Stress and depression are linked to inhibition of plasticity in preclinical models while activation of neurotrophic cascades in the hippocampus and prefrontal cortex appears necessary and sufficient for efficacy across antidepressant treatment modalities. These treatments appear to specifically target homeostatic synaptic plasticity mechanisms. Yet, the implications of pharmacological neurotrophic stimulation in mammals remain unknown. How do neurotrophic changes at the lowest levels (molecular, cellular) alter function at the highest levels (psychology, cognition)? Our ability to measure plasticity in humans opens the door to answering this question. Here, we discuss promising approaches for measuring markers of neurotrophic stimulation in humans.

Ketamine and psychedelics induce rapid neurotrophic activation, making them ideal candidates for this research. Moreover, the recent resurgence of enthusiasm for psychedelic drugs as treatments for psychiatric disorders increases the importance of demonstrating neurobiological mechanisms of therapeutic efficacy, as well as safety, tolerability, and dosing of these treatments in humans.

The synaptic vesicle glycoprotein 2A (SV2A) localizes to secretory vesicles in neurons and is a reasonable biomarker of synaptic density. SV2A can be quantified in vivo using the positron emission tomography (PET)-based radiotracer 11C-UCB-J [1]. SV2A radiolabeling is reduced in individuals with severe depression and increased in the hippocampus and prefrontal cortex one week after exposure to psilocybin in pigs. Recently, mixed results were seen with this tracer 24 h after ketamine [2]. Other PET-based measures, such as aerobic glycolysis, may provide complementary inroads to studying drug-induced LTP and plasticity. However, risks associated with radiation exposure, as well as cost and limited accessibility may limit clinical utility of PET.

Transcranial Magnetic Stimulation (TMS) offers a lower-cost, non-invasive alternative for assessing drug-induced changes in excitability and neuroplasticity in humans. TMS over motor cortex reduces motor thresholds following sub-anesthetic ketamine [3]. This increased excitability is likely a precursor to homeostatic plasticity. TMS-electroencephalography provides a more flexible tool to measure excitability in response to psychopharmacological manipulation [4]. More complex learning paradigms, capturing changes in evoked potentials after tetanic stimulation, have been proposed to measure rate of activity-dependent synaptic plasticity or Hebbian learning (sometimes termed meta-plasticity). However, these tools require further validation.

Resting state functional MRI (rsfMRI) is a non-invasive method for visualizing neurobiological effects of rapid antidepressants with high spatial fidelity. We recently showed that reduced connectivity between emotional brain areas and the default mode network is a marker of the antidepressant response to subanesthetic ketamine [5]. The precision functional mapping (PFM) strategy strengthens rsfMRI by controlling for individual variability, further increasing reliability and specificity. A recent study suggested that PFM may provide a biomarker of homeostatic plasticity (“plasticity pulses”) [6], offering an additional window into population- and circuit-level effects of plasticity-inducing drugs.

Mechanistic studies of classic antidepressants are challenged by the fact that their neurotrophic effects take weeks or months to manifest, whereas the neurotrophic and antidepressant effects of ketamine and psychedelics are rapid. Quantifying the neurotrophic effects of rapid antidepressants in well-designed clinical trials may thus be key to improving treatments, as well as for guiding routine clinical care.