]. The DMN, with the rostral anterior cingulate cortex and medial prefrontal cortex as key brain regions, is primarily involved in intrinsic mental activities, such as recalling the past, envisioning the future, and simulating non-occurring social interactions [84]. The SN, with the anterior cingulate and ventrolateral prefrontal cortices as key brain regions, primarily differentiates between internal and external stimuli to guide behavior [85], and damage to the SN may lead to impairments in social–emotional functioning [86]. The ECN, with the dorsolateral prefrontal and parietal cortices as core regions, participates in processes of attention, decision making, working memory, and response selection [87]. The DAN, composed of the dorsolateral prefrontal cortex, superior temporal gyrus complex, and other areas, is primarily involved in controlling attention processes [88]. In contrast to TD, functional network hyperconnectivity in children with ASD, owing to early brain overgrowth and increased neural density, is located mainly in the medial prefrontal, cingulate, and temporal poles of the DMN, and is associated with socio-emotional disorders [89,90]. Recent studies suggest that early and persistent abnormal connections between the temporal lobe and the cuneus and precuneus lobes during early childhood in patients with ASD may be biomarkers of early language and social dysfunction in children with ASD [91]. There is also hyperconnectivity between brain networks in children with ASD, mainly between the DMN and DAN, DMN and control networks, and visual and sensorimotor networks [92,93,94].
In addition, Sha et al. [110] found reduced leftward lateralization in the fusiform, rostral middle frontal, and medial orbitofrontal cortices of children with ASD. There was also a decrease in rightward asymmetry of both degree centrality and global efficiency in the superior frontal cortex, indicative of node-level degree centrality asymmetries in children with ASD. These asymmetries are associated with executive function, working memory, and sensorimotor impairments. Floris et al. [111] found that compared with TD children, older children with ASD exhibited rightward lateralization in mean motor circuit connectivity, which may contribute to gross motor deficits and atypical gait. Previous studies have rarely explored ASD during infancy. Recent research suggests that key FC networks, such as the DMN and DAN, can be detected in infants at birth, which will aid in the early diagnosis of ASD [112].
5. ASL-Based Alterations in ASD Perfusion
Arterial spin labeling is a non-invasive MRI technique that utilizes magnetically labeled arterial blood water as an endogenous tracer. It quantifies changes in cerebral blood flow (CBF) within functional brain regions, thereby reflecting the association between cerebral perfusion and core symptoms. Reduced CBF in children with ASD may lead to abnormal neuronal development in the brain, and the number of hypoperfused brain regions is positively correlated with age in children with ASD [104]. This abnormal neurodevelopment leads to cognitive, language, and motor developmental impairments in children with ASD [114]. However, CBF values in the frontal lobe show a non-linear correlation with age. At the ages of 2 and 5 years, CBF in the frontal lobe of children with ASD is normal. Around the ages of 3–4 years, there is a decline in CBF. This may be associated with slower growth and development of the frontal lobe in children with ASD starting at age 3, followed by a gradual normalization of frontal lobe development around age 5. However, after the age of 6, CBF in the frontal lobe gradually decreases [114]. The decreased CBF in the left frontal lobe, bilateral parietal lobes, bilateral temporal lobes, and insula in children with ASD is associated with impaired communication and socio-cognitive deficits and decreased self-care skills [115,116,117]. Reduced CBF in the bilateral fusiform and right inferior temporal gyri in adolescents with ASD is associated with deficits in social cognition and facial recognition [123].
6. Proton Magnetic Resonance Spectroscopy–Based Biochemical Metabolite Alterations in ASD
Proton magnetic resonance spectroscopy is a non-invasive neuroimaging technique used to quantify the concentrations of biochemical metabolites in specific regions of the brain. It reveals the pathological basis of ASD by identifying abnormalities in molecular behaviors. The primary metabolites assessed include N-acetylaspartate-containing compounds (NAA), creatine-containing compounds (Cr), choline-containing compounds (Cho), glutamate + glutamine (Glx), myo-inositol (mI), and gamma-aminobutyric acid (GABA). NAA, predominantly located within neurons and axons, serves as a biomarker for neuronal density, heterogeneity, and vitality [127,128]. Compared with TD children, children with ASD show a decrease in NAA concentrations. This decline primarily occurs in the left amygdala [129], bilateral orbitofrontal cortex [118], thalamus [130], anterior cingulate cortex [119,131], temporal cortex, cerebellum [127], and parietal lobe [132]. These reductions reflect impaired, diminished, or immature neuronal function in ASD, which is associated with social deficits and memory impairments [129,132]. Cr refers to the combined signal of creatine and phosphocreatine and plays a crucial role in maintaining energy homeostasis in the central nervous system. Children with ASD exhibit a reduction in the NAA/Cr ratio in the prefrontal white-matter region and anterior cingulate cortex, suggesting alterations in axonal function and cognitive impairments [119,120,128,133]. GABA, the predominant inhibitory neurotransmitter in the cerebral cortex, plays a crucial role in maintaining the balance of neural circuits [127]. Compared with TD children, children with ASD show decreased GABA levels in the frontal cortex, parietal lobe, and somatosensory motor area, reflecting excessive excitability in the cerebral cortex [121,127,134]. The decrease in GABA concentrations in the somatosensory motor area is associated with abnormal processing of tactile information. The reduced GABA concentration in the frontal cortex may be due to deficits in GABAergic interneurons, leading to glial activation, migration defects, and impairments in communication and cognition [127].
Furthermore, studies have found a positive correlation between GABA levels and age in the left parietal lobe of children with ASD [121]. In adults with ASD, there is an increase in GABA concentration in the left dorsolateral prefrontal cortex. The changes in GABA concentration in the prefrontal cortex, from decreased levels in childhood to increased levels in adulthood, reflect the importance of age-related alterations in brain neurometabolism in individuals with ASD [12]. Additionally, in children with ASD, there is a decreased GABA/Cr ratio in the left motor, anterior cingulate cortex, and auditory cortices, which is negatively correlated with the severity of ASD symptoms [122,135]. Glutamate (Glu), as an excitatory neurotransmitter, plays a crucial role in synaptic induction, cell migration, synaptic elimination, and other functions that are essential in neurodevelopmental processes. Glutamine (Gln) participates in the regulation of glutamate recycling and brain ammonia metabolism [127]. Glu, Gln, and GABA interact through the glutamate/GABA-glutamine cycle to maintain cortical excitatory/inhibitory balance, which is crucial for synaptic maturation, refinement of neuronal circuits, and regulation of cognition, emotion, and behavior [132,136]. Glx represents the overall levels of Glu and Gln and their functions in the brain. Compared with TD children, children with ASD have increased Glu concentration in the cingulate gyrus and prefrontal cortex, possibly due to decreased levels of glutamic acid decarboxylase, the enzyme that converts Glu to GABA in the brain [127,131].
7. Glymphatic System Changes in ASD
Evaluating the coupling relationship between neurovascular and cerebrospinal fluid (CSF) may reveal the complex pathophysiological mechanisms of the brain in ASD and may provide new insights into the early diagnosis of ASD. The glymphatic system is a unique network in the central nervous system of the brain, which allows the dynamic exchange of CSF and interstitial fluid through pathways such as the paravascular spaces (PVS). These play an important role in normal homeostasis and interstitial solute clearance. Water in the CSF can transport soluble Aβ and tau proteins and the energy metabolite lactate from the brain tissue through the induction of polarized astrocyte-specific aquaporin-4 into the interstitium [141]. Elevation in Aβ protein levels was observed in the neurons of postmortem brain tissue, blood, and peripheral CSF of individuals with ASD, which may have been associated with an impaired glymphatic system [142]. It was found that 44% of children with ASD had an enlarged PVS [143]. Recent studies have indicated that the function of the glymphatic system in the brains of individuals with ASD can be assessed using DTI along the perivascular space (DTI-ALPS). DTI-ALPS uses the diffusion tensor method to measure the diffusivity rate of water molecules and assess the movement of water molecules in the direction of the PVS. Studies have shown that reduced DTI-ALPS reflects impaired glymphatic function in children with ASD and is positively correlated with age [144].
9. Conclusions
综上所述，自闭症谱系障碍不仅以脑形态、结构功能连接、脑灌注、神经元代谢等异常改变为特征，而且还存在一定程度的类淋巴系统功能损伤。自闭症儿童的年龄、亚型、脑损伤和重塑方面的差异可能会导致研究结果的异质性。
This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13193027
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