Kathleen F. Pagulayan

Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptoms.

Disagreement exists regarding the extent to which persistent post-concussive symptoms (PCS) reported by Iraq combat Veterans with repeated episodes of mild traumatic brain injury (mTBI) from explosive blasts represent structural or functional brain damage or an epiphenomenon of comorbid depression or posttraumatic stress disorder (PTSD). Objective assessment of brain function in this population may clarify the issue. To this end, twelve Iraq war Veterans (32.0 ± 8.5 [mean ± standard deviation (SD)] years of age) reporting one or more blast exposures meeting American Congress of Rehabilitation Medicine criteria for mTBI and persistent PCS and 12 cognitively normal community volunteers (53.0 ± 4.6 years of age) without history of head trauma underwent brain fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological assessments and completed PCS and psychiatric symptom rating scales. Compared to controls, Veterans with mTBI (with or without PTSD) exhibited decreased cerebral metabolic rate of glucose in the cerebellum, vermis, pons, and medial temporal lobe. They also exhibited subtle impairments in verbal fluency, cognitive processing speed, attention, and working memory, similar to those reported in the literature for patients with cerebellar lesions. These FDG-PET imaging findings suggest that regional brain hypometabolism may constitute a neurobiological substrate for chronic PCS in Iraq combat Veterans with repetitive blast-trauma mTBI. Given the potential public health implications of these findings, further investigation of brain function in these Veterans appears warranted.

Neuroimaging, Behavioral, and Psychological Sequelae of Repetitive Combined Blast/Impact Mild Traumatic Brain Injury in Iraq and Afghanistan War Veterans

Abstract Whether persisting cognitive complaints and postconcussive symptoms (PCS) reported by Iraq and Afghanistan war veterans with blast- and/or combined blast/impact-related mild traumatic brain injuries (mTBIs) are associated with enduring structural and/or functional brain abnormalities versus comorbid depression or posttraumatic stress disorder (PTSD) remains unclear. We sought to characterize relationships among these variables in a convenience sample of Iraq and Afghanistan-deployed veterans with (n=34) and without (n=18) a history of one or more combined blast/impact-related mTBIs. Participants underwent magnetic resonance imaging of fractional anisotropy (FA) and macromolecular proton fraction (MPF) to assess brain white matter (WM) integrity; [(18)F]-fluorodeoxyglucose positron emission tomography imaging of cerebral glucose metabolism (CMRglu); structured clinical assessments of blast exposure, psychiatric diagnoses, and PTSD symptoms; neurologic evaluations; and self-report scales of PCS, combat exposure, depression, sleep quality, and alcohol use. Veterans with versus without blast/impact-mTBIs exhibited reduced FA in the corpus callosum; reduced MPF values in subgyral, longitudinal, and cortical/subcortical WM tracts and gray matter (GM)/WM border regions (with a possible threshold effect beginning at 20 blast-mTBIs); reduced CMRglu in parietal, somatosensory, and visual cortices; and higher scores on measures of PCS, PTSD, combat exposure, depression, sleep disturbance, and alcohol use. Neuroimaging metrics did not differ between participants with versus without PTSD. Iraq and Afghanistan veterans with one or more blast-related mTBIs exhibit abnormalities of brain WM structural integrity and macromolecular organization and CMRglu that are not related to comorbid PTSD. These findings are congruent with recent neuropathological evidence of chronic brain injury in this cohort of veterans.

High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury

Studies of traumatic brain injury from all causes have found evidence of chronic hypopituitarism, defined by deficient production of one or more pituitary hormones at least 1 year after injury, in 25–50% of cases. Most studies found the occurrence of posttraumatic hypopituitarism (PTHP) to be unrelated to injury severity. Growth hormone deficiency (GHD) and hypogonadism were reported most frequently. Hypopituitarism, and in particular adult GHD, is associated with symptoms that resemble those of PTSD, including fatigue, anxiety, depression, irritability, insomnia, sexual dysfunction, cognitive deficiencies, and decreased quality of life. However, the prevalence of PTHP after blast-related mild TBI (mTBI), an extremely common injury in modern military operations, has not been characterized. We measured concentrations of 12 pituitary and target-organ hormones in two groups of male US Veterans of combat in Iraq or Afghanistan. One group consisted of participants with blast-related mTBI whose last blast exposure was at least 1 year prior to the study. The other consisted of Veterans with similar military deployment histories but without blast exposure. Eleven of 26, or 42% of participants with blast concussions were found to have abnormal hormone levels in one or more pituitary axes, a prevalence similar to that found in other forms of TBI. Five members of the mTBI group were found with markedly low age-adjusted insulin-like growth factor-I (IGF-I) levels indicative of probable GHD, and three had testosterone and gonadotropin concentrations consistent with hypogonadism. If symptoms characteristic of both PTHP and PTSD can be linked to pituitary dysfunction, they may be amenable to treatment with hormone replacement. Routine screening for chronic hypopituitarism after blast concussion shows promise for appropriately directing diagnostic and therapeutic decisions that otherwise may remain unconsidered and for markedly facilitating recovery and rehabilitation.

Understanding Pain After Traumatic Brain Injury : Impact on Community Participation

Hoffman JM, Pagulayan KF, Zawaideh N, Dikmen S, Temkin N, Bell KR: Understanding pain after traumatic brain injury: impact on community participation. Am J Phys Med Rehabil 2007;86:962–969. Objective:To examine the prevalence of pain 1 yr after moderate to severe traumatic brain injury (TBI) and identify predictors from the time of injury. Additionally, factors related to pain at 1 yr after injury were examined along with the impact of pain on community participation. Design:Prospective cohort study of 146 individuals enrolled during acute inpatient rehabilitation for TBI and community follow-up at 1 yr after injury. Results:Higher reports of depressive symptoms during inpatient rehabilitation and at 1 yr after injury were significantly related to reports of pain at 1 yr when controlling for demographic and injury characteristics. Being female and nonwhite were also factors related to increased reports of pain. Pain and community participation were significantly related until depression was entered into the model. Depression is a significant factor in the relationship between pain and community participation. Conclusion:Whereas pain was frequently reported 1 yr after injury, injury-related factors were surprisingly unrelated. Further evaluation of the role that depression plays in the relationship between pain and community participation will be important to determine appropriate management of pain and depression and to optimize participation in individuals with TBI.

The measurement and magnitude of awareness difficulties after traumatic brain injury: a longitudinal study.

Previous research suggests that reduced self-awareness is common following traumatic brain injury (TBI). However, few studies have examined the magnitude of this problem in a sample representative of hospitalized individuals. In this longitudinal study, individuals with complicated mild to severe TBIs and their significant others (SO) were evaluated at 1 and 12 months postinjury on the Sickness Impact Profile. Awareness was measured by comparing the level of injury-related problems reported by a person with TBI and their SO. Overall, individuals with TBI did not report fewer difficulties than their SO. In contrast, they frequently reported more injury-related difficulties than their SO. As there is no commonly or universally accepted definition for differential awareness, the magnitude of underreporting and over-reporting problems is presented using four different cutoff scores. A minimum discrepancy is proposed for defining awareness difficulties that is based on the standard error of measurement of the test-retest difference of the measure. Reduced self-awareness was inconsistent across both time and functional domains. These results suggest that reduced self-awareness is not the norm at 1 or 12 months postinjury and highlight the need for a more standardized approach to the measurement and classification of self-awareness.

Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction.

Ventral regions of the cerebellum in combat veterans and mice are vulnerable to long-term traumatic brain injury caused by repetitive blast exposure. The cerebellum is vulnerable to blast injury in mice and combat veterans Mild traumatic brain injury (TBI) is often referred to as the “signature injury” of the wars in Iraq and Afghanistan. Most of these TBIs are blast-related. Currently, there is limited understanding of how mild blast causes persistent brain injuries. There is also limited insight into how blast-induced brain injuries in animal models correspond to humans with mild TBI. Meabon et al. report that the cerebellum, a brain structure important for integrating sensory information and movement, is injured by blast exposure in mice in specific areas that correspond to abnormal brain imaging findings obtained in similar cerebellar regions in blast-exposed combat veterans. Blast exposure can cause mild traumatic brain injury (TBI) in mice and other mammals. However, there are important gaps in our understanding of the neuropathology underlying repetitive blast exposure in animal models compared to the neuroimaging abnormalities observed in blast-exposed veterans. Moreover, how an increase in the number of blast exposures affects neuroimaging endpoints in blast-exposed humans is not well understood. We asked whether there is a dose-response relationship between the number of blast-related mild TBIs and uptake of 18F-fluorodeoxyglucose (FDG), a commonly used indicator of neuronal activity, in the brains of blast-exposed veterans with mild TBI. We found that the number of blast exposures correlated with FDG uptake in the cerebellum of veterans. In mice, blast exposure produced microlesions in the blood-brain barrier (BBB) predominantly in the ventral cerebellum. Purkinje cells associated with these BBB microlesions displayed plasma membrane disruptions and aberrant expression of phosphorylated tau protein. Purkinje cell loss was most pronounced in the ventral cerebellar lobules, suggesting that early-stage breakdown of BBB integrity may be an important factor driving long-term brain changes. Blast exposure caused reactive gliosis in mouse cerebellum, particularly in the deep cerebellar nuclei. Diffusion tensor imaging tractography of the cerebellum of blast-exposed veterans revealed that mean diffusivity correlated negatively with the number of blast-related mild TBIs. Together, these results argue that the cerebellum is vulnerable to repetitive mild TBI in both mice and humans.

Cerebrocerebellar Hypometablism Associated With Repetitive Blast Exposure Mild Traumatic Brain Injury in 12 Iraq War Veterans With Persistent Post-Concussive Symptoms

Background: Tau is known to be a key factor in the pathogenesis of various neurodegenerative diseases, categorized as tauopathy. Because the severity of tau pathology links closely to that of neuron loss and the extent of clinical symptom, it is likely that the elucidation of the mechanism underlying tauopathy leads us to the development of tau therapeutics. For this purpose, the animal model is required, which is appropriate for the analysis of tau-neurotoxicity and the drug screening.Methods:We developed novel transgenic nematode (C. elegans) models expressing wild-type or FTDP-17 mutant (P301L and R406W) tau in all neurons at various expression levels using unc-119 promoter, and subjected them to behavioral and biochemical studies. For morphological study, tau-expressing worms were crossbred with pan-neuronal DsRed expressing line. Chemical compounds to be tested were directly administrated onto NGM culture plates. Results: Uncoordinated movement (unc) appeared even in wild-type tau-expressing worms, which was found in an expression level-dependent manner. Neuritic abnormalities are associated with the behavioral deficit. Similar extents of behavioral andmorphological abnormalities were found in R406W tau-expressing animal even in its lowest expression level that does not cause uncoordination in case of wild-type tau. Thus, the tau neurotoxicity depends on its expression level, and FTDP-17 mutation likely enhances its toxicity. Biochemical studies showed that the expressed tau was phosphorylated to a similar extent of PHF-tau, but was not fractionated into RIPA-insoluble aggregates. This suggests that the tau causes neuronal dysfunction without insoluble aggregate formation. We also found the curcumin, a major phytochemical compound in turmeric, improves not only uncoordination but also reduces neuritic abnormalities in wild-type and R406Wmutant tau-expressing nematodes. Methylene blue and treharose, both previously reported to have potent anti-aggregation effects, had no favorable effect. Conclusions: Altogether, it is likely that curcumin improves tau-induced neuronal dysfunction independent of interference with tau aggregation step.

Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction

Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. Microglial/macrophage activation was specifically associated with these restricted microdomains, as evidenced by rapid microglial process retraction, increased ameboid morphology, and escape of blood-borne Q-dot tracers that were internalized in microglial/macrophage cell bodies and phagosome-like compartments. Microdomains of cortical vascular disruption and microglial/macrophage activation were also associated with aberrant tight junction morphology that was more prominent after repetitive (3×) blast exposure. Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.

Compensatory Cognitive Training for Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn Veterans With Mild Traumatic Brain Injury.

Objective: The purpose of the study was to evaluate the efficacy of group-based compensatory cognitive training (CCT) for Operation Enduring Freedom (OEF)/Operation Iraqi Freedom(OIF)/Operation New Dawn (OND) Veterans with a history of mild traumatic brain injury. Method: One hundred nineteen OEF/OIF/OND Veterans with history of mild traumatic brain injury participated at 3 sites, and 50 of the Veterans were randomized to CCT group, while 69 Veterans were randomized to the usual care control group. The CCT group participated in 10 weeks of CCT. Both CCT and usual care groups were assessed at baseline, 5 weeks (midway through CCT), 10 weeks (immediately following CCT), and 15 weeks (5-week follow-up) on measures of subjective cognitive complaints, use of cognitive strategies, psychological functioning, and objective cognitive performance. Results: Veterans who participated in CCT reported significantly fewer cognitive and memory difficulties and greater use of cognitive strategies. They also demonstrated significant improvements on neurocognitive tests of attention, learning, and executive functioning, which were 3 of the cognitive domains targeted in CCT. Conclusions: Findings indicate that training in compensatory cognitive strategies facilitates behavioral change (ie, use of cognitive strategies) as well as both subjective and objective improvements in targeted cognitive domains.

Prevalence of Alcohol Misuse and Follow-Up Care in a National Sample of OEF/OIF VA Patients With and Without TBI

OBJECTIVE Information on prevalence and management of alcohol misuse among Afghanistan and Iraq veterans with traumatic brain injury (TBI) is limited. This study compared rates of alcohol misuse and follow-up care-brief intervention (BI) and addiction treatment-among Afghanistan and Iraq veterans with and without TBI receiving care from the Department of Veterans Affairs (VA). METHODS The sample included veterans ages 18 and older screened with the Alcohol Use Disorders Identification Test alcohol consumption questions (AUDIT-C) in 2012 who received VA health care in the prior year (N=358,417). Overall and age-specific estimates of alcohol misuse (AUDIT-C score ≥5) were compared for men and women with and without TBI by logistic regression. BI and addiction treatment after screening were compared between groups by using multivariable logistic regression. RESULTS Alcohol misuse was higher among men with TBI than among men without TBI (20.3%, 95% confidence interval [CI]=19.9-20.8, versus 16.4%, CI=16.3-16.6) and among women with TBI than among women without TBI (6.8%, CI=5.8-8.1, versus 5.6%, CI=5.4-5.8); younger (age <30) patients with TBI had the highest rates. BI rates did not differ by TBI status (76.4%-80.2%). Addiction treatment rates for those with severe misuse were higher among those with TBI (men, 20.0%, CI=18.4-21.6, versus 15.4%, CI=14.9-15.9; women, 36.6%, CI=21.8-51.3, versus 21.1%, CI=18.2-24.0). CONCLUSIONS Alcohol misuse is common among Iraq and Afghanistan veterans with TBI, particularly young men. BI rates were high and did not vary by TBI status, although addiction treatment rates were higher among patients with TBI than among those without TBI.