Neuroengineers Crack the 'Black Box' of Transcranial Magnetic Stimulation

The body of research exploring repetitive transcranial magnetic stimulation (rTMS) as a potential therapy in psychiatric disorders, particularly major depressive disorder, is immense and growing at a steady clip. Enthusiasm, however tempered, is justified: the treatment of depression, currently the most disabling medical condition in the United States, remains limited to pharmacological solutions and, if those don't deliver, electro-convulsive therapy (ECT). ECT, while an effective last-ditch intervention with barely a shred of its formative brutality, still requires general anesthesia and can lead to deep side effects including patient confusion, memory loss, and an array of physical symptoms including muscle spasms and nausea/vomiting. It's not a casual intervention, by any means. rTMS therapy represents something in between those two poles, a treatment beyond drugs that doesn't require lighting up the brain with loads of electrical current.

While rTMS is well-studied, the research is nearly all focused on therapeutic outcomes rather than the therapy's mechanisms of action. It's something of a "black box" treatment: we see what goes in (magnetic fields) and what comes out (improved patient outcomes), but not much of what happens in between. The reason is simple: the application of those magnetic fields across large portions of the brain effectively cloaks any effects happening at the level of individual neurons; we see instead mass polarization across general regions of the brain. This is what makes a paper out today in the journal Nature Neuroscience, courtesy of a team at Duke University, so intriguing: for the very first time, researchers have achieved the resolution needed to see rTMS' effects on single neurons, paving the way for new rTMS methods that might amplify and refine the therapy's effect.

First, a bit about what rTMS actually is. While ECT directly applies electrical currents through the brain at large, rTMS takes advantage of a different electrical property: magnetization. Put current through a coil of wire and the result is a magnetic field. Place this coil up against some human's skull, and that field will penetrate a couple of inches into the brain, inducing tiny electrical currents in a small enough area such that distinct parts of the brain can be stimulated electrically, without the wholesale neuro-brutality of ECT; TMS can also be used to stimulate the portions of the brain responsible for motor activity, actually inducing patients to involuntarily move their limbs or percieve things that aren't actually there, like pulses of light. Introduce the fields to portions of the brain responsible for mood control and the theory is that, by increasing the electrical potential between nuerons in these regions, you will have sufficiently stimulated the brain to alleviate symptoms of major depression.

If the above doesn't sound wholly optimistic about TMS, you can find plenty of gushing elsewhere. The truth is that the therapy's success isn't a settled issue, despite the FDA's stamp of approval, which was wielded in the face of a finding by the FDA itself that TMS' "clinical effect was perhaps marginal, borderline, questionable, and perhaps a reasonable person could ask whether there was an effect at all." Nonetheless, additional studies conducted since the 2007 FDA decision have found some positive effect, likely enough to justify clinical use for major depression and, at the very least, further study. The caveat is that, at this point, the population likely to see benefit is limited to younger and less treatment-resistant patients, ideally those without accompanying anxiety or other psychiatric disorders. That's a very specific set of individuals.

At the same time, despite the rather severe requirement that rTMS be given daily for multiple weeks, it does represent some hope for patients currently without any, along with the possibility of an ECT-like treatment without the ECT side effects. It's a concept in need of more information.

The current study gets past the would-be information wall of TMS through clever engineering. The task involves picking out extremely tiny currents passing among neurons under the mask of the overall TMS-induced flow, which is thousands of times more powerful. Imagine trying to find a glass of water in a river. Basically, a electrode is placed such that the individual action potential (or impulse) of a neuron can be measured before and after administration of TMS, revealing a current possibly (though not definitely) distinct from the larger TMS effect.

More specifically, researchers were able to accomplish this differentiation using a pair of complimentary techniques. "We used an innovative recording circuit employing serial stages of anti-parallel electrical diode clamps to limit the size of the artifact voltage," explained Warren Grill, the paper's lead author, in an email to Motherboard. In other words, signals were passed through a succession of unique circuits, each one filtering out some new voltage level, until the desired voltage is the only signal left. "Second, we used a second small coil near the TMS coil to sense the applied pulse and subtract this signal from the recorded signal, thereby eliminating the residual artifact." Let's suppose that one's more self-explanatory.

If this observation holds up (and extends from the studied primates to human subjects), it should become possible to to see physiological before and after effects of the therapy at the highest resolutions. In a Duke press release, Grill notes that this technology is readily portable to other labs, effectively making a whole line of research open-source.

"Studies with TMS have all been empirical," Grill says in the Duke release. "You could look at the effects and change the coil, frequency, duration or many other variables. Now we can begin to understand the physiological effects of TMS and carefully craft protocols rather than relying on trial and error. I think that is where the real power of this research is going to come from."