Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Therefore, in close collaboration with Takeda Pharmaceuticals International and Harvard Medical School, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 - a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator.
Studies were conducted in rats and in healthy humans. In the rat study, five escalating TAK-653 doses (0.1–50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans.
In our recent publication in Translational Psychiatry, we describe the studies and the promising results in more detail. To our knowledge, it is the first report of a translational functional biomarker for AMPA receptor potentiation, and it indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.