Innovative Research

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Providing state-of-the-art methodology for clinical, basic science and translational research empowers Duke Anesthesiology to explore revolutionary clinical inquiries by using innovative investigation methods.

Through significant research in neuroscience, molecular biology, molecular and human pharmacology endeavors, our team is making crucial advancements for patients worldwide.


Novel Approach to Pain Management Could Get the Green Light

Green light glasses

Researchers study effects of light-induced analgesia for acute, chronic pain

In the ongoing search for effective acute and chronic pain management that reduces reliance on opioids, Duke researchers are examining the pain-relieving potential of a novel, nonpharmacological treatment: the antinociceptive effect of green-spectrum light exposure.

“The medical community has recognized that pain is helped the most with a multimodal approach,” says Padma Gulur, MD, pain medicine specialist, director of pain management strategy and opioid surveillance for Duke University Health System, and lead investigator for the NIH-funded, two-year clinical trial. “Medications alone rarely control pain fully; you have to look for additional strategies to try and help. The bottom line is that we need lots of tools to manage pain.”

Dr. Padma Gulur
Dr. Padma Gulur

Gulur, who is an internationally recognized expert in the field of pain management, explains that visually mediated cognitive and biological effects of specific color ranges of light are broadly recognized in areas of affect and circadian rhythm, but similar effects on pain perception are less understood.

“In our study, we’re comparing people who are exposed to different wavelengths of blue, clear, and green light to see which one is beneficial by measuring participants’ pain relief and response. We’ve had early results in pilot studies where green seems to help, so now we’re studying the role of the visual cortex in those signals, understanding which wavelengths are particularly useful, and looking at the reasons for this phenomenon,” Gulur says.

“Dr. Gulur’s pioneering clinical protocol will help us understand translationally relevant aspects of fascinating but also puzzling basic science discoveries of how light—especially green light—can attenuate pain, which neural circuits might be involved, and which individual predisposing factors we can identify toward personalized medicine,” says Wolfgang B. Liedtke, MD, PhD, a Duke neurologist and pain medicine specialist who is in charge of two outpatient clinics: one in neurology/headache pain, and one in innovative pain therapy.

Dr. Amanda Nelli
Dr. Amanda Nelli*

With a vision for eventually developing a commercially available wearable technology based on the results of the study, Gulur acknowledges the challenges to come. “How do you feasibly deliver green light to people in a way that doesn’t interfere with their quality of life and increases their compliance with the therapy?” she says. “We can’t change to green screens in every environment, nor can we ask people to sit in rooms with ambient green light for long periods of time. So, part of our study is about refining the science—identifying ways in which we can target the visual cortex in the brain and personalize the experience for patients.”

The light exposure study is a continuation of Gulur’s research goals of finding additional nonpharmaceutical avenues for pain management, including nutritional and musical interventions.

“The possible ramifications of this study are huge,” says Gulur. “We have such a tremendous burden of pain management in the nation now that even if we see 50% of patients benefit from this therapy, then already it becomes something worth trying to give them a better quality of life.”

How do you feasibly deliver green light to people in a way that doesn’t interfere with their quality of life and increases their compliance with the therapy?

“As someone who takes care of many patients suffering from chronic pain who are in need of improved treatment, I am looking forward to the study’s results,” Liedtke adds.

Malone, Lori (August 2020). Novel Approach to Pain Management Could Get the Green Light (Duke Health).
*Dr. Amanda Nelli is involved in this clinical trial as a Duke Anesthesiology postdoctoral researcher.


Mechanisms and Clinical Implications of Myocardial Injury Following Traumatic Brain Injury

Dr. Vijay Krishnamoorthy
Dr. Vijay Krishnamoorthy

Traumatic brain injury (TBI) is a major public health concern, affecting more than 1.7 million individuals annually in the United States. Hypotension after severe TBI results in cerebral hypoperfusion and poor clinical outcomes. Approximately 50 percent of severe TBI patients are treated for hypotension and maintenance of cerebral perfusion; this may be due to unrecognized myocardial injury and cardiac dysfunction. Dr. Vijay Krishnamoorthy’s prior research has demonstrated that: 22 percent of patients with moderate-severe TBI have early cardiac dysfunction, patients with TBI and cardiac dysfunction exhibit signs of sympathetic activation, and patients with TBI and cardiac dysfunction experience hypotension and cerebral hypoperfusion. Sympathetic activation is implicated in cardiac dysfunction and hypotension after TBI, but mechanistic data is limited. The central hypothesis of this study is that severe TBI causes myocardial injury through activation of the sympathetic nervous system and this results in cardiovascular dysfunction, hypotension and poor neurologic outcomes.

Results of this study, as well as a rigorous career development plan, will lead to a larger trial that examines the impact of reduction of sympathetic nervous system activation on myocardial injury and clinical outcomes after severe TBI. The long-term goal of this work is to personalize hemodynamic management in order to improve clinical outcomes after severe TBI.

Secondary Brain Injury infographic

Aims and Hypotheses

Aim: Determine the effect of severe TBI on autonomic nervous system function.

Hypothesis: Compared to patients with orthopedic injury, patients with severe TBI will have increased sympathetic nervous system activation (lower heart rate variability, higher myocardial workload, higher plasma catecholamines, and altered lymphocyte adrenergic receptor gene expression) within 24 hours after injury.

Aim: Determine if autonomic dysfunction contributes to myocardial injury after severe TBI.

Hypothesis: A third of patients with isolated severe TBI will experience myocardial injury (high sensitivity troponin greater than the 99th percentile for a standardized reference population) within 24 hours after injury; increased sympathetic nervous system activation will mediate this relationship.

Aim: Examine the impact of myocardial injury on cardiovascular dysfunction and clinical outcomes after severe TBI.

Hypothesis: During the first week following isolated severe TBI, patients with myocardial injury will have a higher incidence of cardiovascular dysfunction, shock and multi-organ dysfunction, compared to severe TBI patients without myocardial injury. The Extended Glasgow Outcome Scale (GOS-E) score will be worse in patients with myocardial injury following severe TBI.


Critical Care and Perioperative Population Health Research (CAPER) Unit

Mission:

To improve the lives of patients undergoing surgery and critical care globally, through the conduct of large-scale observational research using rigorous population health methods.

Project Example:

One area of inquiry in the CAPER Unit is the pharmacoepidemiology of commonly used perioperative and critical care medications. In this case, researchers examined the day of surgery utilization of gabapentinoids for joint replacement surgery in the United States (Figures 1A and 1B) and its association with post-operative pulmonary complications (Figure 2).

Figure 1A - day of surgery utilization of gabapentinoids for joint replacement surgery in the United States
Figure 1B - day of surgery utilization of gabapentinoids for joint replacement surgery in the United States
Figure 2 - association with post-operative pulmonary complications

RESEARCH PORTFOLIO

CAPER’s research spans multiple areas in perioperative and critical care medicine, with a focus on five research pillars:

METHODS FOR PERIOPERATIVE AND CRITICAL CARE POPULATION HEALTH RESEARCH

  • Improving the rigor of observational research through methodologic innovation

INJURY EPIDEMIOLOGY (TRAUMA, OPIOIDS, PUBLIC HEALTH)

  • Examining trauma, the opioid epidemic and public health

RESUSCITATION, ANALGESIA AND NUTRITION

  • Comparative effectiveness of common critical care and perioperative interventions

MULTI-ORGAN DYSFUNCTION

  • Studying organ dysfunction and clinical outcomes in critical care and perioperative medicine

LEARNING HEALTH

  • Moving from “data to knowledge” to “knowledge to practice”

Exploring the Human Spinal Cord Using Functional MRI

Advancing Understanding of Chronic Pain and Effects of Opioids on Central Nervous System Activity

Dr. Katherine Martucci
Dr. Katherine T. Martucci

The spinal cord is a critical physiological nexus for pain processing and the chronic pain experience. While research on spinal cord mechanisms of chronic pain is abundant within the cell and molecular realm and that of animal models for chronic pain, research on the spinal cord mechanisms from a human clinical perspective is more limited. Technological limits have delayed our ability to study spinal cord activity in humans using non-invasive imaging of the spinal cord. However, spinal cord imaging techniques have been steadily advancing over the last decade so that now reliable and clearer functional MRI (fMRI) images of the spinal cord can be used to study conditions in humans, including for chronic pain.

The Human Affect and Pain Neuroscience (HAPN) Laboratory at Duke Anesthesiology, led by Dr. Katherine Martucci, is one of few research locations globally using and advancing spinal cord fMRI. Their application of spinal cord fMRI is primarily for the study of chronic pain, with a current particular focus on fibromyalgia - a chronic pain condition characterized by widespread pain throughout the body accompanied by comorbid symptoms of cognitive disturbance, depression, anxiety, and fatigue that occurs among both sexes but predominantly in females. As part of a K99/R00 “Pathway to Independence” grant from the National Institutes of Health, Martucci and her team have been advancing the use of spinal cord fMRI to compare spinal cord activity in individuals with fibromyalgia vs healthy controls. For these studies, both healthy individuals without chronic pain and individuals with fibromyalgia underwent a spinal cord scan session to collect both structural MRI scans and resting-state fMRI data. The resting-state fMRI data were collected at the level of the cervical spinal cord (corresponding vertebrae C5, C6, C7). The resting-state data were analyzed using a measure of the amplitude of low frequency fluctuations (ALFF). ALFF is a measure of low frequency oscillatory power (0.01 - 0.198 Hz) related to the blood oxygenation level dependent (BOLD) fMRI signal (ie, correlate estimate of regional neural activity). Through these analyses, differences in spinal cord activity (ie, regional ALFF) were identified between the groups. Specifically, the group of individuals with fibromyalgia showed greater levels of activity in ventral regions of the spinal cord, and lesser levels of activity in the dorsal regions of the spinal cord, as compared to the healthy control participants. These findings were published in the journal Arthritis and Rheumatology (see citation on the next page).

Currently, Martucci and the HAPN Lab are collecting a new set of spinal cord fMRI data from individuals with fibromyalgia and healthy control volunteers to replicate the initially published findings. A larger sample size of neuroimaging data are being collected for the current study at Duke University’s Brain Imaging and Analysis Center using an upgraded spinal cord fMRI sequence that has more advanced images than collected in the previous study.

An additional focus of the lab’s spinal cord research is to identify potential effects of opioid use on spinal cord activity in patients with chronic pain. It is known that opioid use alters brain structure and function, but it has remained relatively unexplored, particularly in humans, how opioid use affects spinal cord activity in chronic pain. Opioid use can influence both local inhibition within the spinal cord and mechanisms of descending control. Martucci and the HAPN Lab are therefore also studying how opioid use may influence spinal cord activity in chronic pain by comparing resting-state fMRI of the spinal cord in fibromyalgia patients who take opioids vs fibromyalgia patients who do not take opioids. Similar analyses as mentioned above, using ALFF, are hoped to allow for identification of regionally altered spinal cord activity associated with opioid status. Ultimately, the focus of this clinical research by the HAPN Lab aims to advance the understanding of spinal cord alterations in fibromyalgia, and chronic pain more generally. Simultaneously, these projects aim to identify potential new avenues for non-invasively determining benefits vs harms of opioid use in individuals by visualizing alterations in spinal cord activity.

Authors: Katherine T. Martucci, PhD. Collaborators: Kenneth A. Weber II, DC, PhD (Stanford University), Allen W. Song, PhD
(Duke Departments of Radiology, Psychiatry and Behavioral Sciences, Neurobiology), Anne Baker, MSW, PhD (HAPN Lab postdoc).

The HAPN Lab is one of few research locations globally using and advancing spinal cord fMRI.

Axial view of an example human cervical spine functional MRI image.

Axial view of an example human cervical spine functional MRI image.

In the center of the image, the cervical spinal cord is identified as the light gray oval region, which is surrounded by a brighter white region of cerebrospinal fluid (CSF). The approximate location of dorsal and ventral horns within the spinal cord (ie, faint lighter gray/white traces within the spinal cord light gray oval) are indicated with arrows.

Sagittal view of group (patient vs. healthy control) differences in spinal cord fMRI activity.

Sagittal view of group (patient vs. healthy control) differences in spinal cord fMRI activity.

Left: full sagittal view of structural MRI image, with rectangular highlighted area showing the fMRI-imaged region within the cervical spine (ie, corresponding to C5, C6, and C7 vertebrae). Right: functional image overlay with structural MRI background. Compared to healthy controls, individuals with fibromyalgia showed several regions of greater (ventral, red) and lesser (dorsal, blue) spinal cord activity (ie, Mean ALFF). D, dorsal; FM, fibromyalgia; HC, healthy controls. P values are uncorrected < 0.05.

Citation of the published research: Martucci, K. T., Weber, K. A. and Mackey, S. C. Altered Cervical Spinal Cord Resting-State Activity in Fibromyalgia. Arthritis and Rheumatology (2019).

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