Rebecca Hendrickson | VA - Academia.edu (original) (raw)
Papers by Rebecca Hendrickson
Narrative Inquiry in Bioethics, 2021
Laterally connected inhibitory circuitry is found throughout the nervous system, including many e... more Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using a novel experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude. Pharmacological manipulation of this inhibition resulted in a shift in many neurons’ stimulus selectivities. Finally, we found that a behavioral response (pregnancy block) evoked by the presence of unfamiliar male urine could be suppressed by the addition of female urine to the stimulus, demonstrating that this system displays a behavioral opponency consistent with neural inhibition. Together, these results indicate that laterally connected inhibitory circuitry in the AOB plays an important role in shaping neural selectivity for natural stimuli
The Journal of Neuroscience, 2008
Laterally connected inhibitory circuitry is found throughout the nervous system, including many e... more Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using an experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude, particularly for male-selective neurons. Pharmacological manipulation of this inhi...
The Journal of Neuroscience, 2008
Laterally connected inhibitory circuitry is found throughout the nervous system, including many e... more Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using an experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude, particularly for male-selective neurons. Pharmacological manipulation of this inhi...
International Journal of Mental Health and Addiction, 2018
The diagnostic prevalence of mood and anxiety disorders in Indian individuals with alcohol use di... more The diagnostic prevalence of mood and anxiety disorders in Indian individuals with alcohol use disorders (AUDs) has important implications for clinical decision making and for cross-cultural psychiatry research. Here, we present a systematic review of comorbid mood and anxiety disorders in Indian patients with AUDs. We find rates of comorbid mood disorders ranging from 6 to 65% (estimated overall effect from a linear random effects model of 18.0%, 95% CI [5.6, 45.1]) and rates of comorbid anxiety disorders ranging from 0 to 30% (estimated overall effect of 2.4%, 95% CI [0.9, 5.8]) in Indian populations. These findings are placed in the context of estimated population prevalence of comorbid mood and anxiety disorders in US adults with AUDs who have recently sought treatment of 40.7 (95% CI [32.6, 48.7]) and 33.4% (95% CI [25.2, 41.6]), respectively. Potential causes of these differences include
Alcohol: Clinical and Experimental Research
Sleep Medicine: X
Objective/Background: Healthcare workers have experienced high rates of psychiatric symptom burde... more Objective/Background: Healthcare workers have experienced high rates of psychiatric symptom burden and occupational attrition during the COVID-19 pandemic. Identifying contributory factors can inform prevention and mitigation measures. Here, we explore the potential contributions of occupational stressors vs COVID-19 infection to insomnia symptoms in US healthcare workers. Patients/Methods: An online self-report survey was collected between September 2020 and July 2022 from N ¼ 594 US healthcare workers, with longitudinal follow-up up to 9 months. Assessments included the Insomnia Severity Index (ISI), the PTSD Checklist for DSM-5 (PCL-5), and a 13-item scale assessing COVID-19 related occupational stressors. Results: Insomnia was common (45% of participants reported at least moderate and 9.2% reported severe symptoms at one or more timepoint) and significantly associated with difficulty completing work-related tasks, increased likelihood of occupational attrition, and thoughts of suicide or self-harm (all p<.0001). In multivariable regression with age, gender, and family COVID-19 history as covariates, past two-week COVID-related occupational stressors, peak COVID-related occupational stressors, and personal history of COVID-19 infection were all significantly related to past two-week ISI scores (b ¼ 1.7 ± 0.14SE, b ¼ 0.08 ± 0.03, and b ¼ 0.69 ± 0.22 respectively). Although similar results were found for the PCL-5, when ISI and PCL-5 items were separated by factor, COVID-19 infection was significantly related only to the factor consisting of sleep-related items. Conclusions: Both recent occupational stress and personal history of COVID-19 infection were significantly associated with insomnia in healthcare workers. These results suggest that both addressing occupational stressors and reducing rate of COVID-19 infection are important to protect healthcare workers and the healthcare workforce.
BackgroundThe COVID-19 pandemic has greatly affected front line health care workers (HCW) and fir... more BackgroundThe COVID-19 pandemic has greatly affected front line health care workers (HCW) and first responders (FR). The infection risk from SARS CoV-2, the high mortality of hospitalized COVID-19 patients and the duration of the pandemic have created sustained and often traumatic stressors affecting HCW and FR.ObjectivesTo assess the relationship of COVID-19 stressor frequency scores to psychiatric rating scale scores amongst HCW and FR. To determine if psychiatric rating scale scores mediate stressor effects on perceived work function and likelihood of remaining in current occupation.DesignObservational, self-report in a convenience sample.Participants118 HCW and FR caring for COVID-19 patients in the United States.Main MeasureCOVID-19 related stressor frequencies were assessed using a 17-item questionnaire. Psychiatric symptoms were assessed with the PTSD Checklist 5 (PCL5), the Patient Health Questionnaire 9 (for depression) (PHQ9), the Insomnia Severity Index (ISI), and the Gen...
The Clinical Neuropsychologist
ABSTRACTMild traumatic brain injury (mTBI) is common in civilians and highly prevalent among mili... more ABSTRACTMild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military Servicemembers and in contact sports athletes. mTBI, especially within military populations, is often comorbid with posttraumatic stress disorder (PTSD), and can increase health-risk behaviors (e.g., sensation/novelty seeking, impulsivity, risk taking, irritability/aggression) and substance misuse/abuse, but underlying mechanisms remain poorly understood. Using an established mouse model of blast mTBI, here we examined the effects of single (1x) and repetitive (3x) blast exposure on ethanol responsivity using a battery of tests, each associated with distinct aspects of alcohol abuse vulnerability. While both single and repetitive blast exposure increased the sedative properties of high-dose ethanol (with no change in tolerance or metabolism), only repetitive blast exposure potentiated ethanol-induced locomotor stimulation and shifted ethanol intake patterns (i.e., increased consumpt...
Frontiers in Behavioral Neuroscience, 2021
Blast exposure (via detonation of high explosives) represents a major potential trauma source for... more Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and correspond...
Journal of General Internal Medicine, 2021
Background The COVID-19 pandemic has greatly affected front-line health care workers (HCW) and fi... more Background The COVID-19 pandemic has greatly affected front-line health care workers (HCW) and first responders (FR). The specific components of COVID-19 related occupational stressors (CROS) associated with psychiatric symptoms and reduced occupational functioning or retention remain poorly understood. Objectives Examine the relationships between total and factored CROS, psychiatric symptoms, and occupational outcomes. Design Observational, self-report, single time-point online assessment. Participants A total of 510 US HCW (N = 301) and FR (N = 200) with occupational duties affected by the COVID-19 pandemic. Main Outcomes and Measures CROS were assessed using a custom 17-item questionnaire. Post-traumatic stress disorder (PTSD), depression, insomnia, and generalized anxiety symptoms were assessed using the PTSD Checklist-5 (PCL5), Patient Health Questionnaire-9 (PHQ9), Insomnia Severity Index (ISI), and General Anxiety Disorder-7 (GAD7). Respondents’ likelihood of leaving current ...
Chronic Stress, 2021
Background The α1-adrenoreceptor antagonist prazosin has in many but not all studies been found t... more Background The α1-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total symptom severity. The particular efficacy of prazosin for nightmares and hyperarousal symptoms suggests there may be a subset of PTSD symptoms that are more tightly associated with an α1-adrenoreceptor mediated noradrenergic mechanism, but cross traditional diagnostic symptom clusters. However, the efficacy of prazosin for individual symptoms other than nightmares and sleep disruption has not previously been examined. Methods In a post hoc reanalysis of a previously published, randomized controlled trial of twice daily prazosin for PTSD, we examined the relative effect of prazosin on individual items of the CAPS for DSM-IV, and tested whether prazosin responsiveness predicted the partial correlation of the changes in symptom intensity at the level of individual subjects. Results were not adjusted for multiple...
Alcoholism: Clinical and Experimental Research, 2021
Background: Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among ... more Background: Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. Methods: Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast-mTBI) affects ethanol (EtOH)-induced behavioral and physiological outcomes using an established mouse model of blast-mTBI. To investigate potential translational relevance, we also examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption questions (AUDIT-C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast-mTBI affected drinking behaviors in Iraq/Afghanistan Veterans.
Oxford Medicine Online, 2018
Disruption of stress-response systems contributes to the pathophysiology of post-traumatic stress... more Disruption of stress-response systems contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Consistent with this, daytime hyperarousal and nighttime sleep disruption, including trauma-related nightmares, are core symptoms of the disorder, often requiring targeted pharmacologic treatment. Although a variety of medications that target sleep–wake and arousal mechanisms are commonly used for this purpose, there remains the best empirical support for prazosin, a brain-active antagonist of the α1 noradrenaline receptor, with emerging evidence for doxazosin, a longer-acting medication with the same mechanism of action. This chapter reviews the evidence for use of prazosin and doxazosin as well as for the sedative hypnotics (benzodiazepines, nonbenzodiazepine hypnotics, and related medications), antihistamines, and sedating antidepressants trazodone and nefazodone to address hyperarousal symptoms and trauma-associated nightmares in PTSD. Clinical recommendations for ...
Journal of the Neurological Sciences, 2020
Mounting evidence points to the significance of neurovascular-related dysfunction in veterans wit... more Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [ 18 F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blastrelated mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.
Frontiers in Digital Health, 2020
Conclusions: These results suggest that an aggregated N-of-1 trial design beginning with an open ... more Conclusions: These results suggest that an aggregated N-of-1 trial design beginning with an open label titration phase may provide superior power over open label or open label and blinded discontinuation designs, and similar power to a traditional crossover design, in detecting an association between a predictive biomarker and the clinical response to the PTSD pharmacotherapeutic prazosin. This is achieved while allowing all participants to spend the first 8 weeks of the trial on open-label active treatment.
Alzheimer's & Dementia, 2019
Journal of Clinical and Experimental Neuropsychology, 2019
Introduction: This study investigated variables associated with subjective decline in executive f... more Introduction: This study investigated variables associated with subjective decline in executive function among Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/ OIF/OND) following a history of blast-related mild traumatic brain injury (mTBI). Method: Fifty-six male U.S. Veterans (M Age = 35.3 ± 8.8 years) with a history of blast-related mTBI (6.6 ± 3.2 years post injury) completed a battery of self-report questionnaires and neuropsychological measures. Participants rated current and retrospectively estimated pre-mTBI executive function difficulties on the Frontal Systems Behavior Scale (FrSBe). A difference score (post-minus pre-mTBI ratings) was the dependent variable (ΔFrSBe). Linear regression models examined variables predicting ΔFrSBe, including: pre-injury characteristics (education, premorbid intelligence), injury-related characteristics (number of blast exposures, losses of consciousness), postinjury clinical symptoms (PTSD Checklist-Military version; Pittsburgh Sleep Quality Index), and post-injury neuropsychological performances on executive function measures (Trail Making Test Part B; Controlled Oral Word Association Test; Auditory Consonant Trigrams; Wisconsin Card Sorting Test). Results: While 11% of participants had a clinically elevated pre-injury FrSBe total score, 82% had a clinically elevated post-injury FrSBe total score. Only self-reported PTSD symptom severity independently predicted perceived change in executive function. Conclusions: Many OEF/OIF/OND Veterans with a history of blast-related mTBI experience subjective decline in executive function following injury. Perceived executive function decline was associated with higher PTSD symptom severity, aligning with previous research associating PTSD with cognitive complaints. Results did not support a correspondence between perceived cognitive change and neuropsychological performances.
Brain Imaging and Behavior, 2018
Reduced working memory is frequently reported by Veterans with a history of blast-related mild tr... more Reduced working memory is frequently reported by Veterans with a history of blast-related mild traumatic brain injury (mTBI), but can be difficult to quantify on neuropsychological measures. This study aimed to improve our understanding of the impact of blast-related mTBI on the working memory system by using resting state functional magnetic resonance imaging (fMRI) to explore differences in functional connectivity between OEF/OIF/OND Veterans with and without a history of mTBI. Participants were twenty-four Veterans with a history of blast-related mTBI and 17 Veterans who were deployed but had no lifetime history of TBI. Working memory ability was evaluated with the Auditory Consonants Trigrams (ACT) task. Resting state fMRI was used to evaluate intrinsic functional connectivity from frontal seed regions that are known components of the working memory network. No significant group differences were found on the ACT, but the imaging analyses revealed widespread hyper-connectivity from the frontal seed regions in the Veterans with a history of mTBI relative to the deployed control group. Further, within the mTBI group, but not the control group, better performance on the ACT was associated with increased functional connectivity to multiple brain regions, including cerebellar components of the working memory network. These results were present after controlling for age, PTSD symptoms, and estimated premorbid IQ, and suggest that long-term alterations in the functional connectivity of the working memory network following blast-related mTBI may reflect a compensatory change that contributes to intact performance on an objective measure of working memory.
Narrative Inquiry in Bioethics, 2021
Laterally connected inhibitory circuitry is found throughout the nervous system, including many e... more Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using a novel experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude. Pharmacological manipulation of this inhibition resulted in a shift in many neurons’ stimulus selectivities. Finally, we found that a behavioral response (pregnancy block) evoked by the presence of unfamiliar male urine could be suppressed by the addition of female urine to the stimulus, demonstrating that this system displays a behavioral opponency consistent with neural inhibition. Together, these results indicate that laterally connected inhibitory circuitry in the AOB plays an important role in shaping neural selectivity for natural stimuli
The Journal of Neuroscience, 2008
Laterally connected inhibitory circuitry is found throughout the nervous system, including many e... more Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using an experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude, particularly for male-selective neurons. Pharmacological manipulation of this inhi...
The Journal of Neuroscience, 2008
Laterally connected inhibitory circuitry is found throughout the nervous system, including many e... more Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using an experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude, particularly for male-selective neurons. Pharmacological manipulation of this inhi...
International Journal of Mental Health and Addiction, 2018
The diagnostic prevalence of mood and anxiety disorders in Indian individuals with alcohol use di... more The diagnostic prevalence of mood and anxiety disorders in Indian individuals with alcohol use disorders (AUDs) has important implications for clinical decision making and for cross-cultural psychiatry research. Here, we present a systematic review of comorbid mood and anxiety disorders in Indian patients with AUDs. We find rates of comorbid mood disorders ranging from 6 to 65% (estimated overall effect from a linear random effects model of 18.0%, 95% CI [5.6, 45.1]) and rates of comorbid anxiety disorders ranging from 0 to 30% (estimated overall effect of 2.4%, 95% CI [0.9, 5.8]) in Indian populations. These findings are placed in the context of estimated population prevalence of comorbid mood and anxiety disorders in US adults with AUDs who have recently sought treatment of 40.7 (95% CI [32.6, 48.7]) and 33.4% (95% CI [25.2, 41.6]), respectively. Potential causes of these differences include
Alcohol: Clinical and Experimental Research
Sleep Medicine: X
Objective/Background: Healthcare workers have experienced high rates of psychiatric symptom burde... more Objective/Background: Healthcare workers have experienced high rates of psychiatric symptom burden and occupational attrition during the COVID-19 pandemic. Identifying contributory factors can inform prevention and mitigation measures. Here, we explore the potential contributions of occupational stressors vs COVID-19 infection to insomnia symptoms in US healthcare workers. Patients/Methods: An online self-report survey was collected between September 2020 and July 2022 from N ¼ 594 US healthcare workers, with longitudinal follow-up up to 9 months. Assessments included the Insomnia Severity Index (ISI), the PTSD Checklist for DSM-5 (PCL-5), and a 13-item scale assessing COVID-19 related occupational stressors. Results: Insomnia was common (45% of participants reported at least moderate and 9.2% reported severe symptoms at one or more timepoint) and significantly associated with difficulty completing work-related tasks, increased likelihood of occupational attrition, and thoughts of suicide or self-harm (all p<.0001). In multivariable regression with age, gender, and family COVID-19 history as covariates, past two-week COVID-related occupational stressors, peak COVID-related occupational stressors, and personal history of COVID-19 infection were all significantly related to past two-week ISI scores (b ¼ 1.7 ± 0.14SE, b ¼ 0.08 ± 0.03, and b ¼ 0.69 ± 0.22 respectively). Although similar results were found for the PCL-5, when ISI and PCL-5 items were separated by factor, COVID-19 infection was significantly related only to the factor consisting of sleep-related items. Conclusions: Both recent occupational stress and personal history of COVID-19 infection were significantly associated with insomnia in healthcare workers. These results suggest that both addressing occupational stressors and reducing rate of COVID-19 infection are important to protect healthcare workers and the healthcare workforce.
BackgroundThe COVID-19 pandemic has greatly affected front line health care workers (HCW) and fir... more BackgroundThe COVID-19 pandemic has greatly affected front line health care workers (HCW) and first responders (FR). The infection risk from SARS CoV-2, the high mortality of hospitalized COVID-19 patients and the duration of the pandemic have created sustained and often traumatic stressors affecting HCW and FR.ObjectivesTo assess the relationship of COVID-19 stressor frequency scores to psychiatric rating scale scores amongst HCW and FR. To determine if psychiatric rating scale scores mediate stressor effects on perceived work function and likelihood of remaining in current occupation.DesignObservational, self-report in a convenience sample.Participants118 HCW and FR caring for COVID-19 patients in the United States.Main MeasureCOVID-19 related stressor frequencies were assessed using a 17-item questionnaire. Psychiatric symptoms were assessed with the PTSD Checklist 5 (PCL5), the Patient Health Questionnaire 9 (for depression) (PHQ9), the Insomnia Severity Index (ISI), and the Gen...
The Clinical Neuropsychologist
ABSTRACTMild traumatic brain injury (mTBI) is common in civilians and highly prevalent among mili... more ABSTRACTMild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military Servicemembers and in contact sports athletes. mTBI, especially within military populations, is often comorbid with posttraumatic stress disorder (PTSD), and can increase health-risk behaviors (e.g., sensation/novelty seeking, impulsivity, risk taking, irritability/aggression) and substance misuse/abuse, but underlying mechanisms remain poorly understood. Using an established mouse model of blast mTBI, here we examined the effects of single (1x) and repetitive (3x) blast exposure on ethanol responsivity using a battery of tests, each associated with distinct aspects of alcohol abuse vulnerability. While both single and repetitive blast exposure increased the sedative properties of high-dose ethanol (with no change in tolerance or metabolism), only repetitive blast exposure potentiated ethanol-induced locomotor stimulation and shifted ethanol intake patterns (i.e., increased consumpt...
Frontiers in Behavioral Neuroscience, 2021
Blast exposure (via detonation of high explosives) represents a major potential trauma source for... more Blast exposure (via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and correspond...
Journal of General Internal Medicine, 2021
Background The COVID-19 pandemic has greatly affected front-line health care workers (HCW) and fi... more Background The COVID-19 pandemic has greatly affected front-line health care workers (HCW) and first responders (FR). The specific components of COVID-19 related occupational stressors (CROS) associated with psychiatric symptoms and reduced occupational functioning or retention remain poorly understood. Objectives Examine the relationships between total and factored CROS, psychiatric symptoms, and occupational outcomes. Design Observational, self-report, single time-point online assessment. Participants A total of 510 US HCW (N = 301) and FR (N = 200) with occupational duties affected by the COVID-19 pandemic. Main Outcomes and Measures CROS were assessed using a custom 17-item questionnaire. Post-traumatic stress disorder (PTSD), depression, insomnia, and generalized anxiety symptoms were assessed using the PTSD Checklist-5 (PCL5), Patient Health Questionnaire-9 (PHQ9), Insomnia Severity Index (ISI), and General Anxiety Disorder-7 (GAD7). Respondents’ likelihood of leaving current ...
Chronic Stress, 2021
Background The α1-adrenoreceptor antagonist prazosin has in many but not all studies been found t... more Background The α1-adrenoreceptor antagonist prazosin has in many but not all studies been found to be effective for PTSD associated nightmares, hyperarousal symptoms, and total symptom severity. The particular efficacy of prazosin for nightmares and hyperarousal symptoms suggests there may be a subset of PTSD symptoms that are more tightly associated with an α1-adrenoreceptor mediated noradrenergic mechanism, but cross traditional diagnostic symptom clusters. However, the efficacy of prazosin for individual symptoms other than nightmares and sleep disruption has not previously been examined. Methods In a post hoc reanalysis of a previously published, randomized controlled trial of twice daily prazosin for PTSD, we examined the relative effect of prazosin on individual items of the CAPS for DSM-IV, and tested whether prazosin responsiveness predicted the partial correlation of the changes in symptom intensity at the level of individual subjects. Results were not adjusted for multiple...
Alcoholism: Clinical and Experimental Research, 2021
Background: Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among ... more Background: Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. Methods: Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast-mTBI) affects ethanol (EtOH)-induced behavioral and physiological outcomes using an established mouse model of blast-mTBI. To investigate potential translational relevance, we also examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption questions (AUDIT-C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast-mTBI affected drinking behaviors in Iraq/Afghanistan Veterans.
Oxford Medicine Online, 2018
Disruption of stress-response systems contributes to the pathophysiology of post-traumatic stress... more Disruption of stress-response systems contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Consistent with this, daytime hyperarousal and nighttime sleep disruption, including trauma-related nightmares, are core symptoms of the disorder, often requiring targeted pharmacologic treatment. Although a variety of medications that target sleep–wake and arousal mechanisms are commonly used for this purpose, there remains the best empirical support for prazosin, a brain-active antagonist of the α1 noradrenaline receptor, with emerging evidence for doxazosin, a longer-acting medication with the same mechanism of action. This chapter reviews the evidence for use of prazosin and doxazosin as well as for the sedative hypnotics (benzodiazepines, nonbenzodiazepine hypnotics, and related medications), antihistamines, and sedating antidepressants trazodone and nefazodone to address hyperarousal symptoms and trauma-associated nightmares in PTSD. Clinical recommendations for ...
Journal of the Neurological Sciences, 2020
Mounting evidence points to the significance of neurovascular-related dysfunction in veterans wit... more Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [ 18 F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blastrelated mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.
Frontiers in Digital Health, 2020
Conclusions: These results suggest that an aggregated N-of-1 trial design beginning with an open ... more Conclusions: These results suggest that an aggregated N-of-1 trial design beginning with an open label titration phase may provide superior power over open label or open label and blinded discontinuation designs, and similar power to a traditional crossover design, in detecting an association between a predictive biomarker and the clinical response to the PTSD pharmacotherapeutic prazosin. This is achieved while allowing all participants to spend the first 8 weeks of the trial on open-label active treatment.
Alzheimer's & Dementia, 2019
Journal of Clinical and Experimental Neuropsychology, 2019
Introduction: This study investigated variables associated with subjective decline in executive f... more Introduction: This study investigated variables associated with subjective decline in executive function among Veterans of Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/ OIF/OND) following a history of blast-related mild traumatic brain injury (mTBI). Method: Fifty-six male U.S. Veterans (M Age = 35.3 ± 8.8 years) with a history of blast-related mTBI (6.6 ± 3.2 years post injury) completed a battery of self-report questionnaires and neuropsychological measures. Participants rated current and retrospectively estimated pre-mTBI executive function difficulties on the Frontal Systems Behavior Scale (FrSBe). A difference score (post-minus pre-mTBI ratings) was the dependent variable (ΔFrSBe). Linear regression models examined variables predicting ΔFrSBe, including: pre-injury characteristics (education, premorbid intelligence), injury-related characteristics (number of blast exposures, losses of consciousness), postinjury clinical symptoms (PTSD Checklist-Military version; Pittsburgh Sleep Quality Index), and post-injury neuropsychological performances on executive function measures (Trail Making Test Part B; Controlled Oral Word Association Test; Auditory Consonant Trigrams; Wisconsin Card Sorting Test). Results: While 11% of participants had a clinically elevated pre-injury FrSBe total score, 82% had a clinically elevated post-injury FrSBe total score. Only self-reported PTSD symptom severity independently predicted perceived change in executive function. Conclusions: Many OEF/OIF/OND Veterans with a history of blast-related mTBI experience subjective decline in executive function following injury. Perceived executive function decline was associated with higher PTSD symptom severity, aligning with previous research associating PTSD with cognitive complaints. Results did not support a correspondence between perceived cognitive change and neuropsychological performances.
Brain Imaging and Behavior, 2018
Reduced working memory is frequently reported by Veterans with a history of blast-related mild tr... more Reduced working memory is frequently reported by Veterans with a history of blast-related mild traumatic brain injury (mTBI), but can be difficult to quantify on neuropsychological measures. This study aimed to improve our understanding of the impact of blast-related mTBI on the working memory system by using resting state functional magnetic resonance imaging (fMRI) to explore differences in functional connectivity between OEF/OIF/OND Veterans with and without a history of mTBI. Participants were twenty-four Veterans with a history of blast-related mTBI and 17 Veterans who were deployed but had no lifetime history of TBI. Working memory ability was evaluated with the Auditory Consonants Trigrams (ACT) task. Resting state fMRI was used to evaluate intrinsic functional connectivity from frontal seed regions that are known components of the working memory network. No significant group differences were found on the ACT, but the imaging analyses revealed widespread hyper-connectivity from the frontal seed regions in the Veterans with a history of mTBI relative to the deployed control group. Further, within the mTBI group, but not the control group, better performance on the ACT was associated with increased functional connectivity to multiple brain regions, including cerebellar components of the working memory network. These results were present after controlling for age, PTSD symptoms, and estimated premorbid IQ, and suggest that long-term alterations in the functional connectivity of the working memory network following blast-related mTBI may reflect a compensatory change that contributes to intact performance on an objective measure of working memory.