Relating Abnormal Tactile Processing and Cortical Dysfunction in Children with Autism Spectrum Disorder

Background:Sensory, tactile, impairments are considered key features of Autism Spectrum Disorder (ASD). Touch is the first- and only sense with which children can actively explore the world. Studies have suggested that abnormalities in the response to touch may exacerbate social and communicative problems. Most studies investigating tactile processing in ASD to date have used subjective parent- and teacher questionnaires. While clinically relevant, these do not inform the underlying neurophysiology of sensory abnormalities in ASD. Increasing evidence suggests a role of GABA, the main inhibitory neurotransmitter, in the pathophysiology of ASD and cortical processing of touch is known to require GABAergic processes. We developed a method to obtain objective psychophysical measurements of tactile thresholds in children with ASD. In addition, we use Magnetic Resonance Spectroscopy (MRS) to measure brain GABA levels in vivo and recently started using Transcranial Magnetic Stimulation (TMS) to probe GABA-receptor function in ASD.

Objectives: Here, we investigate the relationship between pre-synaptic GABA (MRS), post-synaptic GABA-receptors (TMS), tactile thresholds, and clinical ratings in ASD. We hypothesize that altered GABA function associates with psychophysical and clinical sensory abnormalities.

Methods: 145 children with ASD (10.4 ± 1.3 yrs) and 210 typically developing controls (TDC; 10.2 ± 1.2 yrs) were recruited. Informed consent was given per local IRB procedures. Diagnosis was confirmed using the ADOS-2 and ADI-R. Sensory processing was assessed using the SPM and SEQ3. Psychophysics Static and dynamic detection threshold (probing feed-forward inhibition) and amplitude discrimination (probing lateral inhibition) were obtained using a piezoelectric stimulator with vibrations on the left hand (2-alternative forced choice; staircase tracking). MRS GABA levels were measured over right sensorimotor cortex (27 ml voxel) using MEGA-PRESS (TE/TR 68/2000 ms; 320 averages). TMS Single pulse, short-interval intracortical inhibition (SICI; 2.5 ms ISI, probing GABA-A) and long-interval intracortical inhibition paired-pulse measures (LICI; 100 ms ISI, probing GABA-B) were obtained (20 trials per condition).

Results: Children with ASD show abnormally high static detection and amplitude thresholds (both: p < 0.0001; replicating previous work by our lab and others) and no effect of sub-threshold stimulation. GABA levels were reduced in ASD. Abnormal detection thresholds correlated with reduced GABA (R = 0.54). Abnormal detection thresholds significantly predicted SPM total score and SEQ hypersensitivity scores (R > 0.35, p < 0.001), with worse clinical scores for children with higher thresholds and lower GABA levels. Preliminary TMS data suggest that SICI is normal in ASD whereas LICI is abnormal (p < 0.05).

Conclusions: Here, we show a relationship between abnormal tactile perception and inhibitory dysfunction in children with ASD. Data suggest that at the receptor level, GABA-B, rather than GABA-A, is affected in ASD. However, close inspection of the data suggests sensory subtypes with different GABA-related abnormalities and different associated perceptual dysfunctions. Our recent explorations using deep learning elucidate this separation and will be discussed. Other studies linking sensory abnormalities to cortical dysfunction will also be discussed. Understanding the link between cortical function and behavioral outcome is key in developing biologically and potential patient-specific treatments in ASD.