Can a Side of the Brain Determine Sick or Sane?

Image: Courtesy of Alvaro Pascual-Leone DEPRESSION AND CEREBRAL ACTIVITY: Cerebral blood flow determined by single-photon emission tomography was correlated with changes in clinical depression after patients received transcranial magnetic stimulation (TMS) to the left prefrontal cortex. In red areas, blood flow--signifying brain activity--was positively correlated with TMS's antidepressant effect; in green areas, blood flow was negatively correlated. (Reprinted with permission, Psychiatry Research Neuroimaging, 115:1-14, 2002.) Several years ago, Alvaro Pascual-Leone, an associate professor of neurology and neuroscience at Harvard Medical School, decided on a seemingly bizarre approach to studying people with medication-resistant depression. He asked his subjects to wear goggles that restricted sight to either the right or left visual field. He wanted to alleviate their depression with transcranial magnetic stimulation (TMS), and he had a hunch that the goggles might signal which brain hemisphere to treat with this experimental therapy to ensure the greatest clinical benefits. The goggle strategy germinated in discussions with Fredric Schiffer, assistant professor of clinical psychiatry at Harvard and an associate attending psychiatrist at McLean Hospital in Belmont, Mass. From earlier experiments and observations in his private practice, Schiffer had learned that ordinary, taped-up goggles elicit mood changes in many depressed patients.1 Pascual-Leone was initially skeptical but soon changed his tune. "I was surprised and sort of amazed," he recalls, that within seconds of donning the spectacles, "some people really had rather striking and well-defined emotional responses." Recently published, his study suggests that TMS might work better if it targets whichever hemisphere reacts positively to the goggles.2 When people peer out one side of them, one hemisphere is activated more than the other, according to Schiffer, who says he has preliminary data from functional magnetic resonance imaging (fMRI) on four subjects that confirm this effect. Because the axons of many retinal neurons cross the midline, the left brain receives a jolt when the right visual field is stimulated, and vice versa. The finding that such lateralized activation can change patients' moods is consistent with 35 years of research implicating the right hemisphere (RH) in some psychiatric disorders and the left hemisphere (LH) in others. The notion that lateralized activity warrants lateralized treatment, however, is controversial. One objection is that neural activity patterns are too complex and uncharted to justify such treatment. Another is that the corpus callosum, the band of nerve fibers connecting the hemispheres, guarantees that activation will spread to the untreated side anyway. Nevertheless, two factors are slowly pushing psychiatry toward targeted, if not lateralized, physical treatments: the unacceptable collateral damage wreaked by nontargeted therapies; and brain-imaging technologies, such as fMRI, that are identifying small regions underlying psychological states. SCHIZOID, LEFT; DEPRESSED, RIGHT? Detailed observations of the brain hemispheres' distinct psychological roles date back to the 1960s, when the California Institute of Technology's Roger W. Sperry tested so-called split-brain patients who had undergone surgical sectioning of the corpus callosum. Attention soon turned to the hemispheres' roles in psychiatric conditions. Investigating psychoses that accompany epilepsy, Pierre Flor-Henry, now a clinical psychiatry professor at the University of Alberta in Edmonton, linked schizophrenia and manic-depression to LH and RH disturbances, respectively. Flor-Henry is now using electroencephalographs to examine lateral activity in disorders ranging from chronic fatigue syndrome to pedophilia. Stressing the brain's interconnectedness, he cautions, "A disturbance cannot be just in one hemisphere. The fundamental cause might originate in one hemisphere." In patients who do not have epilepsy or brain lesions, laterality patterns can be murky. "Schizophrenics seem to suffer from this double barrel of a problem of having a dysfunctional left hemisphere, and yet overactivation of that hemisphere," says Ruben C. Gur, a neuropsychology professor at the University of Pennsylvania School of Medicine. He notes that this theory has recently gathered support from functional-imaging and pathology studies. Richard J. Davidson, a psychology and psychiatry professor at the University of Wisconsin, Madison, has amassed evidence that people with less left-sided and more right-sided prefrontal activation are vulnerable to depression. (Prefrontal cortex plays a role in emotion.) Gur claims that other investigators have discovered reduced frontal-lobe activity in both hemispheres. Research has been spotty, however. Neuroscientists have just begun to seek funding for functional-imaging projects on depression, according to Gur, who reviews such grant applications for the National Institutes of Health. Depression's association with LH and RH, in fact, might vary from person to person. In the goggle study, 20 patients reported feeling better when exposed to right visual-field stimulation (activating LH), while 15 said their depression improved more with left visual-field stimulation (activating RH).2 Expressing skepticism about one-size-fits-all laterality rules, Pascual-Leone remarks, "As a group, one may be able to characterize dysfunctions as to one lateralization or another, but I don't think that that will hold at the individual level." THEORY INTO THERAPY When Pascual-Leone's subjects received left-sided TMS, the 20 who felt better wearing LH-activating goggles showed an average 42% plunge on a depression-rating scale. In comparison, the 15 subjects whose moods improved with RH-activating goggles exhibited only an 11% drop. A clinically significant decrease is 50%, explains Pascual-Leone, who recalls that the 20 subjects "were still depressed, but they were feeling a lot better." (The study's chief flaw: Subjects did not undergo right-sided TMS to test whether it would benefit the 15 subjects with putative RH abnormalities more than the 20 with possible LH problems.) Marcel Kinsbourne, a neurologist and a psychology professor at New School University in New York, is encouraged by the results. He says that about 30 years ago he introduced "the notion that raising or lowering the activation level of a territory in the cortex is a behavioral variable--something you can work with, make theories with, manipulate." But such theories do not translate easily into therapy. "The problems are kind of obvious," Kinsbourne acknowledges. "You can't just have people walking around with their heads stuck in one direction," as wearing taped-up goggles would require. Yet attempts to refine lateralized therapies remain scarce. Schiffer seems to be the only scientist conducting ongoing psychiatric studies of the modified spectacles, which he has patented. Moreover, no one apparently has followed up on a 1993 paper demonstrating that partially blocked contact lenses can produce lateralized activation.3 The lack of interest has several likely explanations. In psychiatry, says Gur, "there is a bit of a bias against looking at laterality as a major factor, whereas neurologists are very ready to accept that [view]." Neurologists, however, are not typically concerned with psychiatric problems, he adds. Kinsbourne argues that "psychiatrists are totally hung up on the [neurotransmitter] receptor sites" and on using better drugs, while psychologists merely want to do psychotherapy. Schiffer detects a temperamental divide, in which "neuroscientists are very uncomfortable with psychological questions and looking at things psychologically, while people who are psychologically minded are intimidated by waves and graphs and numbers." SHOCKS AND THEIR PROGENY If targeted physical intervention has a future in psychiatry, it probably will follow a trail blazed, oddly enough, by an old nonlateralized treatment: electroconvulsive therapy. ECT triggers therapeutic seizures throughout the brains of depressed patients, even when only one hemisphere--typically the right--is shocked to minimize language impairment and cognitive deficits. Harold A. Sackeim, a psychiatry and radiology professor at Columbia University College of Physicians and Surgeons, recalls a 40- to 50-year debate on the merits of unilateral versus bilateral ECT. Referring to a series of experiments in which he and colleagues jacked up current density in the brain, he says, "We now know that we can reliably make unilateral ECT work where it's as effective as bilateral." The key, he reveals, is to trigger seizures in the prefrontal regions of both hemispheres. Shock therapy's success has whetted researchers' appetites for treatments that are more focused, such as transcranial magnetic stimulation. TMS uses rapidly alternating magnetic fields to induce electrical currents and neurotransmitter release in the cerebral cortex. Commonly applied to one side, TMS boosts or lowers neural excitability, depending on the stimulation frequency. "You appear to get the same antidepressant benefit whether you increase the left [hemisphere] or decrease the right," notes Pascual-Leone. Magnetic stimulation is less effective than ECT in some patients and never more effective, he says. On the plus side, TMS prompts less collateral damage, because its site of action is only about a fingertip's volume. Pascual-Leone likens TMS to "trying to get a fly on a wall using a BB gun, versus using a bazooka with ECT." TMS nevertheless provokes immediate changes in homologous areas of the opposite hemisphere, according to Sackeim. He and a Columbia colleague, associate clinical psychiatry professor Sarah H. Lisanby, are developing magnetic seizure therapy.4 It uses souped-up TMS equipment to induce prefrontal seizures that are more focused and better controlled than those triggered by ECT. The effects are bilateral. Though Sackeim agrees that the brain's affective systems display lateralization, he contends: "It's one thing to put EEG electrodes on sad students and compare them to not-sad students, and find that the sad ones have less alpha [a brain wave signaling relaxed wakefulness] over the right frontal areas. But it doesn't tell you that you can go and modulate activity, person-by-person, with just a unilateral treatment." Douglas Steinberg (dougste@attglobal.net) is a freelance writer in New York City. References 1. F. Schiffer, Of Two Minds, New York: Free Press, 1998. 2. F. Schiffer et al., "Prediction of clinical response to transcranial magnetic stimulation for depression by baseline lateral visual-field stimulation," Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 15:18-27, March 2002. 3. S. E. Levick et al., "Asymmetrical visual deprivation: a technique to differentially influence lateral hemispheric function," Perceptual and Motor Skills, 76:1363-82, 1993. 4. S.H. Lisanby et al., "Magnetic seizure therapy of major depression," Archives of General Psychiatry, 58:303-5, 2001.

Can a Side of the Brain Determine Sick or Sane?

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Image: Courtesy of Alvaro Pascual-Leone
DEPRESSION AND CEREBRAL ACTIVITY: Cerebral blood flow determined by single-photon emission tomography was correlated with changes in clinical depression after patients received transcranial magnetic stimulation (TMS) to the left prefrontal cortex. In red areas, blood flow--signifying brain activity--was positively correlated with TMS's antidepressant effect; in green areas, blood flow was negatively correlated. (Reprinted with permission, Psychiatry Research Neuroimaging, 115:1-14, 2002.)