NOCICEPT – Novel and Conventional Interventions for Cognitive and Emotional Flexibility

The debilitating sequelae from depression, anxiety, and trauma-related disorders necessitate targeted, efficacious, and accessible treatment options for those who do not respond to the current standard-of-care. Repetitive transcranial magnetic stimulation (rTMS) is an FDA-cleared intervention for depression and other disorders which utilizes repeated stimulation in particular patterns to induce synaptic plasticity to strengthen neuronal connections (Brown et al., 2021). rTMS benefits have been enhanced by leveraging NMDA receptor partial agonist, d-cycloserine (DCS) which more than doubled response rates of intermittent theta-burst stimulation (iTBS–a patterned form of rTMS) alone (Cole et al., 2022). Additionally, iTBS parameter modifications produced large benefits in days rather than months when utilizing accelerated session intervals and functional network-guided targeting (Cole 2022). Emerging research has also shown promise regarding utilization of a Cognitive Behavioral Therapy (CBT) intervention, the Unified Protocol (UP) for the Transdiagnostic Treatment of Emotional Disorders, for psychiatric disorders impairing emotional regulation (ER) and cognitive flexibility(CF), and may be profitably augmented with non-invasive brain stimulation (Nasiri et al., 2020). Here we propose the first protocol to combine accelerated TMS (aTMS) with DCS, and the first to combine TMS with UP, to treat the functional impairment in ER and CF in depression, anxiety, and trauma-related syndromes. This will also be the first study to use fMRI-guided treatment to personalize targeting of relevant neural circuits for ER and CF.

This project is supported by the Defense Advanced Research Projects Agency (DARPA).

TIPS – TMS-induced Plasticity of the Synapse

Little is known about the comparative neuronal mechanisms of intermittent theta-burst stimulation (iTBS) and 10-Hz repetitive transcranial magnetic stimulation (rTMS). We hypothesized that iTBS works primarily through NMDA receptor-dependent mechanisms (i.e., long-term potentiation (LTP)), while 10-Hz rTMS may work through a combination of LTP and GABAR reduction. We conducted a double-blind, placebo-controlled, 8-arm crossover study with healthy adult subjects in two phases, iTBS, then 10Hz, with at least 1-week between each session. Each arm consisted of iTBS or 10-Hz rTMS over the left motor cortex (both following standard clinical parameters with exception of 80% resting motor threshold for safety purposes), along with a single dose of placebo (PBO), 100mg d-cycloserine (DCS), 2.5mg lorazepam (LZP), or 150mg dextromethorphan + 100mgdcycloserine (DCS + DMO). Motor-evoked potentials (MEPs) were recorded after drug, before and after rTMS, and normalized to baseline. Kruskal-Wallis and effects-size tests analyzed differences across all groups, and between individual conditions, respectively.

This project was supported by the by the National Institute of General Medical Sciences of the National Institutes of Health, Center for Biomedical Research Excellence, Center for Neuromodulation

MAAT – Mechanism-based Augmentation of Accelerated-TMS

Two recent advances which dramatically improved rTMS effectiveness have highlighted the potential for this therapy to reach the previously unreached. One study condensed the equivalent of 7.5 months of rTMS treatments into 5 days with remarkable success and is now termed ‘accelerated TMS’. Another notable improvement came from adding a medication, previously FDA-approved as an antibiotic (d-cycloserine), but at low-doses has shown it to be capable of increasing rTMS effects on brain excitability. These effects occur through d-cycloserine’s role in enhancing NMDA-dependent synaptic plasticity, which underlies learning and memory. In this BBRF proposal, we hypothesize that these two approaches, which work in different ways, could be combined to generate synergistic additive benefits, and ultimately help millions more recover from depression.

This project is supported by the Brain & Behavior Research Foundation (BBRF).

Determining synaptic mechanisms of TMS in depression [NMDA Modulators + iTBS in dlPFC in depression]

Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and effective tool for brain disorders with demonstrated capacity to modulate brain circuits and behavior. Modulation of circuits occurs at the level of the synapse, and yet, the underlying synaptic-level mechanisms of rTMS at the site of treatment, and in patient populations, are not well understood. Indeed, our knowledge of underlying rTMS mechanisms is largely based on the motor cortex of healthy subjects. The implications of modulating brain activity without knowing the underlying mechanisms are profound. For example, changing rTMS pulse frequency or pulse number yields opposite neurophysiological effects. On the other hand, remarkable improvements in rTMS efficacy have already come
through mechanism-informed pharmacologic augmentation and rTMS parameter selection. Even still, it is likely that we have accessed only a small portion of the potential benefits of rTMS for depression and other brain disorders. To optimize rTMS effectiveness, we must understand the mechanism by which rTMS modulates synapses in the cortical target of patients.

Electric Field Modeling for TMS Dosing

Transcranial Magnetic Stimulation (TMS) induces electric fields (e-fields) in the brain to modulate neuronal activity. The properties of the induced e-fields (strength and direction, relative to the patient’s brain) may have an effect on the biological responses to TMS. Repetitive TMS has been shown to induce lasting effects in cortical excitability, cognitive flexibility, and has known therapeutic effects (Turi et al, 2022). Historically, rTMS protocols set the stimulation intensity (for treatment at dorsolateral prefrontal cortex, dlPFC) relative to the primary motor cortex (M1). The stimulation intensity in most rTMS treatment protocols, including those approved by the FDA for treatment resistant depression, is defined as 120% of the intensity required to produce a response in the M1. The 120% was chosen somewhat arbitrarily as a means of ensuring the dlPFC was activated with magnetic stimulation. In reality, studies have shown that the 120% method can produce markedly different electric fields at the dlPFC as a result of stimulation parameters and differences between the two cortical regions (Caulfield et al, 2021). Using subject MRI and e-field data we can model the electric field at the dlPFC to correlate stimulation parameters with induced physiological effects to produce better clinical outcomes.