Treatments that zap the brain with magnets or electricity are rising in popularity, and some evidence suggests they can help lift depression. But scientists are starting to wonder whether they could be hitting the wrong place in left-handed patients. Now, two small studies suggest this could very well be the case.

“This is the kind of question that’s been desperately needed for many years,” says Jim Coan, a clinical psychologist at the University of Virginia in Charlottesville who was not involved in the project. “Most researchers in this area, including myself, have selected samples that are strongly right-handed, just in order to avoid mess in the data.”

Past studies have suggested that the spots targeted by both kinds of stimulation—located in the left hemisphere—are likely to process “approach” emotions such as happiness, curiosity, and anger, which drive people to reach out and engage with the world. Some studies have also hinted that the brain’s right hemisphere is more involved in so-called “avoidance” emotions such as sorrow and fear. But the studies that support this separation of emotion into the two halves of the brain have relied almost exclusively on right-handed individuals.

To figure out whether something else was happening with lefties, University of Chicago in Illinois neuroscientist Daniel Casasanto designed two studies: one to link personality to patterns of brain activity and another to measure the outcome of common brain stimulation treatments in right-handed and left-handed individuals. The brain stimulation treatments were originally designed to treat depression by boosting feelings of happiness and engagement, which motivate “approach” behaviors such as exploring the world and interacting with friends.

Researchers have long acknowledged that emotions evolved to motivate actions, but Casasanto suspects the link between action and emotion is even closer than people realize. We reach out to the world with our dominant hands, he says, and protect ourselves with our nondominant hands. Perhaps the neural circuits that make us want to reach out are fundamentally entwined with the circuits controlling the motion itself, he says. Casasanto calls this idea the “sword-and-shield” hypothesis, after medieval knights who wielded a sword in one hand and a shield in the other. For right-handers, this would mean that happiness and other approach emotions would be concentrated in the left hemisphere, along with the motor areas that control the right hand. But for left-handers, the whole tangle of approach-oriented feelings and actions would come from the right.

So Casasanto and graduate student Geoffrey Brookshire set up their first test. They recruited 34 right-handed and 12 left-handed volunteers and then assessed their personalities using questionnaires. Eager, outgoing types scored higher on approach motivation, while hesitant, reserved types scored lower. Using electroencephalography (EEG), the researchers then measured subjects’ brain wave patterns while they were resting with their eyes closed. They did not measure how the EEG patterns would change in other situations. But in this resting state, approach-motivated righties showed more activity in their left hemispheres, while approach-motivated lefties showed more activity on the right—just as the sword-and-shield hypothesis predicted. The results were published in 2012 in PLOS ONE.

Next, Casasanto and Brookshire turned to depression treatments involving continuous transcranial direct-current stimulation (tDCS), a brain stimulation technique that involves running a weak electric current between two electrodes on someone’s scalp. Casasanto and Brookshire recruited 25 subjects, and although only four were strongly left-handed, all fell at various points along a spectrum from strongly right-handed to strongly left-handed. Half received typical tDCS treatments to increase activity on the left side of the brain, while half received reverse treatments to stimulate the right side. The more strongly right-handed someone was, the better they felt after 5 days of the standard treatment, and the worse they felt after the reverse treatment. In contrast, the more strongly left-handed someone was, the better they responded to reverse treatment, but the worse they responded to the standard treatment.

Although none of the participants in the studies had depression, Casasanto says the results raise concerns about current treatments for the disease. tDCS is not yet Food and Drug Administration (FDA) approved, but a growing number of people are buying in-home tDCS devices to use on themselves. Other treatments are FDA approved, including those that use magnets to stimulate the brain and boost activity in the left hemisphere.

“Treating all patients as if they were right-handed could potentially have negative consequences,” said Casasanto when he presented his latest findings at the annual meeting of AAAS (which publishes Science) this month. “What [lefties] need is stimulation of their right hemisphere—the one that controls their sword hand.”

John Allen, a psychophysiologist at the University of Arizona in Tucson who was not involved in the project, agrees that left-handers are under-studied, but he thinks Casasanto’s team should be more cautious with their conclusions. In the EEG study, asymmetries in approach emotions showed up in in the middle and back of the brain, not the front where past research said they should be, Allen says. And, he adds, some of the researchers’ methodology makes it hard to know where in the brain the signals were coming from.

“I think these authors have identified an important research topic, but they've just begun to scratch the surface,” Allen says. “Many more studies would need to be done, and some with greater EEG rigor, in order to really determine what's going on.”

*Update, 2 March, 12:25 p.m.: In the paragraph that mentions John Allen, all statements have been clearly attributed to show that these are Allen’s critiques of the methodology.