By Kaitlin Farrell, PhD

I developed an interest in neuroscience at a fairly young age, after dissecting a sheep's brain in high school biology. My undergraduate experience in the neuroscience department at the University of Pittsburgh afforded me fantastic opportunities to explore both research and clinical aspects of the field, fueling my desire to obtain a dual degree. As such, we have a unique opportunity for both of these aspects to inform the other: bench-to-bedside-and-back.

My initial research centered on movement disorders and dopaminergic circuitry, so spinal cord injury research felt like a natural progression for me. However, during my first two years of medical school, I felt drawn to neuroinflammation and the use of biologics to treat autoimmune disorders. My dissertation work combined these areas of interest to explore a lesser-studied aspect of SCI: affective disorders after injury.

Major depressive disorder (MDD) is attributed to an imbalance of the serotonin system that includes neurons of the dorsal raphe nucleus (DRN) involved in modulation of affective features such as attention, working memory and emotional control. In addition to motor, sensory, and autonomic dysfunction, patients with spinal cord injury (SCI) are at three times the risk for MDD compared to the general population. Not only is this condition frequently underdiagnosed in the SCI population, but it has a serious adverse effect on morbidity after injury. Inflammation is implicated in MDD pathology as elevated levels of pro-inflammatory cytokines (TNFα and IL-6) frequently are detected in the serum of MDD patients, and intracerebral administration of TNFα can elicit depressive-like behaviors in rodents. In a rat model we correlated elevated DRN levels of TNFα at 5 weeks post-SCI with depressive phenotype.

My next step was to utilize a novel biologic, XPro1595 (a dominantnegative inhibitor), to attempt prevention of the development of depression after SCI. Acute peripheral inhibition of soluble TNFα with XPro resulted in an increased incidence of depression, yet central intracerebroventricular (i.c.v.) administration had no effect on incidence. These results revealed the complex nature of the immune response after SCI and highlight the progress we need to make in the area of immune modulation.

For the next part of my dissertation, I explored a technique that was novel to both myself and my mentor. Using whole-cell patchclamp electrophysiology, I discovered a decrease in excitability of DRN serotonergic neurons of post-SCI depressed mice based on intrinsic membrane properties. Our findings suggest that intrinsic neuronal changes in serotonergic excitability may contribute to the development of SCI-depression, providing beneficial insight in identifying potential future therapeutic targets.

After defending my dissertation, I returned to the clinical years of medical school. My doctoral training has drastically shaped the way that I approach diagnosis and treatment planning. Knowledge of basic science is crucial to understanding the vast symptomatology of each pathological condition. Additionally, my training in scientific testing and interpretation provides a solid foundation to analyze laboratory values for each patient.

Although the next few years of my training are pre-determined, I look forward to applying my scientific training to advancing therapeutic treatment in the field of neurological disorders.