Neurostimulation in Psychiatry

Transcranial Magnetic Stimulation – Jump-Starting a “Sleeping” DLPFC

As an aspiring psychiatrist, I’ve been fascinated by transcranial magnetic stimulation (TMS) ever since I saw it "wake up" a patient. TMS targets the dominant dorsolateral prefrontal cortex (DLPFC) – a region that brain scans show is often underactive in depression. The DLPFC is a part of the brain's “executive” task oriented network (Frontoparietal Central Executive Network-FPN/CEN), which tends to be underactive in depressed patients. In contrast, the default mode network (DMN) – the internal, self-referential circuit – is often overactive in these same patients. Research in functional neuroscience suggests that these two networks have inverse activity, and suppress each other. Hence, when the FP network turns "on", the DMN will turn "off".

In this model, think of the FPN as the brain regions responsible for activity that allows us to engage with external stimuli we are interested, and pay attention. In contrast, the DMN is the mind-wandering mode that kicks in when you’re not focused; in depression it’s working overtime, fueling ruminative negative thinking. It’s as if social isolation and chronic rumination may lead to FPN circuitry being under-exercised, affecting the patient's ability to switch from DMN activity to FPN activity, and maintain FPN activity.

TMS may rebalance this see-saw. By delivering focused magnetic pulses to the DLPFC, we induce repetitive action potentials in the DLPFC, inducing long term potentiation; a process that upregulates the strength of synapses that are used at a high frequency. From an electrical perspective, we lower the resistance in this part of the circuit, indirectly increasing the activity of the entire network.

The idea is that by activating the frontoparietal network, we can both increase FPN activity, which will help the patient engage with activities they enjoy, and push back against the overactive DMN. Research using fMRI has found that before TMS treatment, depression was marked by abnormally high connectivity within the DMN and low connectivity in the executive networks. After a course of TMS, that pattern shifted TMS normalized the hyperconnectivity within the default mode network (DMN), and enhances anticorrelated connectivity (the networks suppressing each other) between the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal DMN nodes.

In plain terms, TMS may help the brain switch out of autopilot DMN activity and re-engage with the external world. I’ve seen patients who, after TMS, report their fog has lifted: they can concentrate better, feel more motivation, and aren’t as chained to looping thoughts. It’s likely because we’re nudging those frontal circuits to flex their muscles again. The evidence supporting the clinical efficacy of TMS is relatively robust, however some argue that bias may result in an overestimate of efficacy and overgeneralization of ideal treatment population.

A Rural Rotation and the Hunt for Alternatives – Enter tDCS

During my medical school rotations in a rural area, I quickly learned that fancy TMS machines are a rare commodity outside big cities. Our clinic served many patients with depression, but the nearest TMS center was hours away. This got me thinking: are there more accessible neuromodulation options we could use? That’s when I discovered transcranial direct current stimulation (tDCS), a low-tech cousin of TMS that could theoretically be used to target the DLPFC. Unlike the big electromagnetic coil of a TMS machine, tDCS is basically a portable kit with a couple of electrodes and a battery pack. You moisten some sponge electrodes, place them on the scalp, and run a weak current (often 1–2 mA) between them. It’s cheap, portable, and easy to use.

TDCS is gentler in its effects. Instead of inducing action potentials outright, tDCS is nudges neuronal resting membrane potentials in a direction that increases excitability in the targeted areas. In essence, tDCS is thought to prime the brain – making neurons a bit more likely to fire if they get natural input, or a bit less likely, depending on how you place the electrodes. Studies show that tDCS can engage NMDA receptor pathways and initiate long-term potentiation (LTP)-like processes in the cortex similar to TMS, and some research suggests that the magnitude of LTP is dependent upon the frequency of neuronal stimulation that occurs during the tDCS stimulation. In other words, when neuronal firing occurs at a frequency that would naturally induce LTP, combining this with tDCS may increase the level of LTP that occurs. This is really interesting because it suggests that pairing tDCS with some form of therapy or cognitive training could amplify learning.

While the idea of boosting synaptic plasticity with tDCS is compelling, I have to acknowledge that there may be alternate explanations for tDCS's mechanism of action. For example tDCS might work indirectly by stimulating cranial nerves. For instance, one electrode in the typical electrode placement sits over the forehead (supraorbital), right where it can stimulate branches of the trigeminal nerve. Trigeminal stimulation can indirectly stimulate the prefrontal cortex, such as in the monarch eTNS device approved for pediatric ADHD.

Mechanism debates aside, the most important question is: does tDCS actually help patients with depression? The growing body of evidence says yes. Meta-analyses show that tDCS offers modest but significant relief in depression. A recent Flow Neuroscience trial pushed things further: in the largest study of home-use tDCS to date, over half of participants achieved full remission. This user-friendly, remote-monitored headset demonstrated efficacy comparable to or even exceeding traditional antidepressants—all without significant side effects.

Flow’s success has accelerated its regulatory journey. After receiving FDA Breakthrough Device status in 2022, the company has now submitted its device for full approval. If cleared, this would mark the first FDA-approved tDCS system for depression in the U.S., though it's already available over-the-counter in Europe. For rural and underserved communities, this could be a game-changer—making neuromodulation accessible where TMS isn't. And as we continue to refine our understanding of how it works, one thing is clear: tDCS is no longer just a theoretical tool, but a viable clinical option for waking up a depressed brain.