PROVIDENCE – Last week, Butler Hospital was awarded a $12 million, five year federal grant to create a new Center of Biomedical Research Excellence, or COBRE, in Rhode Island, focused on neuromodulation techniques.

The initial goal of the COBRE will be to expand the research infrastructure for clinical applications of non-invasive brain stimulation, targeting disorders of the brain and behavior, including depression, post-traumatic stress disorder, and obsessive-compulsive disorder.

The new COBRE will be working on three specific early-stage research studies, what Dr. Benjamin Greenberg, the principal investigator, described as the necessary first step in designing full-scale clinical trials.

More specifically, the new COBRE will focus on two techniques of non-invasive brain stimulation, what is known as transcranial electrical stimulation, or TES, and transcranial magnetic stimulation, or TMS, according to Greenberg, who is a professor of Psychiatry and Human Behavior at the Alpert Medical School of Brown University, director of the COBRE Center for Neuromodulation at Butler Hospital, and associate director of the Center for Neurorestoration and Neurotechnology at the Providence VA Medical Center.

What follows is an in-depth interview with Greenberg by ConvergenceRI, a deep dive to understand how neuromodulation is changing the paradigm for treatment of behavioral disorders, focused on non-invasive brain stimulation techniques and measuring changes in brain activity through brain imaging, with Rhode Island poised to be a cutting-edge innovator.

GREENBERG: How would you like to do this?

ConvergenceRI: It’s very simple. I will ask you some questions and you can answer them.
GREENBERG: By the way, I found the story about BrainWeek RI, covering Dr. Amy Cameron’s and Dr. Mascha van’t Wout-Frank’s presentations in last week’s ConvergenceRI, to be very good. I thought the writer did a good job. [See link below to ConvergenceRI story, “Crime, punishment and compassion as pathways in the brain.”]

ConvergenceRI: How would you define neuromodulation?
GREENBERG: In this context, we’re talking about non-invasive neuromodulation. Which is using methods that cross the scalp and the skull to change brain activity, or change the likelihood that particular brain regions or networks will be more or less active.

The methods that are going to be used in this COBRE center are transcranial electrical stimulation, and transcranial magnetic stimulation.

ConvergenceRI: In the news release it says that you are going to expand the clinical and research applications for these techniques targeting brain and behavioral disorders. What in particular are the brain and behavior disorders that you are targeting?
GREENBERG: Before we get to that, let me just say that the context ifor transcranial magnetic stimulation is that it is an approved treatment for major depression that doesn’t respond well to medication or behavioral therapies.

It has been approved for more than 10 years and is very active [as a therapy]. There may be as many as a thousand places in the U.S. where you can get this [treatment] now.

There are active programs at Butler Hospital as well as at the Providence VA where the treatment is offered.

The treatment has gone from development to implementation on a wide scale.

ConvergenceRI: How is what you have described different from what used to happen in what was called electro-shock therapy?
GREENBERG: No, it’s not ECT, or electric convulsive therapy.

ECT still goes on, but it is used in a much different way than it was in the past. But the [non-invasive brain stimulation in neuromodulation] is different.

ECT is intended to produce a seizure to produce a therapeutic effect in depression and in some other conditions.

This is different. This is non-convulsive. What happens with TMS is that a strong pulsing magnetic field creates electric currents in the brain. The skull and the scalp are transparent to magnetism, so you can actually affect brain activity by putting one of these powerful electromagnets on the head.

The idea is not to produce a seizure. In fact, when patients get these treatments, they are sitting in a chair, listening to music, sometimes they are reading, and they are getting their brain stimulated with magnetic pulses that turn into electrical activity in the brain itself and affect brain circuitry. But it doesn’t affect a level of consciousness.

It is a very different thing from ECT; it is a common point of confusion, so you are right to bring it up.

ConvergenceRI: What are the targeted behaviors?
GREENBERG: This COBRE center is designed to build a research infrastructure for clinically relevant neuromodulation research in Rhode Island.

The way it works is that the COBRE center is built around projects that are led by promising junior investigators; we have three of them, their projects are intended to address different clinical questions.

In the first research project, what’s being studied is how electrical stimulation affects brain activity and behavior for young adults who may have what’s called “poor executive function.”

In other words, they may be somewhat more prone to being impulsive, and making poor decisions. The study will employ electric stimulation that is called TDCS, or transcranial direct current stimulation, plus an MRI, to actually gauge how brain activity is changing.

ConvergenceRI: Can you explain the connection to clinical conditions?
GREENBERG: The first project results could be applied to lots of different clinical conditions, where control of behavior, and in particular, inhibiting behaviors, might not be good.

That could include anything from attention deficit disorder, to certain kinds of other behavioral problems, to obsessive-compulsive disorder.

The research is designed not to look at a particular diagnosis but at a behavioral feature of a lot of different diagnoses.

ConvergenceRI: What is the second research project?
GREENBERG: The second project is relevant primarily, but not exclusively, to PTSD, or post-traumatic stress disorder.

So, in PTSD, what happens is that there is inappropriate fear expression.

You wind up, as a result of traumatic experience, expressing a great deal of fear and anxiety in all sorts of other settings that are not dangerous.

And that can be incredibly impairing, and that is, of course, particularly important to the work here at the Providence VA and the Center for Neurorestoration and Neurotechnology, or CFNN, which I am the co-director of.

The second research study will also use transcranial electric stimulation, or TDCS, and MRI, to look at how people change as they undergo training and the results in their being anxious when they are presented with certain pictures on a screen, and how they learn that those stimuli, those pictures, are actually safe.

It’s [training in] safety learning and safety memory.

The reason why that is important is because we want to enhance safety learning in people with PTSD.

It’s thought that the problem in PTSD is not necessarily unlearning the particular situations which are actually safe but appear to dangerous to the individual; instead, it is about having a separate kind of learning that is on top of the original learning, that counteracts it, recognizing that these situations might, in fact, be safe.

And that’s what clinical therapy for PTSD does. The therapies fall under the general term, exposure-based therapy, where people are exposed gradually to situations they fear.

It could be a crowded place; it could be an environment where someone has difficulty scanning around and seeing everything around them.

Normally, in clinical care in psychotherapy for PTSD, people are gradually exposed to the kinds of situations [they fear], and they can learn that they’re safe.

The hope is that this kind of mild electric stimulation can make that learning happen faster and can enhance the memory for the learning [to take place].

The second research project is intended to try and figure out the optimal timing of when to do the brain stimulation in comparison to this “extinction” learning, which is what we believe is happening when people undergo these exposure-based therapies.

These are all questions that haven’t been answered yet by other researchers.

ConvergenceRI: And the third research study?
GREENBERG: The third project is [focused on] obsessive compulsive disorder, where we have treatments that are effective in general in medications and again in behavior therapy, which is exposure therapy, similar to what is being done in treating PTSD.

But the treatments don’t work for everybody, and they don’t work well enough for some people, even if they work a little bit, or even moderately.

The third research project is trying to see whether brain stimulation, using TMS, transcranial magnetic stimulation, over a part of the brain that hasn’t been studied in obsessive compulsive disorder, might be helpful in changing the brain circuits that we think are involved in OCD.

All of these projects are early-stage studies designed to get information about how we might be able to use these different brain stimulation methods to address these clinical problems.

Each is really a first step; they are not intended yet to lead to a full-scale clinical trial to test whether therapies based on any of these techniques are going to work in a larger clinical population. But they are essential first steps in order to design those clinical trials that would happen later on.

ConvergenceRI: Clearly, brain imaging is involved in all the work.
GREENBERG: Yes, every one of these projects uses MRI. The MRIs will be done at the Brown University MRI research facility.

ConvergencRI: Five or six years ago, Tom Insel, then the head of NIMH, gave a lecture at Butler Hospital suggesting that there was a need to change DSM 5 to reflect the nature of changing diagnoses with advances in brain imaging.
GREENBERG: The idea is not a new idea, you can have diagnoses that are defined by a particular collection of symptoms; you may have varying impairing obsessions and compulsions that may indicate you have OCD. You may have an inability to focus on things and to keep attention focused so that you are able to complete a task; that could be ADHD.

Those are categorical diagnoses; each is a separate category of things.

What Tom Insel was talking about was diagnosing things along dimensions.

People vary in terms of behavior; most people are kind of in the middle of these behavioral dimensions, but some people are on the extremes.

There are some complementary ways of viewing the kinds of psychiatric problems that people will have. We tend to call them neuropsychiatric [problems] because they often involve the brain.

You can think of them as a diagnosis that falls into a category that you give a label to. Or, you can think of them at the same time as something that relates to people falling along different points on this spectrum of variability in behavior.

These research projects that we are talking about have that aspect, where things can be thought of as dimensional, as well as these categories of diseases. You’re exactly right.

ConvergenceRI: Does this suggest, to make a leap, that addiction use disorders might be treated as dimensional disorder of the brain?
GEENBERG: I don’t know if we want to get into the weeds here, but addiction certainly has characteristics of a dimensional problem; it also tends to have characteristic symptoms that you could think of as a diagnosis.

But there’s another way to think of it, too – as a disorder of motivated behavior. We have systems in our brains that affect motivation to eat, to drink, to sleep, to reproduce – in other words, to pursue pleasurable activities. Those systems get hijacked in addiction.

ConvergenceRI: How does your work change the paradigm for treatment of behavioral disorders?
GREENBERG: TMS is now an approved treatment, which is increasingly widely spread across the country and being rolled out in the VA system.

Up until recently, it was only approved for major depression, or depression in general.

One manufacturer has recently gotten approval to do a particular kind of TMS involving what we call symptom provocation, exposure to symptom-triggering material for OCD.

The question is: can we use these neuromodulation methods as therapies, either with a behavioral intervention, or not, for other conditions.

We are hoping that we will find promising approaches to these clinical conditions and potentially others, by following the general path of using brain stimulation in carefully characterized clinically relevant populations, and then trying to understand its mechanisms of action by using MRI.

ConvergenceRI: Previously I have reported on neuroscience research on toxic stress and in particular, the research that Dr. Audrey Tyrka has done.
GREENBERG: She’s actually involved in this COBRE center.

ConvergenceRI: Tyrka had been looking at epigenetic changes as a result of toxic stress, and the shortening of the telomere as a result.
GREENBERG: Yes, that’s one of the thoughts about how toxic stress might be bad for you.

ConvergenceRI: Her research, along with other neuroscience research on toxic stress, seems to indicate that such stress in infants causes changes in the signaling patterns in the brain, which, when confronted with stressful situations as a child or an adult, can cause surges in cortisol flooding the brain’s circuitry, altering synaptic patterns. Is that the kind of research project that might be undertaken by the new COBRE, looking at how non-invasive brain stimulation, similar to the work with PTSD, might identify exposure therapies to overcome such cortisol surges?
GREENBERG: The center just started this month, so there will be a number, we hope, of promising proposals that will be submitted to us by junior level investigators. They will need to be involved in neuromodulation.