Fine-Tuning the Circuitry in the Brain and Intervening Early On: Exciting Next-Generation Treatment Possibilities

Kafui Dzirasa, M.D., Ph.D. - Brain and behavior research expert on schizophrenia
Kafui Dzirasa, M.D., Ph.D.

From The Quarterly, Winter 2014

This is a time of great insight and creativity in brain and behavior research. With the invention of innovative technologies in genetics and brain imaging, new understanding about the brain’s functioning and circuitry is now possible. These developments, along with studies offering a better understanding of the course of mental illnesses in different subsets of patients, are opening possibilities for a new generation of treatments.

Interestingly, many treatment approaches now coming of age are not pharmacological therapies. Some innovative investigators are studying treatments that share the objective of literally “putting energy back into the brain.” That is how Kafui Dzirasa, M.D., Ph.D., winner of the Foundation’s 2013 Sidney R. Baer, Jr. Prize for Innovative and Promising Schizophrenia Research, characterizes his work to repair malfunctioning brain circuits by using focused magnetic fields. Paolo Cassano, M.D., Ph.D., 2012 NARSAD Young Investigator Grantee, is using light waves to treat people with depression.

Dr. Dzirasa says he and his colleagues at the Laboratory for Psychiatric Neuroengineering at Duke University are trying to “understand the brain’s language,” which he likens to music. “We’re trying to learn the timing and frequency of this music,” he says.

Taken together, all the billions of neurons in the brain and the countless circuits they form have an electrical output that Dr. Dzirasa compares to the sound of a symphony orchestra “if all the instruments were told to play notes without a score, at the same time.” To make music, a real orchestra’s instruments have to sound at particular moments in time, for specific durations and at specific pitches and levels of intensity. “If all the instruments play without pattern, you lose the music,” he points out.

Dr. Dzirasa learns the patterns that form the brain’s “musical line” by making electrical recordings in the mouse brain. He and his colleagues record more than a dozen brain areas simultaneously. The resulting data provide a baseline in healthy animals with which to compare patterns from the same areas in mice that have been genetically engineered to model a mental illness such as schizophrenia.

“Schizophrenia is an illness that involves problems in communication, not in a single area but between different brain regions. We’re looking to create a kind of codex, or a Rosetta Stone, that will enable us to relate changes in the functioning of illness related genes to places in the brain where problems in communication are occurring,” Dr. Dzirasa explains. He aims to develop “neural prosthetics”––electrical devices that act something like pacemakers in the heart, “putting energy back into the brain”—to fix gaps in communication.

The idea of using pacemakers to aid broken brain circuits is not far-fetched. Other methods already in use have demonstrated the principle of applying electromagnetic energy to the brain to achieve therapeutic results. Some apply this energy from outside the body. Transcranial magnetic stimulation (TMS) is one such method, developed in the last decade by Dr. Mark George with NARSAD Grant support. It uses focused magnetic fields to therapeutically change electrical properties in particular brain regions. A non-invasive technique, it does not induce seizures, and in this respect is unlike a much older treatment called electroconvulsive therapy, or ECT. TMS has proven effective in some people with treatment-resistant depression and was approved by the FDA in 2008.

Deep brain stimulation (DBS), pioneered by Foundation Scientific Council Member Helen Mayberg, M.D., applies electrical energy, via a pacemaker-type device, to a very small area in the brain to treat patients with depression who have not responded to other treatments. It remains experimental and is an invasive approach, requiring surgery, but the results are promising for those patients without other treatment options.

At Massachusetts General Hospital, Dr. Cassano uses a kind of laser light, noninvasively, to treat people with depression. Light therapy has been used for many years to treat people with seasonal- affective disorder. The light employed in such treatments is “white light” from the visible part of the spectrum. Dr. Cassano uses a special kind of light called nearinfrared, generated by lasers. Patients who receive the therapy, which is carefully focused toward two brain areas, must wear protective glasses during treatment. This treatment has proved to be safe and effective in experimental treatments of more than 400 people who have had a stroke.

Dr. Cassano explains that the depressed brain has an abnormal metabolism: PET imaging studies have shown that energy levels are abnormally low. A technique called magnetic resonance spectroscopy has also demonstrated that when depressed people recover, they have elevated levels of a molecule called NTP (nucleoside triphosphate), which helps cells produce energy.

Near-infrared light produced by the lasers Dr. Cassano uses penetrates the skin and bodily tissues, and their energy is absorbed inside cells by tiny structures called mitochondria. This additional energy, he theorizes, supplements glucose, brain cells’ main source of energy, to yield antidepressant results in many patients. Nearinfrared light also has been found to increase levels of BDNF (brain-derived neurotrophic factor) proteins, which spur the birth of new nerve cells and enhance the formation of synapses (connections between neurons).

“Depressed patients we have tested with near-infrared light maintain a better mood over time, have quicker reaction times, and retrieve memories more rapidly,” Dr. Cassano says.

Boris Birmaher, M.D., of the University of Pittsburgh, winner of the Foundation’s 2013 Colvin Prize for Outstanding Achievement in Mood Disorders Research, has focused his efforts on children with early signs of bipolar disorder (BP) and finding ways to delay the arrival of the full-blown illness.

After spending many years observing children, adolescents and young adults with BP, he has learned that it is very difficult to diagnose the illness in small children. As Dr. Birmaher points out, some of its hallmarks, such as “euphoria” and “irritability,” are concepts that don’t mean anything to small children; unlike adults with BP, they are unable to report such symptoms.

Even when a diagnosis is made, treatment is especially challenging. Medications commonly used to manage the manic highs and frightening lows of adults with BP are powerful, have side effects, and are therefore problematic to use in the youngest patients––children who may be only six, seven, or eight years old.

Dr. Birmaher’s novel approach to the problem emerged from a commitment he and colleagues at the University of Pittsburgh, University of California, Los Angeles, and Brown University made to closely follow a large group of children diagnosed with BP. The researchers were able to follow 367 children for at least four years after they enrolled in the study. Dr. Birmaher’s insights about treatment emerged gradually, as the data from the study group trickled in over a decade.

Unlike most studies that focus on adults with BP, the scientists focused, not on the most ill children, but rather on those who fared the best. In fact, about 45 percent of the 367 children in the study were found, after four years, to be “doing well, or relatively well, at least in terms of their bipolar symptoms,” Dr. Birmaher says. Some of the children did have difficulties with other aspects of their functioning, but their BP was notably absent.

“The fact that nearly half the kids with BP were doing well is good news for families of kids who have bipolar,” he says. “It is often assumed, from studies in adults, that bipolar disorder is ‘forever’––once you have it, you will always have it. But based on our observations, this is not necessarily so.”

Compared to those who fared poorly, children who were relatively symptom-free after four years had a later age-of-onset of illness; when symptomatic, the relatively symptom-free group experienced depressions that were less severe and manic phases that were less pronounced. They also had fewer suicidal thoughts, less history of sexual abuse, more stable families, and tended to come from the middle or upper classes.

The most important implications for treatment, says Dr. Birmaher, is that all efforts must be made to delay onset of the illness. “If we can delay onset, say, from age 10 or 12 to age 18 or 20, we will be giving children and their brains the chance to mature physically, emotionally, cognitively and socially.” To some degree, being more developed in these ways appears to be protective and predictive of a better outcome.

How to delay the onset of BP is not clear-cut. Dr. Birmaher points to things we do know how to do: involve symptomatic children as early as possible in psychotherapy and give them medications where indicated. Efforts also must be made to treat family pathology, especially ongoing family discord and sexual abuse. Substance abuse or untreated attention-deficit hyperactivity disorder, in addition to chronic family dysfunction, can cause chronic stress and destabilize a vulnerable child’s mood. Whenever possible, these issues must be addressed.

Dr. Birmaher is encouraged by the research findings. Even in young children who will go on to develop BP, he says, simply delaying the arrival of the full-blown illness seems to make it much more likely that as young adults they will be among the 45 percent who appear either to recover within a few years, or enjoy a long remission that could last many years.