INTRODUCTION:Dorsal column stimulation (DCS) of the spinal cord is emerging as a promising new technology to treat Parkinson's disease (PD). However, optimal stimulation settings that maximize its therapeutic effect on PD symptoms are yet to be determined. To optimize DCS therapy, it is necessary to understand its impact on pathological brain oscillations and to deliver stimulation triggered by neurophysiological biomarkers of PD. MATERIALS AND METHODS:We developed beta-triggered DCS (BT-DCS), where DCS was triggered by ongoing corticostriatal beta oscillations, and tested it in the bilateral intra-striatal 6-hydroxydopamine (6-OHDA) rat model of PD. To evaluate the translational potential of DCS in humans, we recorded local field potentials (LFPs) from bilateral subthalamic nucleus (STN) electrodes in a sixty-year-old PD subject with freezing of gait (FOG) symptoms before and three days after implantation of DCS leads. RESULTS:DCS triggered by corticostriatal beta oscillations facilitated a pro-locomotion brain state that improved locomotion, reduced akinesia, and desynchronized ongoing oscillations in the rat model. BT-DCS achieved higher efficacy with less overall charge delivery than continuous stimulation. In the PD subject, DCS increased gait velocity and stride length, reduced freezing episodes, and desynchronized subthalamic nucleus (STN) beta oscillations, while modulating phase-amplitude coupling (PAC). When applied simultaneously with deep brain stimulation (DBS), DCS had a combinatory effect on gait improvement. CONCLUSION:Based on the effective implementation of BT-DCS in modulating supraspinal pathological brain activity in rats, we envision that incorporating a brain biomarker signal in delivering DCS therapy in humans could improve relief from Parkinsonian gait issues.

Dorsal column stimulation (DCS) of the spinal cord is emerging as a promising new technology to treat Parkinson’s disease (PD). However, optimal stimulation settings that maximize its therapeutic effect on PD symptoms are yet to be determined. Here we demonstrate a closed-loop DCS (CLDCS) paradigm – a substantial advancement from previously tested continuous high-frequency DCS – in a bilateral intrastriatal 6-hydroxydopamine (6-OHDA) rodent model of PD. Firstly, CLDCS, triggered by corticostriatal beta frequency oscillations facilitated a pro-locomotion brain state that restored locomotion and reduced akinesia. Secondly, CLDCS was better at disrupting ongoing beta oscillations and achieved it with lesser overall charge delivery than continuous open-loop stimulation. These results indicate that CLDCS is markedly better than traditional spinal cord stimulation methods and can potentially be highly effective in treating PD symptoms. We envision that the CLDCS approach can be beneficial in the treatment of other neurological disorders which showcase similar pathological neuronal oscillations.

Tissue-clearing methods allow every cell in the mouse brain to be imaged without physical sectioning. However, the computational tools currently available for cell quantification in cleared tissue images have been limited to counting sparse cell populations in stereotypical mice. Here, we introduce NuMorph, a group of analysis tools to quantify all nuclei and nuclear markers within the mouse cortex after clearing and imaging by light-sheet microscopy. We apply NuMorph to investigate two distinct mouse models: a Topoisomerase 1 (Top1) model with severe neurodegenerative deficits and a Neurofibromin 1 (Nf1) model with a more subtle brain overgrowth phenotype. In each case, we identify differential effects of gene deletion on individual cell-type counts and distribution across cortical regions that manifest as alterations of gross brain morphology. These results underline the value of whole-brain imaging approaches, and the tools are widely applicable for studying brain structure phenotypes at cellular resolution.

Last summer I worked for an affordable housing organization in Whitesburg, Kentucky. Nestled deep in the Appalachian Mountains of Eastern Kentucky, I helped provide housing rehabilitation and repair services to families who were living in unsafe housing and had strained financial resources. Before coming to Whitesburg, I asked my summer mentor what working in housing and construction could teach me about medicine. “Homes do not fall apart by themselves,” he told me. He explained that housing and health are intimately intertwined and that housing challenges are also public health challenges. This was initially a hard concept to understand, but it became more clear while I was working on my first housing project at a home tucked far away from neighboring towns. It was in an alarming state of disrepair and looked almost uninhabitable. Reflecting on my mentor’s comment, I wondered what could have caused this level of neglect. An elderly woman and her husband welcomed us at the door. She did all the talking while her husband stood by with a vacant look in his eyes. Over the course of the day, she told us stories about her husband’s rich personality and vitality before the diagnosis and how devastating it was to watch his decline as his Alzheimer’s disease worsened. In the beginning, their daughter lived at home and was able to help care for her father, but after getting laid off due to economic hardships in the region, she moved west to Louisville to find a job. Since then, the woman had been the sole caregiver for her husband. They were unable to afford external sources of care, and as his condition worsened, more of her time was occupied by taking care of him. She no longer had the time or financial resources to care for her property. As his health deteriorated, so did their home. By the time she reached out to us, their home had become dangerous—rotting floors, exposed electrical wires, and other hazards made living there unsafe. That day, I understood my mentor’s words. Homes do not fall apart by themselves. They fall apart because of incidental neglect stemming from the amalgamation of burdens and stressors that prevent the owners from maintaining their homes. Illness adds to—and can frequently be the source of—the financial and temporal stressors that challenge a person’s ability to pay for and take care of a house. The condition of a person’s home is intimately connected to their life circumstances, and by extension, their health. Housing damage has significant health implications. Minor neglect can quickly transition into major disrepair, and the resulting safety issues can threaten a family’s well-being. Every day, I saw examples of hazards like black mold, exposed electrical work, missing and broken floorboards, and toxic substances putting families at risk. Each family experienced its own set of hardships, but nearly every set of circumstances could be boiled down to financial and health issues. Some families struggled with addiction, others had to take care of a child with disabilities. Some homeowners were too old to do the manual labor required to care for their homes, while others were physically handicapped and unable to perform the work. Health impacts housing, which in turn impacts health, creating a vicious cycle of disrepair that makes families more vulnerable to further injury or illness. But just as I saw the negative consequences of the housing–health relationship, I was introduced to the positive ones as well. Our organization provided an affordable rental program to provide those who could not afford housing the opportunity to live in safe, secure housing. Affordability offers families control of their home environments, which for individuals struggling with addiction, domestic violence, disabilities, or mental illness makes an immense difference in overall well-being. Safe and affordable housing provides a sense of stability that decreases stress, improves mental welfare, and allows more resources to be invested in health. Just as unsafe housing can damage a family, affordable housing can empower one. In my classes, social determinants of health are taught as a static, cause-and-effect relationship where the emphasis in learning is placed on knowing that they exist rather than exploring why they exist and how they function. I was taught that these determinants were factors that affected health outcomes, but no attention was paid to how health outcomes affected social determinants. Working in affordable housing exposed this gap in my education. Along with teaching me about the systematic causes of health inequities, my experience taught me that these causes were often cyclical in nature. Looking ahead to a career in medicine, I think about this message and remain dedicated to promoting changes that can target these vicious cycles and restore agency to those in need. Acknowledgments: The author would like to thank Seth Long and the employees of HOMES Inc. for enabling the experiences described in this essay.