Rob Malenka, M.D., PH.D.

Professor of Psychiatry, 
Stanford University

The goal of FFOR

The goal of FFOR is to develop a “functional” cure for the most severe, treatment-resistant forms of OCD by deepening our knowledge of the biological origins of the disease including how pathological brain circuit activity mediates OCD symptoms.      

My Passion

I am both a cellular neuroscientist running a laboratory and a psychiatrist with a passion for using cutting edge methodologies to advance understanding of the causes of mental illnesses. OCD is ready to be “attacked” by rigorous, creative, and sophisticated scientists with the motivation to make a difference in the lives of those living with OCD. 

It’s all about the circuits.

Everything the brain does—the ability to see, hear, think, feel and act—is mediated by specific brain circuits; populations of neurons talking to one another in complex ways. There’s evidence that OCD involves dysfunction in specific brain circuits. If we can understand those pathological circuits in a deeper, more sophisticated manner, it will allow us to develop treatments that reverse that pathological circuit activity, which would reduce or eliminate the prominent symptoms of OCD.

A Bold Approach

FFOR’s approach is to create a highly interdisciplinary collaborative effort that brings together scientists with expertise in different disciplines—genetics, neuroscience, neurosurgery and psychiatry—and to provide the incentives and infrastructure for these investigators to share their ideas, and, importantly, share their findings as they come in. FFOR’s Hope is that by breaking down the barriers that discourage collaborative, inter-disciplinary research, we will accelerate progress in understanding the genetic and circuit causes of OCD and thereby be able to develop more effective, individualized treatments and eventually a cure.

Susanne Ahmari, M.D., Ph.D.

Associate Professor of Psychiatry, University of Pittsburgh

OCD is a complex Disease

I think one of the most crucial, understudied areas in OCD is the intersection between anxiety, compulsive behaviors, and obsessions. What is it about the circuits that underlie anxiety and the circuits that underlie compulsive behaviors that interact to drive obsessions and compulsions?

Understanding the root cause

I want to attack the underlying sources that cause OCD. If you think about the people who struggle with OCD and what they have in common, it’s not a specific behavior (like hand washing or checking), nor is it a specific trigger. What they share is difficulty with one or more of the following issues: excessive initiation 
of repetitive tasks, excessive reinforcement of a task, and the inability to terminate a task.

From molecules to circuits

My lab is focused on identifying molecular, cellular, and circuit mechanisms that underlie abnormal repetitive thoughts and behaviors. I feel like this is what I’ve been training for all my scientific life—to try and make these bridges between the clinic and basic neuroscience.

A new way to work

The advantage of the FFOR model for active sharing across projects while working in parallel allows us to move quickly and not waste time—we regularly share the things that work and the things that fail, because both are valuable. There’s so much time wasted in science because of the lack of communication and sharing, yet, it’s essential for progress. If you want to accelerate discovery, you have to figure out how to fast fail.

Suzanne Haber, Ph.D.

Principal Investigator, Haber Lab, University of Rochester

My focus is circuits

My background and interests have always been in the circuitry of the brain. In particular, the parts that mediate things like reward, punishment, aversive behaviors, positive behaviors, and cognitive behaviors—
all of the elements that go into 
decision-making.

Circuits control everything

When a person or an organism makes a good decision or a bad decision, it's usually based on some sort of sensory input, some information processing, and a motor output onto the world. My expertise is focused not on the two ends of sensory input or motor output, but on the processing that happens between the two. I’ve spent my entire career exploring what I call the ‘hard wiring’ in the brain. How is the brain connected? What are these connections and how are they organized? Which part of this part 
of the cortex talks to which part of 
that part of cortex?

circuit dysfunctions and OCD

For many psychiatric disorders, it is now generally believed that there is a disruption in a distributed network of some kind—that there is a circuit dysfunction. What this means for OCD is that we’re moving away from thinking that there is a “sweet spot” in the brain, a little piece of real estate that is abnormal. We’re now thinking more along the lines that it’s the communication between a number of different regions that, together, are modulating a particular behavior.

FFOR and the future of OCD

FFOR’s mission is to change the world of OCD, and they’re doing that through multiple projects running in parallel, each of them coming at the concept of circuitry from a different place, to ultimately locate abnormalities. They’re embracing out-of-the-box ideas and throwing everything at developing a therapy for treatment-resistant OCD, and that’s exciting.

CONOR LISTON, M.D., Ph.D.

Associate Professor of Psychiatry,
Weill Cornell Medicine

My life in the clinic and the lab

I’ve always had an interest in OCD. I’m a neuroscientist and clinically-active psychiatrist, and I treat people suffering from treatment-resistant depression, and others with OCD as well. Much of my research is on the biology of depression—understanding what goes wrong in the brains of people who are depressed, designing better approaches for diagnosing subtypes of depression, and developing new treatments. Our goal is to take some of the approaches we’ve been using in depression and test whether they can be applied to OCD to help us develop better therapies.

I focus on treatment-resistant OCD

There are lots of ways to help people with OCD today, but they don’t work for everybody. Also, the trial and error approach to treatment can take a long time and be very frustrating when a treatment doesn’t work. It would be amazing if we had biomarkers, things we can measure physically, whether it be the blood or brain scans or some other measure, that would tell us something about which patients are most likely to respond to particular treatments so we could predict that in advance. That’s one of the things we’ve been really focused on in depression, using brain scans to discover biological subtypes of depression and using them to predict who will respond to particular treatments. We want to do this for OCD, and that’s where Transcranial Magnetic Stimulation (TMS) comes in—mapping which specific connections are abnormal in which specific individuals might be useful in targeting and tailoring TMS treatments.

When we map the circuits, We map the disease

Ultimately, we’re not just interested in using the scans to map connections in the brain of OCD patients—we’re also using them to discover subtypes of OCD that are defined by different kinds of 
abnormal connections.

Matthew State, M.d., Ph.D.

Chair of Psychiatry and Behavioral Sciences, UCSF, National Academy of Medicine

My background

I specialize in childhood 
onset neuro-developmental disorders, 
both as a child psychiatrist and a 
molecular geneticist.

tourette’s, autism, and OCD

My lab has worked for a long time on the genetics of Tourette’s syndrome (which is closely related to OCD), but our most dramatic success is in the area of Autism Spectrum Disorder (ASD). We’re still a long way from being able to design treatments for neuro-developmental disorders that have autism as a core feature, but if you look at how genetics has changed our understanding over the last 10 years, we can tell you a lot more about the basic molecular cellular processes that are going wrong.

From genetics to brain circuits to human behavior

We want to understand why someone has OCD at the molecular, cellular, and circuit level, and genetics is the route to help us do exactly that. It allows us to sort through and find the change in the genome that tells us why one person is very high risk for OCD and the next person is not. While we have a general idea that the cortical-striatal-thalamic circuits are involved in understanding OCD, genetic insights would help us fill the huge gap of information the field is still lacking.

DNA blueprint for OCD

DNA is one of many ways to understand a biological disorder. It’s the blueprint for biological processes, and is found in every cell of the body. When trying to understand why some people get a disorder and others don’t, we’re not interested in the 99% of genes that make us similar—we’re looking for the 1% that differs.

A future library of OCD molecules

Our hope is to give the other scientists in this collaboration (and, ultimately, scientists around the world) a library of molecular clues that we derive through genetics to say, “Yes, this individual change in this individual gene has a large effect in causing obsessive-compulsive disorder. We know that when this changes, it leads to OCD.”

NOLAN WILLIAMS, M.D.

Assistant Professor of Psychiatry and Behavioral Sciences, Stanford University Medical Center

I work with the most severe cases of depression and OCD

I’m a psychiatrist and neurologist and I specialize in focal neuromodulation, or targeted “brain stimulation,” in which we deliver electrical signals to a single circuit network in the brain in order to bring relief to people who suffer from neurological disorders like depression, epilepsy, and Parkinson’s. In the case of OCD, we use transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) to isolate and tamp down the overactive circuits that are tied to compulsive behaviors. By “muting” or controlling the repetitive obsessive thought that leads to compulsive behaviors, we empower people with OCD to be in control of their actions and their life.

Understanding the limits of tms + dbs

While TMS and DBS have been proven effective on OCD—especially for those whose symptoms are treatment-resistant—they each have their drawbacks. TMS, a treatment where electrical current is transmitted through coils that are placed strategically on the scalp, involves multiple out-patient visits over several weeks or months before there is any sustained effect. DBS, a treatment where electrodes are surgically implanted under the skull and a pacemaker-like device is implanted under the skin to provide ongoing relief, is highly effective, yet invasive and costly.

Scaling a better form of neuromodulation

Our goal is to deliver a modified TMS treatment, but with the sustained effect of DBS. To do that, we’re applying what we’ve learned from repetitive transcranial magnetic stimulation (rTMS), a technique we’ve used to achieve remission-like results for depression, to the treatment targets, dose levels, and frequency for people with treatment-resistant OCD.

Casey Halpern, M.D.

Assistant Professor of 
Neurosurgery, Stanford University

My work with treatment-resistant ocd

I’m a neurosurgeon. I work with those patients who are most severely affected by OCD, whose symptoms do not respond to cognitive behavioral therapy or medication, and help them find relief through a surgical procedure known as deep brain stimulation (DBS). DBS is a therapy that involves electrodes placed strategically in or on specific targets of the brain, and an electrical pulse delivered through a pacemaker-like device placed under the skin. It is often used to treat neurological diseases like Parkinson’s and epilepsy, where a specific part of the brain is implicated in the onset of a seizure or involuntary tremor.

DBS for therapy

My hope is that, for OCD patients who need this kind of invasive therapy, we define the “sweet spot”— a location in the brain where we can place an electrode that can detect the onset of an obsession, deliver a brief amount of electricity to disrupt it, and cause the associated compulsion to vanish. While this approach in its current form provides some relief to the few patients who undergo DBS surgery, outcomes have not been optimized. We plan to develop more successful strategies to target DBS electrodes to each individual’s symptoms. If we can find signals in the brain that correlate with the disease severity and guide DBS future treatment, this major advance could also lead to the development of a non-invasive strategy to benefit a much broader audience.

DBS for research

Our goal is to develop new therapies that don’t require invasive techniques or intervention, but the only way to do that is to get into the brain. If we aren’t able to get into the brain to help those patients with the severest forms of OCD, then we’ll never get out of the brain to help them non-invasively. My role, as a surgeon, is to develop a trial that could improve on what today is considered a very aggressive approach for patients with severe OCD.

Relief that changes (and saves) lives

So many of these patients can’t function in everyday life and would rather quit. That doesn’t necessarily mean they’re suicidal, but if given the choice, they may not actually prefer to live—these are the patients I knew from the beginning of my career that I most wanted to help.

Carol Mathews, M.D.

Professor of Psychiatry, 
University of Florida

Why I chose psychiatry

I’m a clinical psychiatrist with a background in genetic research. I’ve always been interested in psychiatry and the connection between people and how the brain works. While I started my career thinking I wanted to become a neurosurgeon, I realized that what I really wanted was to talk 
to people—I wanted to access their minds while looking in their eyes.

OCD is a genetic disease

OCD is a neuropsychiatric disorder—a brain disease that is biologically driven. While the susceptibility to OCD is genetic, we've not yet seen a gene, or a series of genes that suggests it’s deterministic, that genes are fate. It’s not like Huntington’s disease, for example, where anyone with the genetic mutation will develop the disease in one form or another at some point in their life. Rather, I think of OCD in the same way I think of inherited characteristics like intelligence or height or blood pressure, where there are hundreds and hundreds of genes acting together to increase your risk for developing the disease.

FFOr’s focus and ambition

FFOR’s goal is to understand the biology of treatment-resistant OCD, such that effective treatments can be mounted, tested, and brought to clinical use, resulting in improved quality of life, and, ultimately, remission. To do that, FFOR is replacing the competitive nature of research in the scientific community with a collaborative, systematic approach that facilitates rapid dissemination of findings across the projects and disciplines—from molecules to neurocircuitry to outcome.