The Brain on Whole Body Hyperthermia: A Neuroimaging Study

Overview

The investigators have observed in an open trial that a single session of whole body hyperthermia (WBH) induced rapid antidepressant effects that persisted for at least a week in patients with major depression (MDD) severe enough to warrant inpatient hospitalization. In addition to reducing depression, the single session of WBH induced a prolonged reduction in mean core body temperature, consistent with basic science data from our group suggesting that hyperthermia activates a skin-to-brain pathway that have been shown in animals to be important for mood and body temperature regulation. Consistent with this known anatomy in our preliminary study in depressed patients, reductions in core body temperature were highly correlated with reductions in depressive symptoms over the same time period (one week post WBH). Moreover, patients with higher mean core body temperature prior to treatment had enhanced antidepressant effects. Because increased body temperature is an outcome of poor functioning in the skin-to-brain pathway activated by WBH our data suggests that WBH may actually sensitize this pathway in ways that promote changes in brain functioning known to promote emotional well-being. The results of our first open trial have encouraged us to conduct a larger, more rigorous placebo-controlled, double blind study of WBH for MDD, which is currently underway at the University of Arizona Medical School. Missing from our assessments in this ongoing double-blind study is any measure of the impact of WBH on brain function. The current proposal addresses ths gap in our investigative portfolio by proposing to conduct a second, randomized trial of active vs. sham WBH that will examine the impact of WBH on measures of brain function known from prior studies to be important for both depression and its treatment.

The Investigators have observed in an open trial that a single session of whole body hyperthermia (WBH) induced rapid antidepressant effects that persisted for at least a week in patients with major depression (MDD) severe enough to warrant inpatient hospitalization. In addition to reducing depression, the single session of WBH induced a prolonged reduction in mean core body temperature, consistent with basic science data from our group suggesting that hyperthermia activates a skin-to-brain pathway that targets specific serotonergic nuclei in the raphe. In animal models, these nuclei have been shown to be important for mood and body temperature regultion. Consistent with this known anatomy in our preliminary study in depressed patients, reductions in core body temperature were highly correlated with reductions in depressive symptoms over the same time period (one week post WBH). Moreover, patients with higher mean core body temperature prior to treatment had enhanced antidepressant effects. Because increased body temperature is an outcome of poor functioning in the skin-to-brain pathway activated by WBH our data suggest that WBH may actually sensitize this pathway in ways that promote changes in brain functioning known to promote emotional well-being. The results of our first open trial have encouraged us to conduct a larger, more rigorous placebo-controlled, double blind study of WBH for MDD, which is currently underway at the University of Arizona Medical School. In addition to assessing effects on depressive symptoms in comparison to a sham condition, this study examines the effect of WBH on body temperature, autonomic nervous system function, thermoregulatory cooling, immune, neuroendocrine and monoamine functioning and real-world daily social behavior. Missing from our assessments in this ongoing double-blind study is any measure of the impact of WBH on brain function. The current proposal addresses ths gap in our investigative portfolio by proposing to conduct a second, randomized trial of active vs. sham WBH that will examine the impact of WBH on measures of brain function known from prior studies to be important for both depression and its treatment. These measures will include functional magnetic resonance imaging (fMRI) analyses of resting state brain connectivity as well as assessments of concordance between subgenual anterior cingulate cortex and autonomic nervous system function assessed by electrocardiogram (EKG). Prior to these fMRI assessments a structural MRI will be obtained. The investigators propose to conduct this fMRI/EKGtudy in 30 students (15 males/15 females) recruited from the PSYC150A1 Mass survey, which allows University of Arizona students an opportunity to serve as research subjects for course credit. These potential participants will be between the ages of 18 and 30 and will have self-reported depressive symptomatology of at least moderate severity, as reflected in a Beck Depression Inventory (BDI) II score ≥ 14. Participants will be medically healthy with no history of bipolar I disorder, schizophrenia or active substance dependence. Participants will complete questionnaires one week prior to, the day of, and one week following a single administration of either WBH or sham WBH (delivered with a 1-to-1 ratio). On the morning prior receiving WBH or sham WBH and again 24 hours later all subjects will undergo fMRI/EKG assessment. This design will allow us to evaluate the acute brain effects of WBH and to evaluate the relationship between these changes and both acute and short term (i.e. one week post treatment) improvements in mood.