Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Evoked-Gamma Frequency Oscillations in Autism Spectrum Disorder (ASD).

INTRODUCTION: It has been reported that individuals with Autism Spectrum Disorder (ASD) have abnormal reactions to the sensory environment and visuo-perceptual abnormalities. Electrophysiological research has provided evidence that gamma band activity (30-80 Hz) is a physiological indicator of the co-activation of cortical cells engaged in processing visual stimuli and integrating different features of a stimulus. A number of studies have found augmented and indiscriminative gamma band power at early stages of visual processing in ASD; this may be related to decreased inhibitory processing and an increase in the ratio of cortical excitation to inhibition. Low frequency or 'slow' (≤1HZ) repetitive transcranial magnetic stimulation (rTMS) has been shown to increase inhibition of stimulated cortex by the activation of inhibitory circuits. METHODS: We wanted to test the hypothesis of gamma band abnormalities at early stages of visual processing in ASD by investigating relative evoked (i.e. ~ 100 ms) gamma power in 25 subjects with ASD and 20 age-matched controls using Kanizsa illusory figures. Additionally, we wanted to assess the effects of 12 sessions of bilateral 'slow' rTMS to the dorsolateral prefrontal cortex (DLPFC) on evoked gamma activity using a randomized controlled design. RESULTS: In individuals with ASD evoked gamma activity was not discriminative of stimulus type, whereas in controls early gamma power differences between target and non-target stimuli were highly significant. Following rTMS individuals with ASD showed significant improvement in discriminatory gamma activity between relevant and irrelevant visual stimuli. We also found significant improvement in the responses on behavioral questionnaires (i.e., irritability, repetitive behavior) as a result of rTMS. CONCLUSION: We proposed that 'slow' rTMS may have increased cortical inhibitory tone which improved discriminatory gamma activity at early stages of visual processing. rTMS has the potential to become an important therapeutic tool in ASD treatment and has shown significant benefits in treating core symptoms of ASD with few, if any side effects.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism.

In our previous study on individuals with autism spectrum disorder (ASD) (Sokhadze et al., Appl Psychophysiol Biofeedback 34:37-51, 2009a) we reported abnormalities in the attention-orienting frontal event-related potentials (ERP) and the sustained-attention centro-parietal ERPs in a visual oddball experiment. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. In the present study we examine the effects of low-frequency, repetitive Transcranial Magnetic Stimulation (rTMS) on novelty processing as well as behavior and social functioning in 13 individuals with ASD. Our hypothesis was that low-frequency rTMS application to dorsolateral prefrontal cortex (DLFPC) would result in an alteration of the cortical excitatory/inhibitory balance through the activation of inhibitory GABAergic double bouquet interneurons. We expected to find post-TMS differences in amplitude and latency of early and late ERP components. The results of our current study validate the use of low-frequency rTMS as a modulatory tool that altered the disrupted ratio of cortical excitation to inhibition in autism. After rTMS the parieto-occipital P50 amplitude decreased to novel distracters but not to targets; also the amplitude and latency to targets increased for the frontal P50 while decreasing to non-target stimuli. Low-frequency rTMS minimized early cortical responses to irrelevant stimuli and increased responses to relevant stimuli. Improved selectivity in early cortical responses lead to better stimulus differentiation at later-stage responses as was made evident by our P3b and P3a component findings. These results indicate a significant change in early, middle-latency and late ERP components at the frontal, centro-parietal, and parieto-occipital regions of interest in response to target and distracter stimuli as a result of rTMS treatment. Overall, our preliminary results show that rTMS may prove to be an important research tool or treatment modality in addressing the stimulus hypersensitivity characteristic of autism spectrum disorders.

Event-related potential study of novelty processing abnormalities in autism.

To better understand visual processing abnormalities in autism we studied the attention orienting related frontal event potentials (ERP) and the sustained attention related centro-parietal ERPs in a three stimulus oddball experiment. The three stimulus oddball paradigm was aimed to test the hypothesis that individuals with autism abnormally orient their attention to novel distracters as compared to controls. A dense-array 128 channel EGI electroencephalographic (EEG) system was used on 11 high-functioning children and young adults with autism spectrum disorder (ASD) and 11 age-matched, typically developing control subjects. Patients with ASD showed slower reaction times but did not differ in response accuracy. At the anterior (frontal) topography the ASD group showed significantly higher amplitudes and longer latencies of early ERP components (e.g., P100, N100) to novel distracter stimuli in both hemispheres. The ASD group also showed prolonged latencies of late ERP components (e.g., P2a, N200, P3a) to novel distracter stimuli in both hemispheres. However, differences were more profound in the right hemisphere for both early and late ERP components. Our results indicate augmented and prolonged early frontal potentials and a delayed P3a component to novel stimuli, which suggest low selectivity in pre-processing and later-stage under-activation of integrative regions in the prefrontal cortices. Also, at the posterior (centro-parietal) topography the ASD group showed significantly prolonged N100 latencies and reduced amplitudes of the N2b component to target stimuli. In addition, the latency of the P3b component was prolonged to novel distracters in the ASD group. In general, the autistic group showed prolonged latencies to novel stimuli especially in the right hemisphere. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. We propose the potential application of ERP evaluations in a novelty task as outcome measurements in the biobehavioral treatment (e.g., EEG biofeedback, TMS) of autism.

Effects of low frequency repetitive transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related potentials during processing of illusory figures in autism.

Previous studies by our group suggest that the neuropathology of autism is characterized by a disturbance of cortical modularity. In this model a decrease in the peripheral neuropil space of affected minicolumns provides for an inhibitory deficit and a readjustment in their signal to noise bias during information processing. In this study we proposed using low frequency transcranial magnetic stimulation (rTMS) as a way increasing the surround inhibition of minicolumns in autism. Thirteen patients (ADOS and ADI-R diagnosed) and equal number of controls participated in the study. Repetitive TMS was delivered at 0.5 Hz, 2 times per week for 3 weeks. Outcome measures based on event-related potentials (ERP), induced gamma activity, and behavioral measures showed significant post-TMS improvement. The results suggest that rTMS offers a potential therapeutic intervention for autism.