Psychiatry's Shocking New Tools

The simplicity of tDCS makes it sound almost suspicious, and indeed its origins stretch back into the murk of 19th-century quackery. But the principle of how tDCS seems to work in the brain is roughly the same as that of rTMS. They both seek to make neurons in the prefrontal cortex, the decision-making part of the brain, more excitable, that is, more likely to propagate a signal from neuron to neuron. In tDCS's case a small current, delivered via electrodes on the temples, biases brain cells, making them more likely to emit a spike of voltage, says Alvaro Pascual-Leone, associate professor of neurology studying tDCS at Harvard University, in Cambridge, Mass. The effect, studies have shown, lasts long after the current is turned off.

The concept and technology are so simple, in fact, that Pascual-Leone and his colleagues suggested in The British Journal of Psychiatry that tDCS be used in the developing world as a first-line treatment for depression instead of rather expensive antidepressant drugs. But Sachdev thinks this is a terrible idea. "We need to know a lot more about tDCS before it is accepted as an effective treatment and must await the results of many ongoing trials," he wrote in a rebuttal. "In the meantime, depressed patients in the developing world should be dissuaded from unplugging their car batteries and clamping them on their foreheads."

Pascual-Leone says he has results showing tDCS fought treatment-resistant depression as well as rTMS did in experiments done at the University of São Paulo School of Medicine, in Brazil, but at press time the study had not yet been published in a peer-reviewed journal.

If "hooking the patient up to a car battery" is the least invasive new psychiatric technology, then deep-brain stimulation is its opposite. It is meant only for the most desperate patients, those not helped even by electroconvulsive therapy. It requires having a surgeon bore two holes in the skull, insert a pair of electrodes deep into the brain, run wires beneath the skin of the neck, and connect them with a pacemakerlike device implanted in the chest under the skin. The device sends pulses of electricity to the electrode tips, shutting down activity in the few cubic millimeters of brain tissue there [see illustration, " Deep Brain Stimulation"].

The results can be instantaneous. Thomas Schlaepfer, vice chair and professor of psychiatry and psychotherapy at the University of Bonn, in Germany, described the case of one of his patients to IEEE Spectrum. A host of drugs and even electroconvulsive therapy had failed to lift her depression and halt her desperate urge to kill herself. But last August she had one of Medtronic's deep-brain stimulators implanted. When Schlaepfer turned the device on and asked her how she was feeling, she replied that she was still as depressed as ever but that she would like to start bowling again.

Bowling had once been her favorite pastime, but she had not enjoyed it for years. The inability to enjoy things that once gave you pleasure--psychiatrists call it anhedonia--is a key characteristic of major depression. The parts of the brain responsible for it, the reward centers, are among the prime targets of the new therapy.

Deep-brain stimulation has been in use for years to treat the tremors of Parkinson's disease. In that case, 3- to 5-volt pulses at about 100 Hz are applied to a part of a brain circuit that malfunctions and causes the tremors. The stimulation suppresses the activity of neurons near the electrode, mimicking their surgical destruction, but with a key twist. "Basically, it's reversible and tunable brain surgery," says Schlaepfer. Turn the device on, and that section of the brain goes off-line. Turn it off, and the neurons spring back into action. It's a simplistic view, of course, and scientists still don't know if the electrode's current blocks brain traffic by holding the cells at too high a voltage to propagate a signal, exhausts their supply of chemical transmitters, overlays a meaningless jamming signal on them, or does something different entirely.

The device has also been used to treat severe obsessive-compulsive disorder; indeed, this was its first use in psychiatry. In that treatment, neurosurgeons had been destroying a few cubic millimeters of a particular structure in the brain. Now surgeons have begun inserting electrodes instead of destroying those tiny parts of the brain.

A group based at the University of Toronto and led by neurosurgeon Andres Lozano and neurologist Helen S. Mayberg reported the first trial of deep-brain stimulation for depression only a year ago. (Mayberg has since become a professor at Emory University, in Atlanta.) Imaging studies led them to Broadmann area 25, a pair of structures deep in the brain just above and behind the eyes that become active when people are sad. It has abnormally high blood flow in people with treatment-resistant depression; antidepressant drugs tend to reduce the amount of blood flow there. So the Toronto researchers implanted electrodes powered by a Medtronic stimulator in that spot in six patients. Five of the six responded well initially, and four continued to do so six months out. According to Lozano, those four are still doing well two years later. Lozano, who has been implanting deep-brain stimulators for more than a decade, says that not enough is known about why patients respond or don't respond to the procedure to say if there is a need to tweak the technology. "We don't know if it's the electrodes or the patients," he says.

Although the seminal work was done using stimulators made by Medtronic, another maker of implantable stimulators, Advanced Neuromodulation Systems Inc. (ANS), in Plano, Texas, holds the relevant intellectual property rights, according to Rohan Hoare, the company's vice president of corporate strategy and development. ANS is now replicating Mayberg and Lozano's results in a pilot study using its Libra deep brain stimulation system. The main difference between the Medtronic systems used in Toronto and Bonn and ANS's devices is that Medtronic's delivers a constant-voltage pulse, which allows the current to vary depending on the impedance of the brain, while its competitor delivers constant current, allowing the voltage to vary. ANS's vice president for scientific affairs, Tracy Cameron, notes that most animal research has been done using constant-current stimulators and hypothesizes that this approach may be more in tune with the brain's physiology.

The debates don't end with the technology. Researchers also disagree about which brain structures to stimulate, although all the contenders are in the same neighborhood, behind and above the eyes. Research at Brown University Medical School and Butler Hospital, both in Providence, R.I., stimulate a much larger structure than Broadmann 25, called the anterior limb of the internal capsule. And Schlaepfer and his colleagues in Europe are working on the area related to anhedonia, called the nucleus accumbens.

Assuming that all the new brain stimulation techniques prove effective in the many upcoming trials, the psychiatrist's toolbox will look very different a decade from now. Patients will probably first be offered the less invasive techniques, such as transcranial direct current and magnetic stimulation; then the more invasive ones, such as the seizure therapies; and finally such surgical technologies as deep-brain stimulation and vagus nerve stimulation. "A significant portion of patients will want to try the less invasive treatment first," says Monash University's Fitzgerald. "For some it will be sufficient."

But don't cash out of your drug company stock just yet. Even if the more easily applied therapies are proven effective, drug firms have little to worry about. "Drugs are always the first preference, because you don't have to show up every day," says the University of New South Wales's Sachdev.

Of course, a better way than simply trying one therapy after another is to figure out how each works and why they work well for some people rather than others. That won't happen soon, because it will require experience with many patients and a much better understanding of the brain. And though such brain-imaging technologies as positron-emission tomography have been useful for finding target areas for deep brain stimulation and for understanding the effects of stimulation technologies, they can't yet predict who will respond to a treatment and who won't. "We've got the diagnostic tools; we just need to refine them," says Harvard's Pascual-Leone. And when that's done, psychiatrists will have both a road map of the mind and the tools to fix the potholes.