From BBRF's Brain & Behavior Magazine - July 2019 Issue

Progress in research usually doesn’t follow a straight-line path. But if you chart the advances in schizophrenia research made by Gregory A. Light, Ph.D. since he received his first BBRF grant—a Young Investigator Award in 2003—you can clearly see the line leading from his first working hypothesis at the start of his career to its recent successful application in the clinic.

Dr. Light studies how cognition may be improved in patients with schizophrenia by looking at brain activity patterns through electroencephalography (EEG). By delving deep into understanding how electrical waves measured by EEG are linked to cognition, Dr. Light’s laboratory hopes to enhance recovery in patients with schizophrenia.

Schizophrenia is an illness marked by a variety of symptoms: hallucinations and delusions, apathy, limited emotional expressivity, and difficulty in daily functioning. Many patients also experience cognitive difficulties affecting memory, attention, and planning. Although hallucinations can be helped with antipsychotic medications, cognitive impairment is difficult to treat and make it challenging for many patients to interact with others, hold a job, and enjoy a high quality of life.

In the past year, Dr. Light and his team at the University of California, San Diego and the Mental Illness Research Education and Clinical Center at the VA San Diego Healthcare System, have made notable strides toward their goal of helping patients recover. In a paper appearing in Schizophrenia Research in July 2018, they reported the effectiveness of a method of cognitive remediation called TCT (targeted cognitive training). The study involved 46 participants living with chronic, severe schizophrenia who were receiving state-mandated care in a locked facility 30 miles east of San Diego.

It was “a real-world test” of the methods Dr. Light has been working to develop since he received that early vote of support from BBRF—which was followed by another Young Investigator grant in 2006 and an Independent Investigator award in 2013. In 2014, Dr. Light was honored with the BBRF’s Baer Prize for Innovative and Promising Schizophrenia Research.

“For too long, it has been thought that the neural systems in schizophrenia are fixed, that they can’t be modified—and that the best one can hope for is to manage psychotic symptoms,” he says. “But now we’re learning that cognition itself is remediable and that recovery is a possibility.”

‘PEOPLE WHO NEED HELP THE MOST’

Although a great deal of pathbreaking schizophrenia research has focused on uncovering its roots in genetic variations, Dr. Light’s experience as a student and young scientist led him in another direction. He was determined to find a way of helping “the people who need help the most, those who have established illness, who have been ill for years, who are chronically receiving antipsychotic medications, and are spending their days in locked long-term facilities or board-and-care facilities where too often they don’t receive quality rehabilitative care.”

As an undergraduate in the 1990s, Dr. Light was given the task of helping to assess patients in the 12-story Rochester Psychiatric Center, a facility that was “de-institutionalizing”—releasing its patients to the community. “A long treelined drive led to this building with locked double doors. I remember thinking, ‘This is a pretty serious place,’ figuring they must be delivering round-the-clock care and providing the best intensive services available.”

That is not what he found. “Patients had been there for longer than two of my own lifetimes at that point, since the facility opened in the 1950s.” They had been cared for in the custodial sense, but were not receiving systematic rehabilitation. Since there were no electronic medical records available, Dr. Light’s early work at this facility was focused on interviewing patients to determine their diagnoses and making ratings of their symptoms. “I was surprised that people with schizophrenia who shared the same diagnosis seemed so different from one another. How could these different combinations of symptoms be the same illness? And why couldn’t we do more to help these people beyond housing them for the majority of their lives?”

Yet there was one symptom that he saw in almost all patients. “At some point over the course of the illness they all had experienced auditory hallucinations.” This launched his interest in auditory neuroscience, and led him to seek out mentors who were starting to use advanced technology to dissect what was happening in the brain’s auditory system.

When he moved to San Diego for his graduate and postdoctoral training, Dr. Light joined Drs. David Braff and Neal Swerdlow, who were using EEG and other neuroscience tools to find “core physiologic measures that might be linked to the underlying biology of schizophrenia.” Both, among other honors, have been BBRF Distinguished Investigators, Dr. Braff in 2007 and Dr. Swerdlow in 2016.

They had a theory that the disabling deficits in cognitive function seen in people with schizophrenia are caused, at least in part, by problems receiving or analyzing signals that enter the brain through the senses. Perhaps the brain’s auditory and frontal cortices, for instance, were not processing sounds properly.

Whatever the reasons for cognitive deficiencies, the results were evident to all who worked with patients: most were isolated from other people, often profoundly—a painful if infrequently discussed aspect of living with schizophrenia

AUDITORY MARKERS

In early papers focused on the auditory neuroscience of schizophrenia, Dr. Light speculated that “maybe someday” work on auditory system dysfunction “would contribute to treatments or preventative strategies.” Then he read a paper by Dr. Sophia Vinogradov, whose 2000 BBRF Independent Investigator grant had supported research on using computers to train schizophrenia patients to improve their results on cognitive tests.

With his first BBRF grant, Dr. Light discovered that schizophrenia patients had reduced MMN responses— the “oddball” tones were heard, but the brain responses to those tones were not well differentiated from responses to the other tones.

This research also produced a big surprise: those patients with the lowest scores in the MMN test had the greatest impairments in social functioning. This was a great “aha!” moment in Dr. Light’s research—a discovery that led the federal government to extend robust career support grants to his lab beginning in 2007 and continuing through the present.

“Many now believe that MMN is a breakthrough biomarker for predicting and monitoring response to many treatments for neuropsychiatric disorders,” says Dr. Light. “And it was my first BBRF Young Investigator Award that made possible identifying the robust correlation of mismatch negativity with daily psychosocial and cognitive functioning, which we first reported in 2005. Without hyperbole, I can say that I would not have the career I’ve had if it wasn’t for BBRF—its attention to investigators who are just starting out or at transition points in their careers and in real need of support for innovative ideas.”

Beyond the financial assistance he received, Dr. Light says part of the BBRF boost came in the form of validation, for there was plenty of resistance within the scientific community, early on, to his suggestion that MMN measurements could be used to predict how well people could function socially.

PREDICTING WHO WILL BENEFIT

His second Young Investigator award in 2007 and concurrent federal funding enabled Dr. Light to replicate his earlier results and to test the concept that MMN could predict which patients stood to benefit from cognitive training. He would test this concept in a variety of clinical settings.

In the most recent test, in the facility outside San Diego where he tested TCT in medicated patients with longstanding, chronic illness, not only did TCT provide a real, measurable benefit to two-thirds of these patients in the form of improved results on cognitive tests. The research also demonstrated that MMN measured after the very first hour of training accurately predicted which patients were going to benefit from the full 4-week program. This was confirmed once the training course was completed.

Dr. Light and colleagues still are not sure why some respond to TCT and others do not, but they speculate that MMN and possibly other measures of brain activity (one is called auditory steady-state response) are able to show which patients have sufficient plasticity in their neural circuitry to benefit from this particular type of training—which, in essence, is a form of learning.

Plasticity refers to the ability of neurons to adjust the strength of their connections. Neuroscientists have long understood that such adjustments are part of the mechanical basis of memory and learning.

TCT, the training method recently used by Dr. Light, is itself not revolutionary, he says. His team used a commercially available “brain-training” software program that worked perfectly well. Other programs might also work well, he says. In TCT, auditory exercises are delivered to each patient for 3 to 5 hours weekly, via computer. The patient is asked to make progressively finer discriminations of sounds, beginning with comparatively easy discriminations and steadily moving to harder choices—but only after correct answers have been delivered. “If they get it right, it gets harder; if they make a mistake they go back to where they were challenged. They are constantly being pressed up against their ability level.”

What makes TCT potentially valuable is how it or a similar training method is actually delivered in the clinic. It won’t work, says Dr. Light, to give it to every patient, since about one in three do not stand to benefit, at least from TCT. Some patients may not understand the tasks or cannot concentrate well enough to tolerate the exercises. But patients who can benefit need to be motivated and guided through the training process as it plays out over a period of weeks. “It’s not going to work well in isolation. It has to be delivered by the right people to the people who are most likely to benefit,” says Dr. Light. Ongoing encouragement is needed to maintain the intensity of the training. “It appears the training also needs to be delivered in conjunction with other rehabilitative services for an individual to maximally benefit. It is probably not sufficient to send out laptops to an isolated environment and hope that people will do the exercises on their own.”

It’s not yet known how long the benefits of cognitive training last, although one paper from Dr. Vinogradov’s team showed that gains were still in place 18 months after training concluded. Dr. Light hopes to study the durability of gains in future research. For now, he is encouraged that the chronic, long-medicated patients who derived benefit from TCT in his most recently reported trial also showed a reduction in the severity of their auditory hallucinations and participated in significantly more of the other psycho-social groups and activities offered at their care facility. He speculates that this may be due to their being encouraged while receiving testing, or in noticing their own progress, which may have led them to be willing to try other activities.

This brings the subject of cognitive remediation back to a question long recognized among those who focus on the long-term care of people with schizophrenia. “The problem in scaling up TCT or similar training is much bigger than the intervention itself,” says Dr. Light. “It is more a question of overall care. We need to deliver high-quality, high-intensity care to the patients who need it the most—and right now, we are not doing that for enough people with an established schizophrenia diagnosis.”

Despite this, Dr. Light is very hopeful. In the years since his first BBRF grant, he has learned the value of an approach to helping people with schizophrenia that, in his words, “doesn’t try to fix what’s broken, but instead tries to take what is there and work with it. You work with what you have, and go for improvements. It’s a recovery-oriented approach, and I think it can help a great number of patients, as we learn more, and our methods for delivering and predicting future response to treatments improve.”

— Written By Peter Tarr

Click here to read the Brain & Behavior Magazine's July 2019 issue