VISN 22 Center of Excellence for Stress and Mental Health - Mission-Oriented Basic Research

VISN 22 Center of Excellence for Stress and Mental Health -
Mission-Oriented Basic Research

Jump to: Clinical & Health Services Research

A multimodal imaging study in U.S. veterans of Operations Iraqi and Enduring Freedom with and without major depression after blast-related concussion

Description: Blast exposure is among the most common causes of concussion in OEF-OIF warriors. Although the mechanism is unknown, major depressive disorder (MDD) after head injury is common. The purpose of this study was to use diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to examine the structural and functional neural correlates of MDD in OEF-OIF combat veterans with a self reported history of blast-related concussion.

Impact Statement: These results suggest a biological basis of MDD in OEF-OIF veterans who have experienced blast-related concussion, and may contribute to the development of treatments aimed at improving the clinical care of this unique population of wounded warriors.

Findings: Subjects underwent DTI and performed a validated emotional face matching task during fMRI. We found that subjects in the MDD group (i.e., individuals with a history of blast-related concussion who were experiencing current MDD, n=11) relative to individuals in the non-MDD group (i.e., individuals with a history of blast-related concussion but no current or lifetime history of MDD, n=11) showed greater activity during fear matching trials in the amygdala and other emotion processing structures, lower activity during fear matching trials in emotional control structures such as the dorsolateral prefrontal cortex and lower fractional anisotropy (FA) in several white matter tracts including the superior longitudinal fasciculus (SLF). Greater depressive symptom severity correlated negatively with FA in the SLF.

Contact: Scott Matthews, M.D., scmatthews@ucsd.edu

Collaborations: VA San Diego Healthcare System; Department of Defense

Key Phrases Rehabilitation and Recovery

Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder

Description: The hypothalamic neuropeptide, orexin-A has a number of regulatory effects in humans, and pre-clinical evidence suggests a link to euroendocrine systems known to be pathophysiologically related to posttraumatic stress disorder (PTSD). However, there are no reports of central nervous system (CNS) or peripheral orexin-A concentrations in patients with PTSD, or any anxiety disorder. Cerebrospinal fluid (CSF) and plasma levels of orexin-A were serially determined in patients with PTSD and healthy comparison subjects to characterize the relationships between orexin-A (in the CNS and peripheral circulation) and central indices of monoaminergic neurotransmission and to determine the degree to which CNS orexin-A concentrations reflect those in the circulating blood. an indwelling subarachnoid catheter. Orexin-A concentrations were determined in plasma and CSF and CSF levels of the serotonin metabolite, 5-hydroxyindolacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid (HVA), were determined over the sampling period.

Impact Statement: The results of this study further the understanding of the pathophysiological mechanisms that underlie PTSD. Specifically, these findings suggest low central and peripheral orexin-A activity in patients with chronic PTSD are related to symptom severity and raise the possibility that orexin-A is part of the pathophysiological mechanisms of combat-related PTSD.

Findings: CSF and plasma orexin-A concentrations were significantly lower in the patients with PTSD as compared with healthy comparison subjects at all time points. In addition, CSF orexin-A concentrations strongly and negatively correlated with PTSD severity as measured by the Clinician- Administered PTSD Scale (CAPS) in patients with PTSD. Peripheral and CNS concentrations of orexin-A were correlated in the healthy comparison subjects and peripheral orexin-A also correlated with CNS serotonergic tone. These findings suggest low central and peripheral orexin-A activity in patients with chronic PTSD are related to symptom severity and raise the possibility that orexin-A is part of the pathophysiological mechanisms of combat-related PTSD.

Contact: Dewleen Baker, M.D., dgbaker@ucsd.edu or Dewleen.Baker@va.gov 

Collaborations:Department of Veterans Affairs; University of California San Diego; University of Cincinnati; University of Carolina

Key Phrases Specialized PTSD Treatment

Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder

Description: Intimate-partner violence (IPV) is one of the most common causes of posttraumatic stress disorder (PTSD) among women. PTSD neuroimaging studies have identified functional differences in the amygdala and anterior cingulate cortex (ACC)/medial prefrontal cortex during emotion processing. Recent investigations of the limbic sensory system and its associated neural substrate, the insular cortex, have demonstrated its importance for emotional awareness. This study investigated dysregulation of this limbic sensory system while processing threat-related emotional face in women with and without IPV-PTSD using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging while completing an emotional face-matching task.

Impact Statement: Understanding the neural circuits and their activity in processing emotions in women with PTSD related to intimate-partner violence may help identify the mechanisms that underlie the manifestation of symptoms such as hypervigilance. Knowledge gleaned from this neuroimaging study may assist in the identification of PTSD interventions.

Findings: Women with IPV-PTSD subjects relative to comparison subjects displayed increased activation of the anterior insula and amygdala and decreased connectivity among the anterior insula, amygdala, and ACC while matching to fearful versus happy target faces and while matching angry versus happy target faces. IPV-PTSD subjects relative to comparison subjects also displayed increased dorsal ACC/medial prefrontal cortex activation and decreased ventral ACC activation when matching to a male versus a female target, and the extent of increased dorsal ACC activation correlated positively with hyperarousal symptoms. Women with IPV-PTSD display hyperactivity and disconnection among affective and limbic sensory systems while processing threat-related emotion. Furthermore, hyperactivity of cognitive-appraisal networks in IPV-PTSD may promote hypervigilant states of awareness through an exaggerated sensitivity to contextual cues, i.e., male gender, which relate to past trauma.

Contact: Alan Simmons, Ph.D., ansimmons@ucsd.edu 

Collaborations: University of California San Diego; San Diego State University

Key Phrases Specialized PTSD Services, Rehabilitation and Recovery

Salivary cortisol and prefrontal cortical thickness in middle-aged men: A twin study

Description: The human stress response is mediated by the hypothalamic-pituitary-adrenal axis (HPA) and involves two types of corticosteroid receptor: glucocorticoid and mineralocortocoid. Although glucocorticoid receptors are highly expressed in the prefrontal cortex, the hippocampus remains the predominant focus in the literature examining relationships between cortisol and brain. We examined phenotypic and genetic associations of cortisol levels with the thickness of prefrontal and anterior cingulate cortex regions, and with hippocampal volume in a sample of 388 middle-aged male twins who were 51-59 years old from the Vietnam Era Twin Study of Aging (VETSA). High expression of GR's in the prefrontal cortex may be related to aging or to exposure to stress.

Impact Statement: Understanding the genetic and environmental effects of aging and stress will aid in the planning of healthcare and services for aging Veterans.

Findings: We found that higher salivary cortisol levels were associated with thinner cortex in prefrontal regions in a large-scale study of middle-aged men. Adjusting for the effects of age, general cognitive ability, depression, cardiovascular risk factors, diabetes, smoking, and alcohol use had relatively little impact on the overall results. There were no significant associations of hippocampal volumes with any cortisol measures. The significant correlations between cortisol level and prefrontal ROIs were in partially contiguous regions. This outcome suggests a meaningful pattern rather than a handful of chance results. Our data showing that higher salivary cortisol levels were significantly correlated with prefrontal cortical thinning, and that this association may be genetically regulated may provide insight into the susceptibility of cognitive function to the dysregulation of cortisol secretion during aging.

Contact: William Kremen, Ph.D., wkremen@ucsd.edu

Collaborations: University of California San Diego; National Institutes of Health; National Institutes of Aging; Department of Veterans Affairs (VESTA Registry)

Key Phrases Specialized PTSD Services

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