Michael D. Fox, MD, PhD, has relied on his unique background in electrical engineering throughout his career as a neuroscientist, as he approaches therapeutics with a dynamic, network-based portrait of the brain in mind. Rather than attributing psychiatric symptoms to regions of the brain, Fox attributes the symptoms to the connections between those regions. Applying his electrical engineering background, Fox was able to formulate a “wiring diagram” of the brain — a map of the connections that could be used in targeted therapy.

Fox is the founding director of the Center for Brain Circuit Therapeutics at the Brigham and an associate professor of Neurology at Harvard Medical School. He spends his time treating patients with symptoms unresponsive to medication using deep brain stimulation (DBS), focused ultrasound (FUS), and transcranial magnetic stimulation (TMS). In particular, Fox tends to focus on Parkinson’s and depression, as they have yielded promising results in response to these neuromodulation technologies. His work within the Center for Brain Circuit Therapeutics is hugely influenced by his colleagues at the center, whose diverse skills have made the center an interdisciplinary success. Brigham Clinical & Research News recently spoke with him about his undergraduate beginnings, his latest research and everything in between.

 

How did your degree in electrical engineering shape the way you think as a neuroscientist?

It had a huge impact on the way I think about the brain and the way I think about treatments. In electrical engineering, the first thing you learn is that you need the wiring diagram in order to figure out where the problem is and how to fix it — doesn’t matter if you’re talking about a stereo or a smartphone or, in this case, the human brain. We have a wiring diagram for a stereo. We have a wiring diagram for a smartphone. We didn’t have a wiring diagram for the brain, which makes it really hard to figure out what the problem is, where it’s coming from, and how we fix it. I spent a long time doing brain imaging research as part of a larger community to build this wiring diagram.

 

What is most exciting to you about the Center for Brain Circuit Therapeutics?

The collaboration and multidisciplinary nature. This kind of center can only work if you get buy in from a lot of different departments and individuals with a variety of expertise. The reason I came to the Brigham is because the Brigham has already done an amazing job of bringing together psychiatry, neurology, neurosurgery and neuroradiology. That’s part of the Hale Building for Transformative Medicine and the neurosciences center, and they’ve done it in a way that no other institution has really been able to do. And that was fertile ground for the Center for Brain Circuit Therapeutics to launch.

 

Can you describe some of the treatments offered by the Center for Brain Circuit Therapeutics?

In deep brain stimulation, you get electrodes implanted in your head and a battery pack in your chest, which are then connected by a wire; and those electrodes are implanted into a particular brain circuit to help specific symptoms. The number one use of deep brain stimulation is to treat Parkinson’s disease, but it’s also used for dystonia, epilepsy, obsessive compulsive disorder (OCD) and essential tremor.

For transcranial magnetic stimulation, we hold a big electromagnet outside of the scalp that’s able to stimulate a brain circuit noninvasively. We primarily use this to treat depression, but we also have approvals for obsessive compulsive disorder, for migraine, and, most recently, for nicotine addiction.

With MRI guided focused ultrasound, you can burn a hole in the center of the brain without ever cutting through the skin. The top use for that is for tremor, and that can either be Parkinson’s tremor or essential tremor.

 

You recently published an article in The Journal of Clinical Investigation describing patterns of brain connectivity related to mania. Could you describe your work?

Mania was just the most recent symptom we’ve looked at — we have used the same approach for mapping 20 or 30 different symptoms at this point. We always start with brain lesions: a location in the brain that, when damaged, leads to the symptom. This is a different approach than most current studies that use functional neuroimaging. In most functional neuroimaging studies, you find patients with mania, you put them in a scanner, and you figure out what areas of the brain have brain activity that correlate with the severity of the mania. The problem is that the brain region that correlates with mania might be causing mania, or it could be compensating for mania, or it could be a risk factor for mania incidentally related; it doesn’t tell you that intervening on that location or in that circuit would help mania symptoms.

If you start with brain lesions that cause mania, you know that that part of the brain, when damaged, caused mania. You have a causal connection that we hope will provide a more rapid translation into therapy or a therapeutic target. So, we start with locations of brain damage that cause mania. It gets a little bit tricky when you start looking at these cases, though — it’s not that one brain region is damaged every single time. If it was, we would know exactly where mania comes from. Patients often have damage in completely different places and you’re left scratching your head saying, “Where in the world does mania come from?”

That’s when you bring in the wiring diagram and you can say, “Okay, maybe there is damage here, here, and here because they’re all in one brain circuit, not one brain region.”

 

Are you hoping these kinds of treatments could be a future primary response to these disorders, or are there other like hopes for treatment in the center?

Mania research is still at an early stage; we still need to prove that stimulating this circuit actually helps mania symptoms. If it does and we reach the stage where we are with brain stimulation for depression, where we know that we can use brain stimulation to help symptoms, then the question of whether or not it should be a primary treatment gets into questions of cost and convenience.

 

What have been the most exciting moments at the Center for Brain Circuit Therapeutics so far?

So many moments and innovations — seeing our first patients treated with robotic TMS, working out a circuit for epilepsy that could be used to shut down seizures, finding where spirituality lives in the brain, seeing brain damage locations that lead to criminality, and so many more.

This technology or this platform for mapping out these different functions, symptoms, behaviors, to brain circuits raises a lot of very exciting therapeutic possibilities and even ethical dilemmas; what are the ethical and social and legal repercussions of intervening on that criminality circuit?

Only time will tell which circuits can be appropriately targeted for reproduceable therapeutic effects. Utilizing the wiring diagram of the human brain and these technological innovations for modulating brain circuits has amazing scientific and therapeutic potential. Patients and scientists alike should celebrate in our rapidly evolving understanding of the brain — it’s truly an exciting time for neuroscience.

Collaboration Underway

“The center will only be successful if lots of different people are all collaborating across multiple different departments: psychiatry, neurology, neurosurgery, and radiology,” says Fox. “This is a big collaboration of a lot of really, really good people. They came together to make something like this happen.”To give just a few examples:

  • Michael Hayes, MD, is a neurologist and directs the DBS service, Rees Cosgrove, MD, is a neurosurgeon and directs the FUS service along with Nathan McDannold, PhD, in radiology, while Joe Taylor, MD, PhD, is a psychiatrist and directs the TMS service.
  • On the research front, Shan Siddiqi, MD, is targeting brain circuits with TMS for psychiatric symptoms, Sam Snider, MD, is targeting brain circuits with TMS for neurological symptoms, Ellen Bubrick, MD, is targeting brain circuits with FUS for epilepsy, while Michael Ferguson, PhD, Yogesh Rathi, PhD, Lauren O’Donnel, PhD, and many others are using brain imaging to identify better brain circuit targets.

A growing list of faculty participating in this initiative can be found here.