by Leong Tung Ong, MBBS, and Si Wei David Fan, MBBS 

Both authors are with Faculty of Medicine, University of Malaya in Kuala Lumpur, Malaysia.

Funding: No funding was provided for this article.

Disclosures: The authors have no conflicts of interest relevant to the contents of this article.

Innov Clin Neurosci. 2023;20(10–12):40–47.

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by early-onset impairments in socialization, communication, repetitive behaviors, and restricted interests. ASD exhibits considerable heterogeneity, with clinical presentations varying across individuals and age groups. The pathophysiology of ASD is hypothesized to be due to abnormal brain development influenced by a combination of genetic and environmental factors. One of the most consistent morphological parameters for assessing the abnormal brain structures in patients with ASD is cortical thickness. Studies have shown changes in the cortical thickness within the frontal, temporal, parietal, and occipital lobes of individuals with ASD. These changes in cortical thickness often correspond to specific clinical features observed in individuals with ASD. Furthermore, the aberrant brain anatomical features and cortical thickness alterations may lead to abnormal brain connectivity and synaptic structure. Additionally, ASD is associated with cortical hyperplasia in early childhood, followed by a cortical plateau and subsequent decline in later stages of development. However, research in this area has yielded contradictory findings regarding the cortical thickness across various brain regions in ASD.

Keywords: Autism spectrum disorder, cerebral cortex, neurodevelopmental disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by a diverse array of phenotypic expressions and clinical presentation.1 ASD is characterized by early-onset impairments in socialization, communication, repetitive behaviors, and restricted range of interests.2 ASD has a complex pathophysiology, and the neurological basis of the clinical presentation, which primarily manifests as social and function impairments, has not been completely elucidated.3 Abnormal brain development, resulting from a complex interplay of genetic and environmental factors, is at the root of ASD etiology, typically manifesting during the formative years.4 Furthermore, abnormal brain connectivity and synaptic structure contribute to atypical brain development and maturation in ASD.5

Clinical presentation of ASD exhibits a high heterogeneity in terms of symptom severity and clinical manifestations across diverse age groups.6 This wide range of clinical manifestations encompasses individuals capable of living independently to those with severe impairments in social communications, high levels of disability in daily activities, and/or self-injurious or aggressive behavior.7 This substantial clinical diversity underscores the inherent variability in neuroanatomy and genetics within the ASD population.8

Furthermore, ASD arises from penetrant mutations and chromosomal instability, which lead to hundreds of different genetic variants that complicate efforts to determine a single genetic etiology.9 Similarly, Zabihi et al10 reported that the spatial distribution of abnormal brain development has a high heterogeneity, even with the similar pathophysiology. This complexity in neuroanatomy and genetics further complicates the attribution of specific etiological factors of the brain structures and the prognosis of clinical outcomes.11

In terms of morphological assessment, cortical thickness is the most consistent parameter in assessing abnormal brain anatomy in patients with ASD.11 Nonetheless, studies present conflicting outcomes regarding the cortical thickness in patients with ASD, with some indicating increased measurements and others suggesting decreased measurements.12 Doyle-Thomas et al13 established correlations between cortical thickness of the regions implicated in social and communication functions and scores on the Autism Diagnostic Interview-Revised (ADI-R). Furthermore, previous studies also reported that changes in cortical thickness in specific brain regions are correlated with specific clinical features.12 A longitudinal study by Wallace et al14 also reported that increases in cortical thinning in the temporal lobe cortex were correlated with impairment in social communications. Despite the divergent neuroanatomical findings across studies, ASD most prominently manifests its aberrant developmental trajectory in the frontotemporal and frontoparietal brain regions.11 The atypical cortical developmental trajectory likely underlies structural and functional anomalies in the brain’s connectivity network, contributing to abnormal neuronal processing.15

Patients with ASD have shown early hyperplasia of the cortical development during the early years of life, followed by cortical plateau and decline in successive stages.12 A study by Lainhart et al16 suggested that 15 to 20 percent of children with ASD exhibit macrocephaly between ages 3 to 5 years, with head circumference plateauing thereafter.16 Furthermore, children with ASD between the ages of 2 to 4 years reportedly manifested increased white matter and gray matter volume, especially in the temporal and frontal lobes.17,18 Although brain growth in children with ASD reaches a plateau around the age of two years, growth rates demonstrate a declining trend, compared to neurotypical children.19 By mid-childhood (ages 5–10 years), the average brain volume in children with ASD aligns with that of neurotypical children.19

A detailed analysis of the brain structure changes that includes developmental trajectories and spatial locations might aid in the understanding of the relationship between the behavioral and biological profiles of ASD.20 Therefore, this review aims to provide insight on the neurobiology of ASD by focusing on the neuroanatomical and functional changes of different cerebral structures in patients with ASD.

Frontal Lobe

Changes in the thickness of the frontal lobe in ASD are correlated with the severity of social impairments and repetitive behaviors.12 Furthermore, abnormalities in the development and maturation of the frontal lobe in ASD are also associated with social impairments.21 Dysregulation of the cortical folding is observed in the right middle frontal (dorsolateral prefrontal cortex) and right lateral orbitofrontal regions.22 The former is involved in the top-down executive control through the frontoparietal network, while the latter regulates emotion through the affective processing intrinsic network.23,24 Dysfunction in the cortical gyrification of these regions may affect the self-regulation of emotion.25,26 Genetic and environmental influences contribute to the distinctive patterns of cortical folding development in children with ASD.27 Therefore, the self-regulation ability may be developed through the cortical gyrification in the right, middle, frontal gyrus and right, lateral, orbitofrontal cortex and also nurtured through daily interactions and encounters.22 In addition to dysfunction of cortical folding, ASD also has less pronounced adaptive changes, which lead to self-regulation impairment.22

Structural variations in the orbitofrontal cortex have been demonstrated in ASD.3 The orbitofrontal cortex governs self-regulation, theory of mind, social cognition (including arousal and affective empathy), the social-rewarding process, and social-emotional behaviors.13,28 Dysfunction in this region affects the limbic system and sensory association, resulting in social deficits and stereotyped behaviors.29 Changes in the balance between excitatory and inhibitory neurons in the orbitofrontal regions have been identified through postmortem brain tissue examination, leading to the altered connectivity between the amygdala and other cortical structures, potentially underpinning distinctive emotions and social traits in children with ASD.30 Abnormal functional connectivity between the orbitofrontal cortex and amygdala, identified through functional imaging, may impair sensory stimulus response regulation, leading to sensory hypersensitivity in ASD.31 In addition, excessive aggressive behavior in ASD might be attributed to dysfunction in the fronto-limbic-striatal circuits comprising the prefrontal cortex, amygdala, and hypothalamus.32

The left medial orbitofrontal area, located in the frontal and cingulate regions, is integral to the ventral social affective processing system, correlating with social affect scores from the Autism Diagnostic Observation Schedule (ADOS) and ADI-R.33 Neuroimaging has consistently shown that the ventromedial frontal cortex and ventral striatum activate more in response to negative feedback, necessitating behavioral change.34 These brain regions are essential in the processing feedback and adjusting behavior accordingly.34 In addition, ASD demonstrated significant thinning in the mirror neuron system, encompassing the pars opercularis of the inferior frontal gyrus and the adjacent ventral area, which are essential in social recognition.35 This system facilitates understanding of the actions of others and experiences by generating shared internal action representations, which is crucial for social-communicative function.35 Functional brain imaging studies have shown dysfunction of mirror neuron systems correlates with impairment emotional engagement, empathy, and social interactions in ASD.36–38

Zoltowski et al20 reported that decreased sulcal depth along the precentral and postcentral gyrus in ASD are associated with more severe autism-related behaviors.20 Furthermore, structural indices in the primary motor cortex along the precentral gyrus notably differ between individuals with ASD and neurotypical individuals.20 Structural differences in these regions lead to impairment between motor and tactile processing, affecting the differentiation of tactile information from different bodily locations and different movements types.20 Furthermore, changes in the motor cortex also lead to impaired and delayed motor development, resulting in alteration in acquisition of motor skills and communicative movements.39,40 Braden et al41 demonstrated hypoconnectivity of the frontoparietal network in ASD, contributing to executive function and social-communication difficulties. Reduced intrinsic functional connectivity in the right frontoparietal network is linked to severe repetitive behavior in ASD.42 Decreased prefrontal-striatal connectivity in ASD may disrupt the habitual and goal-directed action control, leading to motor stereotypies.43 However, other studies suggest increased intrinsic functional connectivity in the frontotemporal nodes correlates with more severe restricted and repetitive behaviors and higher ADOS-Restricted and Repetitive Behaviors (RBB) scores.44,45

Impairments in other specific frontal lobe structures, such as the left pars triangularis and Rolandic operculum, may contribute to communication difficulties in ASD.46 The left pars triangularis, which is bound superiorly by the inferior frontal sulcus, plays a critical role in expressive language production.46 Dysfunction in this region contributes to language impairments in individuals with ASD.19,47,48 Meanwhile, the left Rolandic operculum, which is located within the precentral and postcentral gyri, is pivotal for prosody production and perception.46 Individuals with ASD exhibit abnormal levels of activation of left Rolandic operculum, which may be implicated in the prosody impairments in ASD, such as diminished tone and rhythm variation in speech.49,50 Furthermore, variations in morphology, gray matter thickness, and white matter connectivity of the inferior frontal gyrus, crucial for expressive language, in ASD correlate with autism-related behaviors.12 Thinning of the inferior frontal gyrus is associated with increased autism-related behaviors.20 The rostral middle frontal gyrus, part of the dorsolateral prefrontal cortex, also contributes to language function.51 Its potential lesion might explain the tendency of individuals with ASD to employ simple sentences during conversations.51

Temporal Lobe

Several studies have elucidated temporal lobe thickness and the volume alterations from childhood to adulthood.19,41,52 A longitudinal study demonstrated a slower growth rate of white matter in the temporal lobe among individuals with ASD, compared to controls.53 Interestingly, Libero et al52 reported that individuals with ASD showed increased local gyrification index of the temporal gyri at three years of age, followed by a decrease local gyrification index from 3 to 5 years. Longitudinal MRI studies have further demonstrated significant cerebral white and gray matter enlargement in toddlers with ASD by the age of two years, followed by a decrease in total gray matter volume in patients with ASD at the age of 10 years.9,18,54 Notably, Hardan et al55 also demonstrated accelerated decreases in the cortical thickness and gray matter volume in individuals with ASD who are 8 to 12 years of age.55 Additionally, the study by Braden and Riecken41 also highlighted that the left temporal lobe has atypical cortical growth trajectories continuing into adulthood. Adults with ASD exhibited increased cortical thinning with age, primarily in the temporal lobe.41 Individuals with ASD also have thicker transverse temporal gyrus during childhood, compared to adulthood.19

Ni et al22 demonstrated dysregulation of cortical folding in the left premotor regions and left superior and inferior temporal gyri in ASD. The superior temporal gyrus is crucial in processing the acoustic-phonetic features of sound and speech, underpinning perception and knowledge.56 Patients with ASD have shown abnormalities in Wernicke’s area, situated within the superior temporal gyrus, which is responsible for receptive speech and language ability.48,57 Aberrations in Heschl’s gyrus within the superior temporal gyrus, integral to auditory processing, are also observed in ASD.58,59 Moreover, the superior temporal gyrus and the adjacent structure, the superior temporal sulcus, contribute to nonlanguage social cognition, including behavior recognition and response to socially relevant information.60 Abnormalities in these structures, such as cortical thinning, reduced gyrification, and decreased sulcus depth, contribute to social interaction impairments in ASD.61,62 Specifically, cortical thinning in the right superior temporal gyrus correlates with higher Social Responsiveness Scale (SRS) scores, indicating severe social-communication difficulties.63 Whole-brain voxel-based morphometry MRI studies have demonstrated bilateral reductions in gray matter concentration in the superior temporal sulcus and decreased white matter concentration in the right temporal pole.64 However, Zoltowski et al20 reported that increased gyrification and sulcus depth in the right superior temporal gyrus were associated with greater autism-related behaviors. Similarly, Jou et al65 also reported significant increases in right superior temporal gyral volumes in children with ASD. Discrepancies in changes in the thickness of the superior temporal gyrus in the research studies may be attributed to differences in the ages of the subjects with ASD.

Furthermore, studies have also demonstrated decreased sulcal depth in the middle temporal gyrus, correlating with greater autism-related behaviors.20 The middle temporal gyrus is a critical node in the brain’s language network, crucial for language comprehension.66 ASD also exhibits reductions in the gray matter and white matter volumes in the superior temporal region, potentially leading to abnormal activation of circuitry.67 Squarcina et al12 demonstrated gray matter volume depletion in the right inferior temporal gyrus in ASD. The inferior temporal gyrus is involved in the ventral visual pathways, visual and dorsal attention system, frontoparietal control network, and integration of the multimodal sensory system.24 Furthermore, these structures also play a role in emotional processing, which is essential for optimal self-regulation, facilitating the transfer of information from unimodal sensation systems to heteromodal cognition systems.68,69

The fusiform gyrus, located in the inferior temporal lobe, is essential for processing and computing high-level visual information, such as facial and object perception.70 The left fusiform gyrus is involved in processing facial perception, while the right fusiform gyrus is responsible for object recognition and general visual perception.71 Studies have reported leftward volumetric asymmetric of the anterior and posterior temporal fusiform gyrus in individuals with ASD, compared to neurotypical individuals.72,73 Furthermore, histopathological studies in ASD have shown cellular abnormalities in the fusiform gyrus, including decreased total neuron numbers, neuron densities, and perikaryal volumes in different cortical layers.74 Volumetric reductions across various cortices in ASD may be attributed to underlying alterations in white matter.75 Dougherty et al73 reported that volume symmetry index inversely correlates with ADOS and Gotham autism severity scores, suggesting a link between volumetric asymmetry and symptom severity. The study also indicated that patients with ASD with increasing symptom severity display greater rightward fusiform asymmetry, while the average ASD population exhibits leftward asymmetry.73 Therefore, individuals with less symptom severity may display leftward volumetric asymmetry, while those with higher symptom severity may display rightward volumetric asymmetry.73 Importantly, studies have consistently reported that ASD populations have facial processing impairments, leading to difficulties in recognizing facial emotions and face memory.76,77 These impairments in ASD can be attributed to abnormalities in the circuitry involving fusiform gyrus and amygdala.77

A meta-analysis by Casale et al78 demonstrated volumetric reductions in the hippocampal area in ASD, including the entorhinal cortex, located at the medial regions of the temporal lobe. The entorhinal cortex has numerous connections with other cortices and serves as the primary mediator of cortical information transfer into and out of the hippocampus proper, and it is crucial for memory processing.79 Therefore, reductions of volume in these regions may lead to episodic memory impairments.80

Parietal Lobe

A lobar analysis conducted by Zielinski et al19 showed an increase in age-related cortical thinning within the right, left, and total parietal cortices among ASD groups, in comparison to the neurotypical control group. In children with ASD, there is also a decrease in the thickness of both the bilateral primary somatosensory cortices and right superior parietal lobe, and these reductions are positively correlated with increased self-injury scores and repetitive injuries.81 This increase in the incidence of self-injury may be attributed to diminished volume of the left ventroposterior nucleus of the thalamus, specifically the left primary somatosensory relay nucleus.81 These pre-existing abnormalities and impaired development in the primary somatosensory cortex may be contributory factors to self-injurious behavior in children with ASD.81 In addition, lesions in the posterior parietal cortex might be responsible for impairments in sensorimotor integration and object-directed actions.82 Duerden et al81 reported that an augmented somatosensory response to tactile stimuli and proprioception might be linked to higher repetitive injury in ASD. Alterations in the parietal lobe-mediated processes may lead to atypical sensory processing, potentially resulting in self-injury among individuals with ASD.83 Zoltowski et al20 demonstrated changes in the morphology of associative parietal regions, including the superior parietal lobule and precuneus. These changes have been shown to cause differences in sensory association, as well as deifcits in complex social and communication skills in ASD.20 Preceneus activation has also been associated with processing of the theory of mind and self-processing operations, both of which may be impaired in ASD.84

DeRamu et al85 discovered higher activation in the left inferior parietal lobule, particularly the angular gyrus, in children with ASD. Both bilateral inferior parietal regions play a pivotal role in perceiving emotions in facial stimuli, particularly the perception of eyes and brows.86 Furthermore, the inferior parietal lobule is integral to action processing and executive functioning, including auditory spatial working memory.87,88 It also plays a crucial role in praxis acquisition and expression and the performance of social skills.89 Weaker connectivity between the right central inferior parietal lobe and left cerebellum has been associated with poorer praxis acquisition and social-communicative skills in children with ASD.89 Finally, children with ASD exhibit visual facial processing disorders and an inability to distinguish between self and others, often due to dysfunction of the right supramarginal area in the inferior parietal lobe.90,91

Children with ASD also display abnormalities of the angular gyrus.47 The angular gyrus is essential in semantic information processing, attention and spatial cognition, self-processing, reading and comprehension, and emotion regulation.92,93 Individuals with ASD also demonstrate structural changes in the intraparietal sulcus, characterized by increased depth in comparison to neurotypical individuals.94 The bilateral intraparietal sulcus plays a part in the mirror neuron system and is implicated in interpreting the actions, behaviors, and intentions of others, thus affecting neurocognitive functions, such as language, social cognition, and empathy.95,96 Furthermore, children with ASD demonstrate alterations in both the anatomy and function of the postcentral gyrus, involving increased connectivity with the medial thalamus and increased activation.97,98 The postcentral gyrus houses the primary somatosensory cortex responsible for proprioception and tactile processing.99 Abnormalities in somatosensory function may contribute to differences in tactile reactivity in ASD.20 Individuals with ASD frequently exhibit impaired responses to tactile processing due to inhibited responses.100 Puts et al100 have shown that individuals with ASD have an increased threshold for static detection of stimulus and poor discrimination of amplitude in vibrotactile tasks. Alterations in the detection threshold might underlie core ASD symptoms, such as hypersensitivity to stimuli or difficulties in social communication.101

Occipital Lobe

Brain imaging studies have demonstrated structural anomalies in the occipital lobe of individuals with ASD, compared to neurotypical individuals.55 The lingual gyrus, which contains the primary visual cortex, is located in the occipital lobes and is essential for visual processing.3 Furthermore, the striate cortex, located in the calcarine fissure, along with adjacent regions, such as the lingual gyrus, the caudal part of the precuneus, and the cuneus, is crucial for processing visual information.46 Zielinski et al19 demonstrated an increase in cortical thickness in the visual cortex, along with age-related cortical thinning. In addition, the severity of visual hypersensitivity is positively correlated with increased cortical thickness in the visual cortex.55 This suggests that individuals with ASD experience heightened sensitivity to visual stimuli during childhood, with a decrease in intensity as they reach adulthood.55 Furthermore, increased cortical thickness in the lingual gyrus is also associated with social impairments stemming from visual sensory abnormalities in ASD.102 However, other studies have demonstrated a decrease in cortical thickness and sulcal depth in the inferior occipital cortex and the superior occipital cluster, which are associated with greater autism-related behaviors.20 Changes in the receptive field properties within the early visual processing regions, as reported in the functional MRI responses, exhibit correlations with structural alterations in the occipital lobes and more severe autistic symptoms.103,104 Early brain overgrowth hypothesis in ASD may explain the thicker occipital cortex in school-aged children, compared to adults.67

The left lateral occipital cortex exhibits increased gyral height and sulcal depth in individuals with ASD, compared to neurotypical individuals.14 Furthermore, ASD is associated with increased cortical thickness in the bilateral cuneus and the right pericalcarine region of the occipital lobe during childhood.19 Remarkably, cortical thickness in the left lateral occipital lobe is negatively correlated with age in adults with ASD.41 Individuals with ASD display a significant accelerated decline in the gray matter volume and thickness of the occipital cortex, compared to neurotypical individuals.19 These structural changes in the occipital lobe in ASD may impact visual attention and working memory, which are known to decline with age in neurotypical individuals.105

Other Cortical Structures

Cortical thinning of the bilateral insula is associated with higher SRS scores.63 The insula has numerous cortical connections, including the orbitofrontal cortex, parietal cortex, temporal cortex, amygdala, and anterior cingulate.106 A meta-analysis demonstrated significant hypoactivity of the insula in ASD, leading to difficulties in social recognition, facial processing, and theory of mind.61 The insula also has an important role in interoception, visceral sensation, and autonomic control, which are essential in social cognition and monitoring one’s internal state.63 Furthermore, the insula is responsible for the physiological condition of the body, forming the foundation for emotions and feelings.107 Monitoring the internal state through the insula is critical for social cognition, underpinning self-awareness.107 A decrease in the gyrification of the posterior insula and central and parietal opercula is observed in ASD, which is involved in interoceptive stimuli sensory processing.20,108 Studies have also demonstrated that declines in the cortical thickness of these regions have a positive correlation with age and are associated with social traits in ASD.109

Zoltowski et al20 reported an increase in the cortical thickness of the anterior insula and anterior cingulate in ASD. In addition, Doyle-Thomas et al13 also demonstrated a positive correlation between increased cortical thickness of the rostral anterior cingulate cortex and the severity of social impairments, with this abnormality persisting from childhood into adulthood. Several MRI studies have also shown increased thickness and decreased gray volume in the anterior cingulate cortex.46 Abnormalities in the anterior cingulate cortex and dorsal medial frontal cortex in ASD are linked to defects in social orienting and joint attention.110,111 The anterior insula and anterior cingulate together form the salience network, which is crucial for attention processing of competing stimuli and regulating emotion responses.13,112 Increases in cortical thickness may result from decreased myelination during development or increased neuronal cell bodies.113 These alterations may induce changes in both the structural and functional aspects of salience network connectivity, contributing to the hallmark features of ASD, namely heightened sensory reactivity and socioemotional processing deficit.42,114 Furthermore, ASD is associated with reductions in gamma-aminobutyric acid type B (GABAB) receptors binding density in the superficial layers in the anterior cingulate cortex, resulting in synaptic regulation and a disrupted balance between excitatory and inhibitory brain functions.115 Conversely, Laidi et al116 demonstrated a decrease in the cortical thickness of right anterior cingulate cortex in ASD, which is associated with affective disorders, such as increased interoceptive awareness and alexithymia.116–118

Conclusion

Neuroanatomical changes in the cerebral cortex in ASD may vary between studies due to the heterogeneity of presentation. Nevertheless, multiple studies have shown significant structural and functional changes in various cerebral cortex regions in children with ASD, compared to neurotypical children. Neuroimaging is an important tool in elucidating the pathophysiology of ASD by assessing atypical brain trajectories and neuroanatomical alterations in affected individuals. Large-scale, longitudinal, noninvasive imaging studies are necessary to follow patients from infancy through adolescence to better comprehend the various ASD phenotypes. In the future, ASD may be classified into distinct categories based on the genetic or neuroanatomical features, facilitating the development of novel treatments.

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