Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression

Mild Traumatic Brain Injury and Treatment Response in Prolonged Exposure for PTSD

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98185/1/jts21813.pd

Mental Health Service Utilization before and after Receipt of a Service‐Connected Disability Award for PTSD: Findings from a National Sample

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146624/1/hesr12859.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146624/2/hesr12859-sup-0001-AppendixSA1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146624/3/hesr12859_am.pd

Determinants of National Guard Mental Health Service Utilization in VA versus Non‐VA Settings

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134155/1/hesr12446.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134155/2/hesr12446-sup-0001-AppendixSA1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134155/3/hesr12446_am.pd

Predictors of PTSD Symptom Change Among Outpatients in the U.S. Department of Veterans Affairs Health Care System

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136244/1/jts22156.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136244/2/jts22156_am.pd

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting‐state amygdala connectivity

The neurosteroids allopregnanolone and dehydroepiandrosterone (DHEA) are integral components of the stress response and exert positive modulatory effects on emotion in both human and animal studies. Although these antidepressant and anxiolytic effects have been well established, to date, little research has examined their neural correlates, and no research has been conducted into the effects of neurosteroids on large‐scale networks at rest. To investigate the neurosteroid impact on intrinsic connectivity networks, participants were administered 400 mg of pregnenolone ( N  = 16), 400 mg of DHEA ( N  = 14), or placebo ( N  = 15) and underwent 3T fMRI. Resting‐state brain connectivity was measured using amygdala as a seed region. When compared with placebo, pregnenolone administration reduced connectivity between amygdala and dorsal medial prefrontal cortex, between amygdala and precuneus, and between amygdala and hippocampus. DHEA reduced connectivity between amygdala and periamygdala and between amygdala and insula. Reductions in amygdala to precuneus connectivity were associated with less self‐reported negative affect. These results demonstrate that neurosteroids modulate amygdala functional connectivity during resting state and may be a target for pharmacological intervention. Additionally, allopregnanolone and DHEA may shift the balance between salience network and default network, a finding that could provide insight into the neurocircuitry of anxiety psychopathology. Hum Brain Mapp 35:3249–3261, 2014 . © 2013 Wiley Periodicals, Inc .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107578/1/hbm22399.pd

Neural dysregulation in posttraumatic stress disorder

Objective—Convergent neuroimaging and neuropsychological research demonstrates disrupted attention and heightened threat sensitivity in PTSD. This might be linked to aberrations in largescale networks subserving detection of salient stimuli, i.e. the salience network (SN), and stimulus-independent, internally-focused thought, i.e. the default mode network (DMN). Methods—Resting state brain activity was measured in returning veterans who served in Iraq or Afghanistan with (n=15) and without PTSD (n=15) and in healthy community controls (n=15). Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions (posterior cingulate, ventromedial prefrontal cortex, and bilateral anterior insula) and all other voxels of the brain. Results—Compared to control groups, PTSD participants showed reduced functional connectivity within DMN (between DMN seeds and other DMN regions), including rostral ACC/ vmPFC (Z=3.31; p=.005, corrected) and hippocampus (Z=2.58; p=.005), and increased connectivity within SN (between insula seeds and other SN regions), including amygdala (Z=3.03; p=.01, corrected). PTSD participants also demonstrated increased cross-network connectivity. DMN seeds exhibited elevated connectivity with SN regions, including insula (Z=3.06; p=.03, corrected), putamen, and supplementary motor area (Z=4.14; Z=4.08; p<.001), and SN seeds exhibited elevated connectivity with DMN regions, including hippocampus (Z=3.10; p=.048, corrected). Conclusions—During resting state scanning, PTSD participants showed reduced coupling within DMN, greater coupling within SN, and increased coupling between DMN and SN. Our findings suggest a relative dominance of threat-sensitive circuitry in PTSD, even in task-freeconditions. Disequilibrium between large-scale networks subserving salience detection versus internally focused thought may be associated with PTSD pathophysiolog

Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder

Background: Converging neuroimaging research suggests altered emotion neurocircuitry in individuals with posttraumatic stress disorder (PTSD). Emotion activation studies in these individuals have shown hyperactivation in emotion-related regions, including the amygdala and insula, and hypoactivation in emotion-regulation regions, including the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). However, few studies have examined patterns of connectivity at rest in individuals with PTSD, a potentially powerful method for illuminating brain network structure. Methods: Using the amygdala as a seed region, we measured resting-state brain connectivity using 3 T functional magnetic resonance imaging in returning male veterans with PTSD and combat controls without PTSD. Results: Fifteen veterans with PTSD and 14 combat controls enrolled in our study. Compared with controls, veterans with PTSD showed greater positive connectivity between the amygdala and insula, reduced positive connectivity between the amygdala and hippocampus, and reduced anticorrelation between the amygdala and dorsal ACC and rostral ACC. Limitations: Only male veterans with combat exposure were tested, thus our findings cannot be generalized to women or to individuals with non–combat related PTSD. Conclusion: These results demonstrate that studies of functional connectivity during resting state can discern aberrant patterns of coupling within emotion circuits and suggest a possible brain basis for emotion-processing and emotion-regulation deficits in individuals with PTSD