What parts of the brain are affected by Autism Spectrum Disorder (ASD)?

Brain Regions Affected by Autism Spectrum Disorder

Autism spectrum disorder affects multiple interconnected brain regions rather than a single focal area, with the most consistent abnormalities occurring in the frontal cortex, temporal cortex, cerebellum, and white matter connectivity pathways, alongside disrupted frontal-subcortical circuits that drive core social and cognitive symptoms. 1

Primary Cortical Regions

Frontal Cortex

The frontal lobe demonstrates the most robust and consistent abnormalities across autism studies:

• The medial and dorsolateral prefrontal cortices (BA 9,10) show significantly reduced activity in individuals with ASD compared to neurotypical controls during sensory perception tasks. 2
• Frontal lobe anomalies are consistently documented in large-scale morphometric analyses, including alterations in white matter integrity and cortical thickness. 2
• The left rostral frontal and left medial prefrontal regions show abnormal relationships between cortical thickness and pragmatic language abilities, with thinner cortex associated with more impaired communication in ASD. 3
• Increased frontal lobe volume is observed, particularly in young children under 6 years of age. 4

Temporal Cortex

The temporal regions show widespread involvement in ASD pathology:

• The superior temporal gyrus demonstrates decreased activity during language and social processing tasks. 1
• Right superior temporal gyrus shows increased regional gray and white matter volumes in toddlers aged 2-3 years with ASD. 5
• Increased temporal lobe volume is consistently observed across multiple studies. 4
• Temporal-parietal dysfunction contributes to severe language and communication difficulties, particularly in nonverbal or minimally verbal individuals. 2

Occipital Cortex

Visual processing regions show differential activation patterns:

• The secondary visual cortex (V2, BA 18) demonstrates greater recruitment in autistic individuals compared to controls during visual processing tasks. 2
• The occipital cortex is consistently involved in ASD pathology across multiple brain regions. 2
• Decreased occipital cortex activity occurs during action observation tasks. 1

Subcortical and Deep Brain Structures

Cerebellum

The cerebellum plays a critical and underappreciated role in ASD, with pure cerebellar dysfunction capable of profoundly impacting social behavior. 2

• Mouse models with TSC1 loss localized specifically to the cerebellum demonstrate abnormal social interaction, repetitive behaviors, and vocalizations, providing the first strong evidence that cerebellar dysfunction alone can drive social deficits. 2
• Reduced cerebellar volume is consistently observed in ASD patients compared to typically developing controls. 4
• White matter abnormalities extend to cerebellar regions, correlating with symptom severity. 2

Limbic System

The limbic structures contribute substantially to core ASD symptoms:

• Limbic system abnormalities, including the amygdala, contribute to core ASD symptoms with high-strength evidence. 1
• The amygdala's major involvement in fine-grained intangible knowledge representations and high-level guidance of gaze largely drives ASD symptomatology. 6
• The hippocampus demonstrates functional abnormalities, with TSC1+/− mouse models showing impaired hippocampal learning and atypical social behavior. 2
• Increased fractional anisotropy is observed in limbic lobes of toddlers with ASD aged 2-3 years. 5

Other Subcortical Regions

• The insula (BA 13) shows differential activity patterns in ASD. 2
• The caudate nucleus demonstrates disturbances driven by disrupted interconnected brain regions. 6
• The thalamus shows increased activity during visual processing tasks. 2

White Matter and Connectivity Abnormalities

Aberrant connectivity rather than focal lesions appears central to ASD pathophysiology, representing a fundamental shift from earlier models based on tuber localization to current understanding of widespread network dysfunction. 2, 1

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. 1
• Increased global white matter volume is documented, particularly in patients with PTEN mutations who have ASD. 1
• Whole brain volume increases are observed, particularly in children under 6 years of age. 4

Specific White Matter Tract Abnormalities

• Abnormalities exist in normal-appearing white matter in the corpus callosum, internal capsule, and cerebellum, with these pathologies correlating directly with ASD symptom severity. 2, 1
• The corpus callosum shows reduced volume and increased fractional anisotropy in young children with ASD. 4, 5
• White matter pathology manifests as disorganized axonal tracts, increased axonal growth, abnormal myelination, and aberrant synapse formation. 2, 1
• White matter hypointensities cluster in periventricular regions and are observable on T1-weighted MRI sequences. 1

Connectivity Patterns

• Distance underconnectivity is associated with autism symptom severity, with abnormal functional connectivity having disproportionate effects on frontal-subcortical circuits. 1
• Primary disruptions occur in frontal networks, with frontal-subcortical dysfunction supported by neurobehavioral findings in both children and adults. 1
• The posterior cingulate cortex shows increased fractional anisotropy values in ASD toddlers. 5

Parietal and Cingulate Regions

• The temporoparietal cortex (TPC) is one of four social brain regions that largely drive ASD symptomatology. 6
• The primary somatosensory cortex (BA 2) and supramarginal gyrus (BA 40) show differential activity during tactile processing. 2
• The angular gyrus (BA 39) demonstrates differential activity during auditory processing. 2
• The dorsal anterior cingulate (BA 32) shows altered activation patterns. 2

Age-Related Considerations

The neuroanatomical profile of ASD varies substantially across development, with the most pronounced volumetric increases occurring before age 6 years. 4

• Brain imaging abnormalities are detectable as early as 2-3 years of age, with significant increases in global gray and white matter volumes and regional alterations in the right superior temporal gyrus. 5
• Increased cortical thickness in the frontal lobe, increased surface area, and cortical gyrification are observed in young children. 4
• Findings remain inconsistent regarding the developmental trajectory of brain volume and cortical thinning with age in ASD. 4

Clinical Implications

No single brain region has been implicated in the development of ASD, suggesting that neurobiological heterogeneity exists even in single-gene disorders like tuberous sclerosis complex. 2, 1

• The orbitofrontal cortex (OFC), along with the amygdala, temporoparietal cortex, and insula, comprises the four social brain regions that extensively explain ASD symptomatology. 6
• Disrupted brain regions can drive disturbance of strongly interconnected regions to produce further symptoms, affecting the visual cortex, inferior frontal gyrus, caudate nucleus, and hippocampus. 6
• White matter abnormalities in PTEN-associated ASD may serve as biomarkers for neurobehavioral deficits and potential treatment targets. 1