More than 100 million Americans suffer from chronic pain. The choice to prescribe pain relief in the form of opioids to people for long periods of time has been controversial due to the risk of addiction and reports of limited efficacy to manage chronic nonmalignant pain (e.g., neuropathic pain). The heavy burden of chronic pain in America prompts the need for alternative methods of non-addictive analgesia. One potential method of relieving pain is through non-invasive electrical or magnetic stimulation of the brain. In human patients, the most effective target of noninvasive stimulation is, surprisingly, the motor cortex. Motor cortex is best known for its role in eliciting voluntary movements and has a somatotopic motor map with broad connections throughout the brain and spinal cord, including understudied connections with the anterior cingulate cortex (ACC), mediodorsal thalamus (MD), basolateral amygdala (BLA), and periaqueductal gray (PAG). These connections between motor cortex and the regions known to be important for the affective component of pain may be the underlying circuits that cause analgesia during motor cortex stimulation (MCS) of human patients suffering from chronic pain. To fully dissect the mechanism of MCS, I propose to use a mouse model of chronic neuropathic pain.
In Aim 1, I will first identify the motor cortex neurons that respond when mice experience pain and further quantify their downstream connections with pain regions like the ACC, MD, BLA, and PAG.
In Aim 2, I will image the activity of neurons in motor cortex during the development of chronic pain and during MCS-induced pain relief.
In Aim 3, I will use optogenetic stimulation to selectively target MCS to subpopulations of neurons and determine which are inducing analgesia. This resulting dataset will include activity patterns of nociceptive motor cortex neurons and the cellular identity of their neuronal targets in other pain-relevant brain regions. This information will be available for clinicians to optimize MCS treatment protocols to activate specific subpopulations and tuned to neuronal activity patterns. This project will take place in the collaborative environment of Prof. Mark Schnitzer?s (sponsor) lab at Stanford, an expert environment for innovative neuroscience and imaging techniques. Together with the mentorship of leading pain neuroscientists, Profs. Greg Scherrer and Sean Mackey (co-sponsors), the proposed training plan provides an excellent opportunity for me to combine new scientific ideas with cutting-edge technology. I will gain valuable experience in using clinical treatments to ask scientific questions and create useful experimental designs. This project will help to formulate me into an intendent scientist and position me to start my own lab program studying pain circuitry and its intersect with motor circuits and behavioral outcomes. Collectively, we will dissect the circuits underlying a currently effective, noninvasive treatment for chronic pain relief and uncover a broader picture of how pain precept is generated in the brain.
. More than 100 million Americans suffer from chronic pain today, some of whom become addicted to opioid methods of pain relief. Noninvasive stimulation of motor cortex has been found to be an effective opioid- alternative method of pain relief, but no one knows how it works. This research project proposes to identify which circuits from the motor cortex connect with known pain regions to alleviate pain in order to provide clinicians with the knowledge they need to improve treatment.
