Slimsdizz (Wikimedia Commons)
Source: Slimsdizz (Wikimedia Commons)

Brain stimulation might sound like some Frankensteinian demonstration from a Victorian science fair. But in reality, it is a contemporary technique making a huge impact in neuroscience by addressing a longstanding limitation of traditional methods for investigating human brain function. Such techniques, like EEG and fMRI, can only be used to infer the effects of a stimulus or task on brain activity, and not vice versa. For example, a scientist might use EEG to study the effect of a task like arm movement on brain activity, but how can one study the effect of brain activity on arm movement?

Today, noninvasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) are offering alternatives to old paradigms. TMS can excite or suppress underlying brain tissue safely and ethically, allowing researchers to study causal relationships between brain circuits and behavior. What's more, TMS may have therapeutic value in treating brain disorders such as depression.

Wikimedia Commons, National Institutes of Health
Source: Wikimedia Commons, National Institutes of Health

Here's how it works. A circular coil of wire is fixed over a subject's head, and the current in the wire induces a magnetic field. Because charged particles in a magnetic field experience a force perpendicular to the direction of the field, the movement of ions in underlying brain tissues is altered by this field. This disrupts the firing of neurons in cortical tissue, simulating a brain "lesion". For instance, activating the coil over Broca's area—a brain region necessary for speech production—causes participants to stutter and stop talking mid-sentence. However, the participant can still sing a song if instructed to, thus demonstrating that speaking and singing depend on different neural circuits.

As its name suggests, TMS can also excite brain tissue, depending on the frequency of the pulses applied. Used over motor cortex, for example, TMS can induce twitching in specific muscles. A particularly creative experiment illustrating this effect was performed by researchers at the University of Washington in Seattle. Rajesh P. N. Rao and his colleagues used the output of one subject's EEG as the input to another subject's TMS coil. As the first subject imagined flexing his right index finger, the EEG recorded electrical activity related to this imaginary movement from the scalp over motor cortex. The electrical output recorded with EEG was then fed to the second subject's TMS coil, fixed over the same scalp region, causing the second subject to actually twitch his finger!

2014 Rao et al. (Creative Commons license)
Source: 2014 Rao et al. (Creative Commons license)

TMS can, in a narrow sense, even make the blind see again. In individuals who lost most of their sight due to eye injury, TMS applied over visual cortex induces the visual experience of shapes and color called phosphenes, much like the shapes and colors you might see after rubbing your eyes.

Therapeutic uses of TMS seek to correct brain activity in a variety of disorders ranging from depression to obsessive compulsive disorder (OCD). Studies of TMS for depression show relief from depressive symptoms when stimulation is applied over a cortical region called dorsolateral prefrontal cortex. The results of these studies are usually measured relative to a sham condition, in which fake stimulation is used to ensure the results were not due to a placebo effect. TMS offers new hope for depression patients who don't respond to drug treatments and may also be effective in treating other disorders. But like many psychiatric treatments, researchers still aren't sure how and why TMS offers relief from symptoms. Given the vast number of cells and synapses in the area of brain to which TMS is applied, the effects of even a simple magnetic pulse are impossible to fully calculate.

Wikimedia Commons, National Institutes of Health
Source: Wikimedia Commons, National Institutes of Health

While the exact mechanism by which TMS treats depression is uncertain, it may exert its therapeutic effects by similar abstract principles as electroconvulsive therapy, or ECT, which treats severe depression by inducing a seizure. This experience is different from an epileptic seizure, because the patient is administered anesthesia and muscle relaxants after giving his or her consent to be treated. So why is a seizure actually helpful? Carey Bagdassarian, Senior Lecturer of Interdisciplinary Studies at the College of William and Mary, has speculated that the electric shock given by ECT may "push" the brain out of a depressed state much like a strong push perturbs a ball out of a deep valley. In this analogy, the landscape of valleys is the mathematical space spanned by relevant brain variables such as neuronal firing rates. It's important to keep in mind that this speculation has yet to be formalized or directly tested (what happens if the "push" is given in the wrong direction?). However, researchers in the UK have found that ECT treatment for depression does, in fact, reduce correlations between patterns of metabolic activity in frontal brain regions and the rest of the brain. This suggests that ECT releases frontal brain circuits from a depressed state that may constrain their activities, like the metaphorical valley suggested by Bagdassarian.

Whether justified or not, ECT's reputation with the public has been damaged by reports of  memory loss and allegations of abuse. TMS, however, may offer a subtler, more nuanced alternative for rebooting the brain, perhaps by a similar mechanism. Like ECT, TMS treatments for depression appear to alter the correlations between metabolic activity in the dorsolateral prefrontal cortex and another region of the brain known as the subgenual cingulate. But unlike ECT, TMS rarely elicits seizures when administered properly, and its stimulation can be aimed at specific regions of the cerebral cortex, arguably making TMS a more flexible and versatile tool than ECT. 

Frontiers for Young Minds, Shamir et al 2014 (Creative Commons License)
Illustration of Deep Brain Stimulation
Source: Frontiers for Young Minds, Shamir et al 2014 (Creative Commons License)

Beyond TMS and ECT, brain stimulation is continuing to blossom into a family of techniques with differing strengths and applications. Deep brain stimulation, or DBS, surgically implants electrodes to stimulate core brain structures that cannot be reached from the scalp, such as the thalamus and basal ganglia. While invasive, the technique shows huge promise for treating Parkinson's disease. On the other hand, transcranial direct current stimulation, or tDCS, is a technique that has raised alarm with numerous reports of do-it-yourself style self-experimentation by garage amateurs (I don't recommend this). The technique itself is relatively simple, involving the application of a weak, continuous current across the head. While it shows some efficacy for treating depression, a sobering demonstration in human cadavers earlier this year suggests that tDCS current may not pass through the brain at all, raising fierce debate as to its true mechanism of action.

A person doesn't choose the brain he or she is born with. Brain stimulation offers hope that we can fix circuits in diseased brains of patients with otherwise intractable depression and similar disorders.  Not all clinical trials of TMS will succeed, and the possibilities allowed by more accessible techniques, such as tDCS, must be approached responsibly. But unquestionably, brain stimulation ushers in a new era of controlling the brain is ways hitherto impossible. 

References

Rao, Rajesh PN, et al. "A direct brain-to-brain interface in humans." PloS one 9.11 (2014): e111332.

Gothe, Janna, et al. "Changes in visual cortex excitability in blind subjects as demonstrated by transcranial magnetic stimulation." Brain 125.3 (2002): 479-490.

Bagdassarin, Carey, e-mail message to author, October 28, 2016.

Perrin, Jennifer S., et al. "Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder." Proceedings of the National Academy of Sciences 109.14 (2012): 5464-5468.

Fox, Michael D., et al. "Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate." Biological psychiatry 72.7 (2012): 595-603.  

Alonzo, Angelo, et al. "Transcranial direct current stimulation (tDCS) for depression: Analysis of response using a three-factor structure of the Montgomery–Åsberg depression rating scale." Journal of affective disorders 150.1 (2013): 91-95.

Underwood, Emily. "Cadaver study challenges brain stimulation methods." Science 352.6284 (2016): 397-397.

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