With the advent of noninvasive brain stimulation techniques, clinicians now have at their disposal easy, safe methods to modulate brain activity. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) use magnetic fields or electrical currents delivered from outside the brain to change neuronal excitation in the brain. But what are the best targets? What are the most promising indications? Where does neuromodulation give the biggest bang for the buck? Joan A. Camprodon, MD, PhD, director of the Division of Neuropsychiatry at Mass General and founding director of the Mass General Transcranial Magnetic Stimulation service, wants to figure that out. By integrating clinical and research efforts, Camprodon and his group are working to uncover the brain circuits that are altered in neuropsychiatric disease, and the best ways to deploy noninvasive neurostimulation to right them.

For starters, Camprodon says that the effective use of neuromodulation requires clinicians to transcend traditional clinical diagnostic boundaries when evaluating patients. Rather than treat by disease, the neuropsychiatry division focuses on clinical dimensions—the aspects of mood, behavior or cognitive function that are altered in neuropsychiatric disease. “Instead of just saying that a patient has depression, or schizophrenia, or stroke, or epilepsy, we focus on transdiagnostic problems such as maladaptive reward processing or amotivation, ineffective inhibitory control or impulsivity, dysexecutive effects such as poor planning or multitasking, et cetera,” he explains. Those clinical domains more closely correspond to brain circuits that may be amenable to neuromodulation.

Next, Camprodon’s group is letting an old, but effective treatment inform their new efforts. The first form of brain stimulation used in clinical practice, electroconvulsive therapy (ECT), still offers a viable approach to treatment-resistant major depressive disorder, mania, psychosis and catatonia, among others. ECT is quite effective—for some forms of depression, response rates range from 70 to 90 percent. While safe, the procedure does require general anesthesia, and comes with the potential for side effects that include transient memory loss. Despite its long history of use, just how ECT works is not clear. While the jolts cause brain-wide generalized seizure, recent thinking is that the electrical reset does not affect all brain circuits uniformly. Depression and schizophrenia respond to ECT, but not anxiety, OCD, or eating disorders. The adverse effects of ECT are quite specific too, affecting mainly memory and sparing other domains like executive function and language. In addition, some clinical domains, including anhedonia, amotivation, and suicidal behavior respond ECT no matter what disorder they occur with. “We think that there are specific circuits, such as those related to reward, that are particularly sensitive to the seizures, so that the ECT produces plastic changes in those, but not in other places, that support the therapy’s benefit. Now, if I can learn how ECT does its magic, then I could I could try to facilitate those same changes with TMS," Camprodon says.

To sort out the circuitry that’s affected by ECT, Camprodon’s group is using multimodal imaging to map brain connectomics. Studies involving structural MRI, functional MRI, and diffusion tractography noninvasively determine brain anatomy, function and connectivity. They also use EEG to look at patterns of neuronal activation in nodes and circuits.

So far, they’ve identified circuits that support the response to ECT for depression, and now are trying to look individually at dimensions like anhedonia, amotivation and suicide. “If we can learn first how to improve amotivation or anhedonia in depression, we could use these strategies to treat amotivation more globally in a number of neurologic and psychiatric disorders--in frontotemporal dementia, in Alzheimer’s disease, in patients with neural Lyme disease or multiple sclerosis,” Camprodon says.

One domain that Camprodon is especially interested in targeting is executive function, the brain circuit that supports organization, planning and mental focus. Problems with executive function occur across the spectrum of neurologic and psychiatric conditions, and are among the most disabling symptoms in many conditions. There are no good treatments to improve cognition, says Camprodon, but the anatomy of the circuits that support good executive function is known. In a transdiagnostic study, his group is evaluating TDCS to treat executive dysfunction in patients with traumatic brain injury, frontotemporal dementia, ADHD, schizophrenia, depression and bipolar disorder.

If Camprodon’s work seems to blur the borders between neurology and psychiatry, that’s by design, he says. “We’ve moved from a traditional description of neuropsychiatry as a subspecialty for patients with neurological disorders who presented with psychiatric symptoms. We still do that, but now we use a broader definition. It’s not just who we see, but how we see them—with a circuit-centered approach to evaluating and treating each patient, no matter their diagnosis.”