What brain regions are affected in Autism Spectrum Disorder (ASD)?

Brain Regions Affected in Autism Spectrum Disorder

Autism spectrum disorder affects multiple brain regions rather than a single localized area, with the most consistent abnormalities occurring in the temporal cortex, frontal cortex, occipital cortex, cerebellum, and white matter connectivity pathways, particularly involving the corpus callosum and internal capsule. 1

Cortical Regions

Temporal, Frontal, and Occipital Cortex

• Most regions of the brain, including temporal, frontal, and occipital cortex, have been found to be involved in ASD pathology. 1
• The medial and dorsolateral prefrontal cortices show reduced activity in individuals with ASD compared to neurotypical controls during non-social sensory perception tasks. 1
• Frontal lobe anomalies are consistently documented in large-scale morphometric analyses, including alterations in white matter and cortical thickness. 1
• The superior temporal gyrus demonstrates decreased activity in ASD, particularly during language and social processing tasks. 1

Limbic System Structures

• The American Academy of Child and Adolescent Psychiatry identifies limbic system abnormalities as contributing to core ASD symptoms with high strength of evidence. 2
• The amygdala plays a major role in ASD pathophysiology through its involvement in fine-grained intangible knowledge representations and high-level guidance of gaze. 3
• The orbitofrontal cortex (OFC) is implicated as one of four key social brain regions driving ASD symptomatology. 3

Temporoparietal and Posterior Regions

• The temporoparietal cortex (TPC) and posterior superior temporal sulcus (STS) are key neural structures giving rise to ASD, particularly affecting social information processing. 4, 3
• The insula represents another critical social brain region with documented dysfunction in ASD. 3

Subcortical and Cerebellar Involvement

Cerebellum

• The cerebellum is consistently involved in ASD pathology, with mouse models demonstrating that pure cerebellar dysfunction can profoundly impact social behavior. 1
• Mice with TSC1 loss localized to the cerebellum show abnormal social interaction, repetitive behaviors, and vocalizations, providing strong evidence for cerebellar contributions to social deficits. 1

Other Subcortical Structures

• The caudate nucleus shows disturbances secondary to disrupted social brain regions. 3
• The hippocampus demonstrates abnormalities, with TSC1+/− mice showing impaired hippocampal learning and atypical social behavior. 1

White Matter and Connectivity Abnormalities

Global White Matter Changes

• Early brain overgrowth in ASD is particularly pronounced in white matter and represents a critical developmental abnormality that precedes the onset of autistic symptoms. 2
• Increased global white matter volume has been documented, particularly in patients with PTEN mutations who have ASD, where white matter abnormalities directly correlate with reduced cognitive ability. 2

Specific White Matter Tracts

• Abnormalities exist in so-called normal-appearing white matter in regions including the corpus callosum, internal capsule, and cerebellum. 1
• White matter pathology correlates with severity of ASD symptoms in multiple studies. 1
• The pathology manifests as disorganized axonal tracts, increased axonal growth, abnormal myelination, and aberrant synapse formation. 1
• White matter hypointensities cluster in periventricular regions and are observable on T1-weighted MRI sequences. 2

Connectivity Patterns

• Aberrant connectivity rather than focal lesions appears central to ASD pathophysiology, with primary disruptions in frontal networks. 1
• Distance underconnectivity is associated with autism symptom severity, with abnormal functional connectivity having disproportionate effects on frontal-subcortical circuits. 1
• Frontal-subcortical dysfunction in PTEN-ASD is supported by neurobehavioral findings in both children and adults. 1

Visual Processing Regions

• Early visual cortices show differential activity patterns in ASD, with autistic groups demonstrating altered activation compared to controls during visual processing tasks. 1
• The occipital cortex shows decreased activity during action observation tasks in individuals with ASD. 1
• Visual processing abnormalities mirror behavioral findings of atypical binocular rivalry and global motion perception. 1

Clinical Implications

No single brain region has been implicated in the development of ASD, suggesting that neurobiological heterogeneity exists even in single-gene disorders. 1 This distributed pattern of abnormalities reflects the complex nature of ASD pathophysiology, where disruptions in multiple interconnected brain regions and white matter pathways collectively produce the characteristic behavioral phenotype. 1, 3

The transition from models based on focal brain lesions to those implicating aberrant connectivity represents a fundamental shift in understanding ASD neurobiology. 1 White matter abnormalities in PTEN-associated ASD may serve as biomarkers for neurobehavioral deficits and potential treatment targets. 2