Local activity alterations in autism spectrum disorder correlate with neurotransmitter properties and ketamine induced brain changes

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition (E/I) ratio is discussed as a potential pathomechanism but in-vivo evidence of disturbed neurotransmission underlying these functional alterations remains scarce. We compared rs-fMRI local activity (LCOR) between ASD (N=405, N=395) and neurotypical controls (N=473, N=474) in two independent cohorts (ABIDE1 and ABIDE2). We then tested how these LCOR alterations co-localize with specific neurotransmitter systems derived from nuclear imaging and compared them with E/I changes induced by GABAergic (midazolam) and glutamatergic medication (ketamine). Across both cohorts, ASD subjects consistently exhibited reduced LCOR, particularly in higher-order default mode network nodes, alongside increases in bilateral temporal regions, the cerebellum, and brainstem. These LCOR alterations negatively co-localized with dopaminergic (D1, D2, DAT), glutamatergic (NMDA, mGluR5), GABAergic (GABAa) and cholinergic neurotransmission (VAChT). The NMDA-antagonist ketamine, but not GABAa-potentiator midazolam, induced LCOR changes which co-localize with D1, NMDA and GABAa receptors, thereby resembling alterations observed in ASD. We find consistent local activity alterations in ASD to be spatially associated with several major neurotransmitter systems. NMDA-antagonist ketamine induced neurochemical changes similar to ASD-related alterations, supporting the notion that pharmacological modulation of the E/I balance in healthy individuals can induce ASD-like functional brain changes. These findings provide novel insights into neurophysiological mechanisms underlying ASD.

Fig. 1.

Local functional activity alterations in subjects with autism spectrum disorder (ASD) and its neurotransmitter co-localizations. (A) Results from voxel-wise comparisons between subjects with ASD and typically developed controls (TD) regarding local synchronization (LCOR). Positive T-values (red-yellow) indicate increased LCOR in ASD subjects compared to TD, negative T-values (blue) represent decreased LCOR. Left: Results from voxel-wise comparisons within the Autism Brain Imaging Data Exchange (ABIDE) 1 (sagittal view). Right: Results from voxel-wise comparisons within the replication dataset ABIDE2 (sagittal and axial view). (B) Grouped bar plot depicting the spatial co-localizations of whole-brain LCOR alterations in subjects with ASD compared to TD with 16 different receptor and transporter distributions. The asterisk (*) represents significant co-localizations (p < .05). (C) Scatterplots showing the negative relationship between LCOR alterations in ASD (T-values) and the nuclear imaging derived spatial NMDA, mGluR5 and GABAa receptor distributions.

Fig. 2.

Mean local activity (LCOR) after ketamine (KET) and midazolam (MDZ) administration in regions significantly altered in autism spectrum disorder (ASD) and correlation of the neurochemical co-localization profiles between ASD, KET and MDZ condition. (A) Boxplots comparing LCOR following KET and MDZ administration relative to placebo (PLC) condition. Delta LCOR is defined as the mean LCOR in the KET or MDZ condition minus the mean LCOR in the PLC condition. The plots display Delta LCOR values within all voxels that showed significant decreases (left) or increases (right) in individuals with ASD compared to typically developing controls (TD) in the Autism Brain Imaging Data Exchange 1 (ABIDE1) dataset. (B) Scatterplots illustrating the relationship between the 16 Fisher’s z-values for KET (left) and MDZ (right) versus PLC, and ASD versus TD in the ABIDE1 and ABIDE2 datasets. The 16 Fisher’s z-values represent the LCOR-neurotransmitter co-localization profiles for the respective contrast.