Michelle E. Costanzo

PTSD symptom severity is associated with increased recruitment of top-down attentional control in a trauma-exposed sample.

Background Recent neuroimaging work suggests that increased amygdala responses to emotional stimuli and dysfunction within regions mediating top down attentional control (dorsomedial frontal, lateral frontal and parietal cortices) may be associated with the emergence of anxiety disorders, including posttraumatic stress disorder (PTSD). This report examines amygdala responsiveness to emotional stimuli and the recruitment of top down attention systems as a function of task demands in a population of U.S. military service members who had recently returned from combat deployment in Afghanistan/Iraq. Given current interest in dimensional aspects of pathophysiology, it is worthwhile examining patients who, while not meeting full PTSD criteria, show clinically significant functional impairment. Methods Fifty-seven participants with sub-threshold levels of PTSD symptoms completed the affective Stroop task while undergoing fMRI. Participants with PTSD or depression at baseline were excluded. Results Greater PTSD symptom severity scores were associated with increased amygdala activation to emotional, particularly positive, stimuli relative to neutral stimuli. Furthermore, greater PTSD symptom severity was associated with increased superior/middle frontal cortex response during task conditions relative to passive viewing conditions. In addition, greater PTSD symptom severity scores were associated with: (i) increased activation in the dorsolateral prefrontal, lateral frontal, inferior parietal cortices and dorsomedial frontal cortex/dorsal anterior cingulate cortex (dmFC/dACC) in response to emotional relative to neutral stimuli; and (ii) increased functional connectivity during emotional trials, particularly positive trials, relative to neutral trials between the right amygdala and dmFC/dACC, left caudate/anterior insula cortex, right lentiform nucleus/caudate, bilateral inferior parietal cortex and left middle temporal cortex. Conclusions We suggest that these data may reflect two phenomena associated with increased PTSD symptomatology in combat-exposed, but PTSD negative, armed services members. First, these data indicate increased emotional responsiveness by: (i) the positive relationship between PTSD symptom severity and amygdala responsiveness to emotional relative to neutral stimuli; (ii) greater BOLD response as a function of PTSD symptom severity in regions implicated in emotion (striatum) and representation (occipital and temporal cortices) during emotional relative to neutral conditions; and (iii) increased connectivity between the amygdala and regions implicated in emotion (insula/caudate) and representation (middle temporal cortex) as a function of PTSD symptom severity during emotional relative to neutral trials. Second, these data indicate a greater need for the recruitment of regions implicated in top down attention as indicated by (i) greater BOLD response in superior/middle frontal gyrus as a function of PTSD symptom severity in task relative to view conditions; (ii) greater BOLD response in dmFC/dACC, lateral frontal and inferior parietal cortices as a function of PTSD symptom severity in emotional relative to neutral conditions and (iii) greater functional connectivity between the amygdala and inferior parietal cortex as a function of PTSD symptom severity during emotional relative to neutral conditions.

Connecting combat-related mild traumatic brain injury with posttraumatic stress disorder symptoms through brain imaging.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) may share common symptom and neuropsychological profiles in military service members (SMs) following deployment; while a connection between the two conditions is plausible, the relationship between them has been difficult to discern. The intent of this report is to enhance our understanding of the relationship between findings on structural and functional brain imaging and symptoms of PTSD. Within a cohort of SMs who did not meet criteria for PTSD but were willing to complete a comprehensive assessment within 2 months of their return from combat deployment, we conducted a nested case-control analysis comparing those with combat-related mTBI to age/gender-matched controls with diffusion tensor imaging, resting state functional magnetic resonance imaging and a range of psychological measures. We report degraded white matter integrity in those with a history of combat mTBI, and a positive correlation between the white matter microstructure and default mode network (DMN) connectivity. Higher clinician-administered and self-reported subthreshold PTSD symptoms were reported in those with combat mTBI. Our findings offer a potential mechanism through which mTBI may alter brain function, and in turn, contribute to PTSD symptoms.

Psychophysiological response to virtual reality and subthreshold posttraumatic stress disorder symptoms in recently deployed military.

Objective Subthreshold posttraumatic stress disorder (PTSD) has garnered recent attention because of the significant distress and functional impairment associated with the symptoms as well as the increased risk of progression to full PTSD. However, the clinical presentation of subthreshold PTSD can vary widely and therefore is not clearly defined, nor is there an evidence-based treatment approach. Thus, we aim to further the understanding of subthreshold PTSD symptoms by reporting the use of a virtual combat environment in eliciting distinctive psychophysiological responses associated with PTSD symptoms in a sample of subthreshold recently deployed US service members. Methods Heart rate, skin conductance, electromyography (startle), respiratory rate, and blood pressure were monitored during three unique combat-related virtual reality scenarios as a novel procedure to assess subthreshold symptoms in a sample of 78 service members. The Clinician-Administered PTSD Scale was administered, and linear regression analyses were used to investigate the relationship between symptom clusters and physiological variables. Results Among the range of psychophysiological measures that were studied, regression analysis revealed heart rate as most strongly associated with Clinician-Administered PTSD Scale–based measures hyperarousal (R2 = 0.11, p = .035,) reexperiencing (R2 = 0.24, p = .001), and global PTSD symptoms (R2 = 0.17, p = .003). Conclusions Our findings support the use of a virtual reality environment in eliciting physiological responses associated with subthreshold PTSD symptoms.

Compelling evidence that exposure therapy for PTSD normalizes brain function

Functional magnetic resonance imaging (fMRI) is helping us better understand the neurologic pathways involved in posttraumatic stress disorder (PTSD). We previously reported that military service members with PTSD after deployment to Iraq or Afghanistan demonstrated significant improvement, or normalization, in the fMRI-measured activation of the amygdala, prefrontal cortex and anterior cingulate gyrus following exposure therapy for PTSD. However, our original study design did not include repeat scans of control participants, rendering it difficult to discern how much of the observed normalization in brain activity is attributable to treatment, rather than merely a practice effect. Using the same Affective Stroop task paradigm, we now report on a larger sample of PTSD-positive combat veterans that we treated with exposure therapy, as well as a combat-exposed control group of service members who completed repeat scans at 3-4 month intervals. Findings from the treatment group are similar to our prior report. Combat controls showed no significant change on repeat scanning, indicating that the observed differences in the intervention group were in fact due to treatment. We continue to scan additional study participants, in order to determine whether virtual reality exposure therapy has a different impact on regional brain activation than other therapies for PTSD.

Functional Neuroimaging Correlates of Burnout among Internal Medicine Residents and Faculty Members

Burnout is prevalent in residency training and practice and is linked to medical error and suboptimal patient care. However, little is known about how burnout affects clinical reasoning, which is essential to safe and effective care. The aim of this study was to examine how burnout modulates brain activity during clinical reasoning in physicians. Using functional Magnetic Resonance Imaging (fMRI), brain activity was assessed in internal medicine residents (n = 10) and board-certified internists (faculty, n = 17) from the Uniformed Services University (USUHS) while they answered and reflected upon United States Medical Licensing Examination and American Board of Internal Medicine multiple-choice questions. Participants also completed a validated two-item burnout scale, which includes an item assessing emotional exhaustion and an item assessing depersonalization. Whole brain covariate analysis was used to examine blood-oxygen-level-dependent (BOLD) signal during answering and reflecting upon clinical problems with respect to burnout scores. Higher depersonalization scores were associated with less BOLD signal in the right dorsolateral prefrontal cortex and middle frontal gyrus during reflecting on clinical problems and less BOLD signal in the bilateral precuneus while answering clinical problems in residents. Higher emotional exhaustion scores were associated with more right posterior cingulate cortex and middle frontal gyrus BOLD signal in residents. Examination of faculty revealed no significant influence of burnout on brain activity. Residents appear to be more susceptible to burnout effects on clinical reasoning, which may indicate that residents may need both cognitive and emotional support to improve quality of life and to optimize performance and learning. These results inform our understanding of mental stress, cognitive control as well as cognitive load theory.

Neural basis of nonanalytical reasoning expertise during clinical evaluation

Understanding clinical reasoning is essential for patient care and medical education. Dual‐processing theory suggests that nonanalytic reasoning is an essential aspect of expertise; however, assessing nonanalytic reasoning is challenging because it is believed to occur on the subconscious level. This assumption makes concurrent verbal protocols less reliable assessment tools.

Functional neuroimaging correlates of thinking flexibility and knowledge structure in memory: Exploring the relationships between clinical reasoning and diagnostic thinking

Abstract Background: Diagnostic reasoning involves the thinking steps up to and including arrival at a diagnosis. Dual process theory posits that a physician’s thinking is based on both non-analytic or fast, subconscious thinking and analytic thinking that is slower, more conscious, effortful and characterized by comparing and contrasting alternatives. Expertise in clinical reasoning may relate to the two dimensions measured by the diagnostic thinking inventory (DTI): memory structure and flexibility in thinking. Aim: Explored the functional magnetic resonance imaging (fMRI) correlates of these two aspects of the DTI: memory structure and flexibility of thinking. Methods: Participants answered and reflected upon multiple-choice questions (MCQs) during fMRI. A DTI was completed shortly after the scan. The brain processes associated with the two dimensions of the DTI were correlated with fMRI phases – assessing flexibility in thinking during analytical clinical reasoning, memory structure during non-analytical clinical reasoning and the total DTI during both non-analytical and analytical reasoning in experienced physicians. Results: Each DTI component was associated with distinct functional neuroanatomic activation patterns, particularly in the prefrontal cortex. Conclusion: Our findings support diagnostic thinking conceptual models and indicate mechanisms through which cognitive demands may induce functional adaptation within the prefrontal cortex. This provides additional objective validity evidence for the use of the DTI in medical education and practice settings.

A pilot study exploring the relationship between internists’ self-reported sleepiness, performance on multiple-choice exam items and prefrontal cortex activity

Abstract Background: Studies of resident fatigue and performance have shown mixed results. However, research has not examined daytime sleepiness and performance among attending physicians. The purpose of this study was to explore the relationship between sleep, performance and prefrontal cortex (PFC) activity. We hypothesized that sleepiness scores would negatively correlate with multiple-choice question (MCQ) performance and would also correlate with PFC activity. Methods: Board-certified physicians completed an Epworth Sleepiness Scale (ESS) and then answered MCQs from licensing examinations while in a functional Magnetic Resonance Imaging (fMRI) scanner. Results: Seventeen board-certified internists completed the study. The mean number of correct responses was 18.5/32. The correlation between the ESS and MCQ score was −0.30, and higher ESS scores were negatively associated with statistically significant changes in medial PFC (mPFC) activity. Conclusions: Attending physicians who reported higher sleepiness scores performed worse on licensing exam questions. Notably, our cohort had normal to mild sleepiness scores. Moreover, higher sleepiness scores were negatively associated with changes in mPFC activity on fMRI, which is consistent with emerging work implicating the PFC in fatigue-related cognitive impairment. Our findings have implications regarding the impact of sleep on physician performance during examinations and potentially on their care of patients.

White matter microstructure of the uncinate fasciculus is associated with subthreshold posttraumatic stress disorder symptoms and fear potentiated startle during early extinction in recently deployed Service Members

Early intervention following combat deployment has the potential to prevent posttraumatic stress disorder (PTSD), but there is a need for greater understanding of the factors that contribute to PTSD symptom progression. This study investigated: (1) fear-potentiated startle during a fear extinction, (2) white matter microstructure, and (3) PTSD symptom severity, in 48 recently deployed service members (SMs) who did not have sufficient PTSD symptoms to meet criteria for a clinical diagnosis. Electromyography startle during a conditional discrimination paradigm, diffusion tensor imaging, and the Clinician Administered PTSD Scale were assessed in a cohort of SMs within 2 months after their return from Iraq or Afghanistan. Significant correlations were found between left uncinate fasciculus (UF) white matter tract integrity and total PTSD symptoms, r=-0.343, p=0.018; the left UF and hyperarousal symptoms, r=-0.29, p=0.047; right UF integrity and total PTSD symptoms r=-0.3371, p=0.01; right UF integrity and hyperarousal symptoms r=-0.332, p=0.023; left UF and startle during early extinction, r=.31, p=0.033. Our results indicate that compromise of UF tract frontal-limbic connections are associated with greater PTSD symptom severity and lower startle response during extinction. In a subthreshold population, such a relationship between brain structure, physiological reactivity, and behavioral expression may reveal vulnerabilities that could have significant implications for PTSD symptom development.

Psychophysiological investigation of combat veterans with subthreshold post-traumatic stress disorder symptoms

OBJECTIVE Military service members (SMs) with subthreshold combat-related post-traumatic stress disorder (PTSD) symptoms often have clinically significant functional impairment, even though they do not meet full PTSD criteria. We therefore assessed the psychophysical responses of SMs, upon their return from Afghanistan or Iraq, to a fear conditioning paradigm to better understand the biological underpinnings of symptom severity. METHODS Heart rate (HR), skin conductance, electromyography startle, and respiratory rate (RR) were monitored throughout three distinct phases of the paradigm-fear acquisition, fear inhibition, and fear extinction-while plasma catecholamines (epinephrine, norepinephrine, and dopamine) were measured at the end of fear inhibition. RESULTS Those with higher PTSD symptom severity demonstrated elevations in HR and startle response to danger cues; elevated self-reported depression and anxiety; impaired functional status; poor skin conductance discrimination between danger and safety; and increases in HR and RR during fear extinction. Moreover, an inverse relationship was seen between plasma dopamine and HR during fear inhibition for those with high symptoms. CONCLUSION Overall, the physiological responses we observed in our subthreshold PTSD population parallel what has been previously observed in full PTSD, making a case for addressing subthreshold PTSD symptoms in combat veterans.