In January, we announced our 2019 Innovator Award grantees. The Innovator Award is designed to provide seed funding for bold and innovative work with the potential to transform hydrocephalus research. In this third installment of our Meet the Innovator Award Grantees Blog Series, we interviewed Dr. Joel Geerling, one of four scientists who received a 2019 Innovator Award. Dr. Geerling is an Assistant Professor of Neurology at the Carver College of Medicine at the University of Iowa. Maggie Tish, a Graduate Student who works in Dr. Geerling’s lab, also participated in the interview. Their research will focus on linking changes in the brain with symptoms experienced by adults with Normal Pressure Hydrocephalus (NPH). The goal is to better understand the neural networks affected by NPH in order to develop symptom-specific treatments.
What sparked your interest in hydrocephalus research?
As a cognitive neurologist, I see a lot of patients who have bladder problems with a variety of neurologic diseases. Even in the case of hydrocephalus, some patients will have incontinence problems and some won’t. It’s hard to predict. Neurosurgeons can put a shunt in patients with hydrocephalus and a minority of them will regain some bladder function, but most do not. Beyond shunting, we have no ability to treat bladder symptoms caused by neurologic diseases affecting the brain. We have no way of predicting which patients will or won’t lose continence and no effective ways of treating those that do. What specifically cause these symptoms – and conversely, what neural circuits normally maintain continence – seemed like a big missing piece of basic scientific research and an important thing to investigate.
What do you find most interesting about hydrocephalus research?
The ventricular system is such a simple-sounding part of the brain. It is covered quickly and almost dismissively in most neuroscience courses, and students including my former self can get the impression that the study of cerebrospinal fluid circulation through the ventricles and related diseases is a mature science. I think maybe for that reason it has been a little understudied. Adults with hydrocephalus have been somewhat left behind by the neuroscience community. Clinically, most of the task of helping these patients has fallen on neurosurgeons. Our neurosurgeons here at UIHC, led by Dr. Matt Howard, are among the best in the world at caring for these patients and guiding them through the decision and process of shunt placement. But we have virtually no understanding of the cell and molecular changes that link enlarged cerebral ventricles to neural circuit dysfunction that underlies the symptoms of NPH (urinary incontinence, gait problems, and cognitive impairment). It’s important to gain an understanding of why these symptoms occur, as well as why hydrocephalus occurs in each patient.
How long have you been researching hydrocephalus?
For almost two years.
What do you hope to learn from your research funded by the Innovator Award Grant? What questions do you hope your research will answer?
We are working to identify the neuroanatomical and functional basis of specific symptoms. Once we accomplish this, we can adapt neural circuit tools to treat specific neurologic symptoms of chronic idiopathic, communicating hydrocephalus. The first part of our plan involves seeing if we could generate an animal model for chronic hydrocephalus in adult mice. Having an animal model would allow us to perform controlled scientific experiments to make rapid progress in this line of investigation. Having a mouse model, in particular, is important because we have an unprecedented level of genetic access to specific cell types and neural circuit tools in this species. We adapted a well-established technique that was used in the past to produce acute, severe hydrocephalus, and Maggie is using it to produce varying degrees of mild to moderate, chronic hydrocephalus in adult mice, which then, over several weeks to months, develop neurologic symptoms that are similar to human patients with NPH. In every experimental and control mouse, we get one “before” and several “after” MRIs and analyze serial, 3D images of the brain to monitor the pattern and progression of cerebral ventricular enlargement. Across the same months before and after, Maggie is monitoring their urinary continence, gait, and cognitive function. We are seeing bladder problems develop in one-third to one-half of the mice, but interestingly – and similar to human patients – this doesn’t have a simple correlation with the severity of hydrocephalus. Our initial goal is to analyze the individual, neuroanatomical changes in the brain along with individual symptom patterns to understand how different hydrocephalic symptoms result from changes in specific neural pathways and not others. We are starting with bladder control and trying to locate which brain region(s) exhibit a change that correlates specifically with incontinence, first at the millimeter level of regions and fiber tracts and, ultimately, at the level of specific neurons and the synaptic connections that control continence. We hope and expect to learn in mice, and then in the human brain, which changes predict bladder problems compared to the ones that don’t. At the same time, we are measuring how the mice walk and balance, and we are assessing their cognitive function, and hope to make similar progress in these more complex symptoms.
What makes your project unique?
It’s our focus on neural circuits that are responsible for normal function, and how hydrocephalus intersects with normal function and damages it. Our project is also unique because it focuses on adults with chronic, communicating hydrocephalus. Our number one focus right now is looking at the neural circuits controlling the bladder. Along the way, however, we hope to make a dent on cognition and gait, but those are secondary to our primary focus on the bladder. My scientific background is in neuroanatomy, specifically in the neural circuit control of micturition, appetite, and other basic neural circuits. When the need for more and better work on the neural circuits controlling the bladder became apparent roughly five years ago, we developed a technique to non-invasively measure the timing and amount of mouse voiding by using a thermal camera. Maggie is a co-first-author on this work, along with a collaborator from Beth Israel-Deaconess Medical Center, and it was just published last month in the Journal of Neuroscience Methods. This technique allows us to monitor bladder function as often and for as long as we like, making a chronic set of experiments in mice, like ours, practical for the first time.
How important is HA’s Innovator Award grant for your project?
Very important. The funding gives us breathing room to run more experiments and therefore make more rapid progress on this project. As importantly, having funding from an esteemed organization adds gravity and signals the seriousness and importance of this line of investigation, which will help our momentum going forward. Some of the things that we’re doing, like getting serial MRIs on the mice, are really powerful in that they help accelerate the experiments and allow us to design and target our experimental assays better, but they’re expensive and we wouldn’t be able to afford as many without the HA award. Hopefully within a year or so, depending on what we find in our data, we can apply for an NIH grant to continue and expand this research.
What is the long-term plan for the project?
At this stage of the project, it’s really about building a foundation with a highly reliable model, plus a rigorous set of tests with results that can be replicated by others, so we can move forward on our neural circuits focus. Eventually, we hope to be able to treat specific neurologic symptoms in hydrocephalic mice by activating or inhibiting specific subtype of neurons in specific locations. These results would pave the way for a more targeted, symptom-specific approach in NPH patients. My patients who complain of bladder systems with hydrocephalus tell me that at first they felt a sensation we call urgency, where it’s uncomfortable, but they can control it and not leak. Then, as it progresses, distractions like a phone ringing will steal their focus and they begin losing control intermittently. Finally, they progress to a stage with no control at all, for which our only treatment is adult diapers – I should add that within a year or few, adult diapers are poised to begin out-selling baby diapers in the U.S., and already do in a couple of other countries. Ultimately, it would be nice if we had some type of neural circuit therapy to treat that. This therapy may require injecting a “chemogenetic” vector or implanting an electrode or light fiber targeting one or more specific brain regions. However, neurons in the brain are the most diverse cell type in the body, so it’s theoretically possible that there could be a drug that could target the neurons of interest and address bladder symptoms without causing too many other side effects. Overall, this is a very complex, difficult problem, but our patients deserve the best that we can do to better understand it and then to design and test therapies that could relieve their neurologic symptoms.