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.

Keywords: autism spectrum disorders; excitability; fragile X syndrome; paired pulse stimulation; plasticity; theta burst stimulation; transcranial magnetic stimulation.

Figure 1

Schematic summary of applied methodology. Cortico-spinal excitability can be evaluated by comparing motor-evoked potentials (MEPs) recorded from the peripheral muscle in response to a single pulse to the primary motor cortex. These responses can then be obtained both at baseline and following continuous or intermittent theta burst stimulation (TBS), producing a measure of local cortical plasticity. TBS involves applying bursts of high frequency magnetic stimulation (three pulses at 50 Hz) repeated at intervals of 200 ms. After TBS is applied to the motor cortex in an intermittent fashion (iTBS), single pulse TMS-induced MEPs show increased amplitude for a period of 20–30 min, whereas continuous TBS (cTBS) leads to a suppression of the TMS-induced MEPs for approximately the same amount of time (Huang et al., 2005). Post-TBS enhancement (following iTBS) or suppression (after cTBS) of the cortical activity is considered an index of LTP and LTD-like induction of plasticity in the targeted brain area. Paired pulses to the primary motor cortex with either 3 or 100 ms interstimulus interval can be applied during a separate session to evaluate intracortical inhibition.

Figure 2

Schematic summary of the TBS experimental design. Cortico-spinal excitability was assessed using single pulse TMS. TBS was applied either as cTBS or iTBS to assess LTD- and LTP-like plasticity respectively. This procedure was then repeated 24 h later. The difference between the MEPs at baseline and following TBS can be used as an index of plasticity (LTD- or LTP-like depending on whether c or iTBS was applied) while the plasticity measure on day 1 compared to day 2 provides an index of metaplasticity.

Figure 3

Baseline responses to SICI and LICI paradigms. Bars indicate the average degree of suppression of the MEP as compared to baseline single pulse measures. Blue bars represent patients with FXS; red bars, participants with ASD; and yellow bars, healthy control participants. A value of less than one indicates suppression while a value of greater than one indicates enhancement.

Figure 4

Baseline corrected MEP amplitude following cTBS (in red) and iTBS (in blue) on day 1 and day 2 for the control group (A), FXS group (B), and ASD group (C). Values are represented as proportion of baseline amplitude with a line at 1.0 (representing baseline amplitude).