Instructor, Psychiatry and Behavioral Sciences
Corticosteroid impacts on neural correlates of emotion. My research focuses on harnessing what we learn from neuroimaging studies in psychiatric populations and from studying healthy people to improve and develop novel/add-on therapeutic techniques for the treatment of depression.
Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.
View details for DOI 10.1038/npp.2014.259
View details for PubMedID 25292261
View details for PubMedCentralID PMC4330499
To test our hypothesis that pre-treatment executive function and brain regional activation during executive function would discriminate between responders and non-responders to cognitive behavioral therapy (CBT) in elderly depressed outpatients.Clinical cohort study.University-affiliated hospital.Sixty outpatients (age 59 years and older) completed 12 weeks of CBT between July 2010 and December 2011. Forty-four completed fMRI procedures.The main outcome consisted of a conversion from a clinical diagnosis (Mini-International Neuropsychiatric Interview) of depression to no clinical diagnosis of depression or a significant improvement in diagnostic criteria. Brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting task (WCST) was the primary predictor variable.67% of patients had a positive response to CBT. Decreased activation in the left inferior frontal triangle and right superior frontal gyrus as well as increased activity in the right middle frontal gyrus and left superior frontal gyrus predicted a positive response to CBT. Demographic and neurocognitive measures of WCST performance were not significant predictors of a positive CBT outcome, whereas the measure of WCST-induced activity in the prefrontal cortex was a significant predictor.These data are among the first to suggest that measures of prefrontal brain activation during executive functioning predict response to CBT in older adults. Further exploration of the specific underlying processes that these prefrontal cortical regions are engaging that contributes to better CBT outcomes is warranted in larger, randomized studies.
View details for DOI 10.1016/j.jagp.2014.02.001
View details for Web of Science ID 000346204400003
View details for PubMedID 24656506
Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.
View details for DOI 10.3389/fnagi.2014.00153
View details for PubMedID 25071562
Early adversity is a strong and enduring predictor of psychiatric disorders including mood disorders, anxiety disorders, substance abuse or dependence, and posttraumatic stress disorder. However, the mechanisms of this effect are not well understood. The purpose of this review is to summarize and integrate the current research knowledge pertaining to the long-term effects of early adversity on psychiatric disorders, particularly in late life. We explore definitional considerations including key dimensions of the experience such as type, severity, and timing of adversity relative to development. We then review the potential biological and environmental mediators and moderators of the relationships between early adversity and psychiatric disorders. We conclude with clinical implications, methodological challenges and suggestions for future research.
View details for DOI 10.1007/s11920-013-0352-9
View details for PubMedID 23443532
The glucocorticoid hormone cortisol is known to have wide-ranging effects on a variety of physiological systems, including the morphology and physiology of the amygdala and hippocampus. Disruptions of cortisol regulation and signaling are also linked with psychiatric disorders involving emotional disturbances. Although there is much evidence to suggest a relationship between cortisol signaling and the brain physiology underlying emotion, few studies have attempted to test for direct effects of cortisol on the neurophysiology of emotion. We administered exogenous synthetic cortisol (hydrocortisone, HCT) using two different dosing regimens (25 mg/day over 4 days, 100 mg single dose), in a double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study. During fMRI scanning, healthy subjects viewed images designed to induce happy, sad, and neutral emotional states. Subjective emotional reactions were collected for each experimental stimulus after fMRI scanning. Mood ratings were also collected throughout the 4 days of the study. Both dose regimens of HCT resulted in decreased subgenual cingulate activation during sadness conditions. The 25 mg/day regimen also resulted in higher arousal ratings of sad stimuli. No effects of HCT were observed on any mood ratings. Few reliable effects of HCT were observed on brain activity patterns or subjective emotional responses to stimuli that were not sad. The inhibitory effects of cortisol on sadness-induced subgenual cingulate activity may have critical relevance to the pathophysiology of major depression, as both subgenual hyperactivity and decreased sensitivity to cortisol signaling have been documented in patients with depression.
View details for DOI 10.1038/npp.2012.249
View details for Web of Science ID 000316161300012
View details for PubMedID 23303057