David Darrow, a neurosurgeon and Alexander Herman, a psychiatrist, co-direct a shared research lab at the University of Minnesota Medical School. Their work in biological psychiatry and cognitive neuroscience focuses on the neural mechanisms behind neuropsychiatric conditions such as depression and Parkinson’s disease and cognitive processes such as memory and decision-making. Their aim is to translate that research into new understanding of the brain and new treatments for brain conditions.
A Mutually Beneficial Partnership
For the past three years, Darrow and Herman have been working with colleagues at the Uniformed Services University (USU) in Maryland, part of the Department of Defense (DoD), to explore whether transcranial neurostimulation can improve cognitive outcomes after traumatic brain injury (TBI). Transcranial electrical stimulation (tES) is a non-invasive way to stimulate brain activity by using electrodes attached to a patient’s head that can generate weak electromagnetic waves at different frequencies and strength to influence electrical activity in the brain.
“TBI and psychological health are two significant interests of the DoD, because TBI is a very common training and battlefield injury, and it is often accompanied by depression and fatigue in soldiers and then veterans,” said Darrow. “In our lab and in my other lab at Hennepin County Medical Center, we also research how injuries and other brain pathologies cause additional challenges like depression, fatigue, and brain fog.“
The collaboration with USU has been very productive, because their colleagues’ work is complementary to their own. Their primary partner there, Senior Scientist Peter Bedocs, MD, PhD, is a researcher in trauma medicine with extensive experience designing and running clinical trials and animal studies.
“Support from DoD provides a lot of opportunity to take an existing line of inquiry and find a new angle on it that would be more relevant to combat and the battlefield,” said Herman. “And in the process, we can explore different scientific approaches, so it's not just another funding source. But it also allows us to step back a little bit and say, ‘How can we think about problems differently?’”
“Sometimes they have resources that we don't have and sometimes we have resources that they don't have,” Darrow said. “So, we can design experiments that answer the sort of questions that normally would be very challenging for us, and we can help them build on models that might otherwise be too idiosyncratic to generalize from.”
For example, their USU colleagues have well-vetted animal models of injuries and disease. One of these models can simulate the TBI caused by a bomb blast. Darrow and Herman can look at other animal models, such as ones for PTSD, in conjunction with the blast TBI model and investigate what the common brain circuits are, and whether there are interventions that can help.
“It’s very helpful to look at more than one animal model, and the same thing is true on the human side,” Darrow said. “At Hennepin County, we see older patients suffering from neurological problems like Parkingson’s and epilepsy, and we see young patients who suffer brain damage, sometimes after risky behavior, from car crashes and other accidents. When we are looking at brain injuries, it’s useful to compare them with soldiers who have TBI—they are often in their 20s and 30s and super fit. Looking across that heterogeneous group we hope to come up with a real model that's actually generalizable to what's going on with TBI."
Unlocking the Brain’s Secrets
Darrow and Herman measure what’s going on in patients’ brains using measurements of brain activity that can be seen in functional Magnetic Resonance Imaging (fMRI) or detectable as electromagnetic waves through an electroencephalogram (EEG), which uses electrodes on the outside of a patient’s head. What if physicians could observe how a patient performs a task or a test and could then make a preliminary mental health diagnosis? Herman and Darrow ask research subjects to perform several tests and record their brain activity. They then use algorithms and machine learning to figure out what the brain is doing to make decisions.
“Today we actually can validate theories that people have had for many years about how people go about their lives making decisions,” Darrow said. “We ask people with a range of brain conditions to complete tasks that measure things like actions and rewards, cognitive flexibility, and fear-threat analysis, all trying to get at different subsystems of the brain. It’s our belief that by observing behavior, we can actually move beyond a single diagnosis of depression, and we can say, ‘Yeah, you have depression in this part of your brain.’ At the risk of oversimplifying, that's how we move into the next era of treating psychiatric disorders, by actually understanding what the brain is doing. Essentially, we want to be able to ask, ‘What circuit of the brain is making you depressed?’ by looking at your behavior, at how you do these tasks.”
With their DoD-supported collaboration, Herman and Darrow are doing more than recording brain activity. With the same electrodes on the surface of the scalp, they can simultaneously apply electrical current to stimulate the brain of TBI patients, a potential treatment that they’ve previously tested in patients with epilepsy, who have electrodes implanted inside the skull. On both projects they collaborate with Alexander Opitz in Biomedical Engineering, who is an expert in brain electric field modeling.
Fighting Fatigue with Neurostimulation
“One of the most common symptoms we see with people who have had brain disorders and brain injuries is mental fatigue,” said Herman. “Tasks that require use of a person’s working memory, where the brain stores information briefly rather than long-term, can trigger fatigue in a way that makes it very difficult for that person to perform simple tasks. What we have found is that if we asked a person with TBI to do an online test of working memory that gets increasingly difficult, say, asking them to remember a series of letters, if we give the test again and stimulate the brain at the right frequency, it boosts their performance on the test.”
The idea, Darrow said, is to sync the brain up a little bit and make it a little bit more stable, allowing the tracks in the brain to work more efficiently, and the task doesn’t seem as hard to the patient. Inside the brain, with this mild stimulation, they believe, the broken tracks or highways of circuits inside the brain become easier for a patient to use.
Darrow and Herman had observed this effect in earlier studies of TBI at the University of Minnesota, and, knowing that TBI represented a significant number of military casualties for the United States over the previous two decades, they understood it would likely be of interest to DoD.
“We said, well, if we can boost their brain power—let's say we can boost it five percent—with a little bit of tickling their scalp, that is amazing!” Darrow said. “Because people can do that anywhere. This is low yield, and at the same time, we thought this is absolutely perfect for war fighters. They get rattled, they get TBI, and they have all these issues. Can we boost their healing process a little bit and get their brainwaves synced up just a little bit more?”
Around that time, in 2022, the University and Fairview put out a request for collaborative proposals with researchers and clinicians at USU, a project led by the University of Minnesota’s Greg Bielman, associate dean of DoD research and partnerships and a professor in the Department of Surgery, with funding that had been championed by Minnesota’s Congressional delegation. Darrow and Herman began exploring potential partners at USU who were also interested in novel TBI treatment. Upon finding receptive colleagues, they collaborated on a proposal, which was accepted and supported with a $2.4 million grant.
“It is a lot easier if you have a partner at DoD, or even at the VA, to do this kind of work, someone who knows the ins and outs of working with DoD,” said Darrow “We’ve been lucky to have great partners like Dr. Bedocs, who has a lot of experience and a lot of respect within the military medical research community.”
A Cost-Effective Treatment
The researchers recently proposed a new project to DoD funders where they would explore another form of non-invasive neurostimulation, stimulating the vagus nerve through the skin of the ear, which has shown promise in treating post-traumatic stress disorder (PTSD), anxiety, and opioid addiction.
“This would be relatively inexpensive treatment, in contrast to some of the newest drug and cell therapy interventions, which are often quite costly, so it would be a great example of low-cost medical innovation at a time when a portion of the public is more skeptical about science,” said Herman. “This kind of applied work with DoD also gives us, as researchers, an opportunity to reach a different audience. You could argue, for instance, that some of the current political challenges that agencies like NIH and NSF face is that the public doesn’t always understand the mission—what the connection is between government spending and their lives. But the military side of this is understood in a different way, which is, ‘We need to take care of these people that we sent into harm's way, who were injured in the process.’ I think it brings more of the public into some of the broader biomedical scientific mission.”