Transcranial magnetic stimulation provides means to assess cortical plasticity and excitability in humans with fragile X syndrome and autism spectrum disorder

Abstract

Fragile X Syndrome (FXS) is the most common heritable cause of intellectual disability. In vitro electrophysiologic data from mouse models of FXS suggest that loss of fragile X mental retardation protein affects intracortical excitability and synaptic plasticity. Specifically, the cortex appears hyperexcitable, and use-dependent long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are abnormal. Though animal models provide important information, FXS and other neurodevelopmental disorders are human diseases and as such translational research to evaluate cortical excitability and plasticity must be applied in the human. Transcranial magnetic stimulation paradigms have recently been developed to non-invasively investigate cortical excitability using paired pulse stimulation, as well as LTP- and LTD-like synaptic plasticity in response to theta burst stimulation (TBS) in vivo in the human. TBS applied on consecutive days can be used to measure metaplasticity (the ability of the synapse to undergo a second plastic change following a recent induction of plasticity). The current study investigated intracortical inhibition, plasticity and metaplasticity in full mutation females with FXS, participants with autism spectrum disorders (ASD), and neurotypical controls. Results suggest that intracortical inhibition is normal in participants with FXS, while plasticity and metaplasticity appear abnormal. ASD participants showed abnormalities in plasticity and metaplasticity, as well as heterogeneity in intracortical inhibition. Our findings highlight the utility of non-invasive neurophysiological measures to translate insights from animal models to humans with neurodevelopmental disorders, and thus provide direct confirmation of cortical dysfunction in patients with FXS and ASD.

Abnormal Mechanisms of Plasticity and Metaplasticity in Autism Spectrum Disorders and Fragile X Syndrome

“…Specifically, and consistent with our previous studies (Oberman et al , 2012, compared with the control group on day 1, the ASD group showed a significantly greater duration of response to cTBS, whereas the FXS group showed a significantly shorter duration (on average no discernable response). Our results confirm and extend those findings.…”

“…cTBS was applied according to the standard protocol that was consistent with our previous studies in ASD and FXS (i.e., three pulses of 50-Hz rTMS repeated every 200 ms for a total of 40 seconds [for a total of 600 pulses]) at an intensity of 80% of AMT (Huang et al 2005(Huang et al , 2008Oberman et al 2010Oberman et al , 2012Oberman et al , 2015. Corticospinal excitability was assessed both before and after cTBS by measuring peak-to-peak amplitude of MEPs induced in the contralateral first dorsal interosseus (FDI) muscle in response to supra threshold (120% of resting motor threshold [RMT] intensity) single-pulse TMS.…”

“…Data analysis followed the methods described and applied previously in (Oberman et al , 2012. Briefly, data were analyzed using SPSS version 19 by an experimenter who was blinded to the identities of the participants.…”

“…Consistent with previous studies in our laboratory suggesting that enhanced duration of modulation after cTBS may be a reliable endophenotype in ASD (Oberman et al 2012), our primary outcome measure was empirically defined as the number of minutes after cTBS until the amplitude of the MEPs returned to baseline excitability levels (''time to baseline''). Two between-subjects one-way ANOVAs with post hoc t-tests were conducted.…”

“…ASD is diagnosed by clinical criteria, and the exact brain dysfunction that leads to the behavioral phenotype in nonsyndromic ASD remains unknown. However, altered mechanisms of synaptic, use-dependent plasticity and metaplasticity are likely essential components of the ASD pathophysiology (Dolen and Bear 2009;Markram and Markram 2010;Oberman et al 2010Oberman et al , 2012Oberman 2015).…”