Faculty Bibliography

BACKGROUND:Mild traumatic brain injury (mTBI) secondary to blast exposure is the most common battlefield injury in Southwest Asia. There has been little prospective work in the combat setting to test the efficacy of new countermeasures. The goal of this study was to compare the efficacy of N-acetyl cysteine (NAC) versus placebo on the symptoms associated with blast exposure mTBI in a combat setting. METHODS:This study was a randomized double blind, placebo-controlled study that was conducted on active duty service members at a forward deployed field hospital in Iraq. All symptomatic U.S. service members who were exposed to significant ordnance blast and who met the criteria for mTBI were offered participation in the study and 81 individuals agreed to participate. Individuals underwent a baseline evaluation and then were randomly assigned to receive either N-acetyl cysteine (NAC) or placebo for seven days. Each subject was re-evaluated at 3 and 7 days. Outcome measures were the presence of the following sequelae of mTBI: dizziness, hearing loss, headache, memory loss, sleep disturbances, and neurocognitive dysfunction. The resolution of these symptoms seven days after the blast exposure was the main outcome measure in this study. Logistic regression on the outcome of 'no day 7 symptoms' indicated that NAC treatment was significantly better than placebo (OR = 3.6, p = 0.006). Secondary analysis revealed subjects receiving NAC within 24 hours of blast had an 86% chance of symptom resolution with no reported side effects versus 42% for those seen early who received placebo. CONCLUSION/CONCLUSIONS:This study, conducted in an active theatre of war, demonstrates that NAC, a safe pharmaceutical countermeasure, has beneficial effects on the severity and resolution of sequelae of blast induced mTBI. This is the first demonstration of an effective short term countermeasure for mTBI. Further work on long term outcomes and the potential use of NAC in civilian mTBI is warranted. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT00822263.

BACKGROUND:This study examines the effect of initiating medications with anticholinergic activity on the cognitive functions of older persons. METHODS:Participants were 896 older community-dwelling, Catholic clergy without baseline dementia. Medication data was collected annually. The Anticholinergic Cognitive Burden Scale was utilized to identify use of a medication with probable or definite anticholinergic activity. Participants had at least two annual cognitive evaluations. RESULTS:Over a mean follow-up of 10 years, the annual rate of global cognitive function decline for never users, prevalent users, and incident users was -0.062 (SE = 0.005), -0.081(SE = 0.011), and -0.096 (SE = 0.007) z-score units/year, respectively. Compared to never users, incident users had a more rapid decline (difference = -0.034 z-score units/year, SE = 0.008, p<0.001) while prevalent users did not have a significantly more rapid decline (p = 0.1). CONCLUSIONS:Older persons initiating a medication with anticholinergic activity have a steeper annual decline in cognitive functioning than those who are not taking these medications.

BACKGROUND:Computerized neurocognitive testing (NCAT) has been proposed to be useful as a screening tool for post-deployment cognitive deficits in the setting of mild traumatic brain injury (mTBI). We assessed the clinical utility of post-injury/post-deployment Automated Neurocognitive Assessment Metric (ANAM) testing, using a longitudinal design to compare baseline ANAM tests with two post-deployment ANAM tests in a group of Marines who experienced combat during deployment. METHODS AND FINDINGS/RESULTS:Post-deployment cognitive performance and symptom recovery were compared in a subsample of 1324 U.S. Marines with high rates of combat exposure during deployment. Of the sample, 169 Marines had available baseline and twice repeated post-deployment ANAM results. A retrospective analysis of the ANAM data, which consisted of a self-report questionnaire about deployment-related blast exposure, recent history of mTBI, current clinical symptoms, and cognitive performance. Self-reported concussion sustained anytime during deployment was associated with a decrease in cognitive performance measured between 2-8 weeks post-deployment. At the second post-deployment test conducted on average eight months later, performance on the second simple reaction time test, in particular, remained impaired and was the most consistent and sensitive indicator of the cognitive decrements. Additionally, post-concussive symptoms were shown to persist in injured Marines with a self-reported history of concussion for an additional five months after most cognitive deficits resolved. Results of this study showed a measurable deployment effect on cognitive performance, although this effect appears to resolve without lasting clinical sequelae in those without history of deployment-related concussion. CONCLUSIONS:These results highlight the need for a detailed clinical examination for service members with history of concussion and persistent clinical symptoms. Reliance solely upon computerized neurocognitive testing as a method for identifying service members requiring clinical follow-up post-concussion is not recommended, as cognitive functioning only slowly returned to baseline levels in the setting of persistent clinical symptoms.

OBJECTIVE:Drawing on two different populations, Israeli police and Hungarian civilians, the present study assessed the ability of individuals with posttraumatic stress disorder (PTSD) to generalize previous learning to novel situations. Past neuroimaging studies have demonstrated diminished medial temporal lobe (MTL) activation and/or reduced hippocampal volume in individuals with PTSD. Our earlier computational models of cortico-hippocampal function and subsequent experimental tests of these models in MTL-impaired clinical populations argue that even mild hippocampal dysfunction may result in subtle impairments in generalization. Therefore, we predicted that individuals with PTSD would show impaired generalization. METHOD/METHODS:We compared the performance of five groups from two countries, including 19 Israeli police with PTSD and 22 trauma-exposed police without PTSD, and 22 Hungarian civilians with PTSD, 25 trauma-exposed civilians without PTSD, and 25 individuals without PTSD unexposed to the same trauma. Participants were tested on a two-phase learning paradigm, the Acquired Equivalence Task, which measures the ability to generalize past learning to novel situations. RESULTS:We found that both PTSD and non-PTSD participants were capable of learning the initial stimulus-outcome associations, F(4, 108) = 1.79, p = .14. However, as predicted, only individuals with PTSD showed a selective deficit in generalization of this learning to novel situations (F(4, 108) = 8.35, p < .001, Partial η2 = 0.26). CONCLUSIONS:Individuals with PTSD show a selective impairment in generalization of past learning similar to other clinical populations with MTL/hippocampal dysfunction. This is consistent with an emerging view of PTSD as being not only an anxiety disorder but also a learning disorder.

In their recent paper, Goldstein et al. show murine brain tau neuropathology after explosive blast with head rotation but do not present additional evidence that would delineate whether this neuropathology was principally caused by blast exposure alone or by blast exposure plus head rotational injury.

OBJECTIVE:This study evaluated usage of the Army Knowledge Online (AKO) Telemedicine Consultation Program for neurology and traumatic brain injury (TBI) cases in remote overseas areas with limited access to subspecialists. We performed a descriptive analysis of quantity of consults, response times, sites where consults originated, military branches that benefitted, anatomic locations of problems, and diagnoses. METHODS:This was a retrospective analysis that searched electronic databases for neurology consults from October 2006 to December 2010 and TBI consults from March 2008 to December 2010. RESULTS:A total of 508 consults were received for neurology, and 131 consults involved TBI. For the most part, quantity of consults increased over the years. Meanwhile, response times decreased, with a mean response time of 8 hours, 14 minutes for neurology consults and 2 hours, 44 minutes for TBI consults. Most neurology consults originated in Iraq (67.59%) followed by Afghanistan (16.84%), whereas TBI consults mainly originated from Afghanistan (40.87%) followed by Iraq (33.91%). The most common consultant diagnoses were headaches, including migraines (52.1%), for neurology cases and mild TBI/concussion (52.3%) for TBI cases. In the majority of cases, consultants recommended in-theater management. After receipt of consultant's recommendation, 84 known neurology evacuations were facilitated, and 3 known neurology evacuations were prevented. CONCLUSIONS:E-mail-based neurology and TBI subspecialty teleconsultation is a viable method for overseas providers in remote locations to receive expert recommendations for a range of neurologic conditions. These recommendations can facilitate medically necessary patient evacuations or prevent evacuations for which on-site care is preferable.

Overactive bladder (OAB) is a common condition, particularly in the elderly. Anticholinergic agents are the mainstay of pharmacological treatment of OAB; however, many anticholinergics can cross the blood-brain barrier (BBB) and may cause central nervous system (CNS) effects, including cognitive deficits, which can be especially detrimental in older patients. Many anticholinergics have the potential to cause adverse CNS effects due to muscarinic (M(1)) receptor binding in the brain. Of note, permeability of the BBB increases with age and can also be affected by trauma, stress, and some diseases and medications. Passive crossing of a molecule across the BBB into the brain is dependent upon its physicochemical properties. Molecular characteristics that hinder passive BBB penetration include a large molecular size, positive or negative ionic charge at physiological pH, and a hydrophilic structure. Active transport across the BBB is dependent upon protein-mediated transporter systems, such as that of permeability-glycoprotein (P-gp), which occurs only for P-gp substrates, such as trospium chloride, darifenacin and fesoterodine. Reliance on active transport can be problematic since genetic polymorphisms of P-gp exist, and many commonly used drugs and even some foods are P-gp inhibitors or are substrates themselves and, due to competition, can reduce the amount of the drug that is actively transported out of the CNS. Therefore, for drugs that are preferred not to cross into the CNS, such as potent anticholinergics intended for the bladder, it is optimal to have minimal passive crossing of the BBB, although it may also be beneficial for the drug to be a substrate for an active efflux transport system. Anticholinergics demonstrate different propensities to cross the BBB. Darifenacin, fesoterodine and trospium chloride are substrates for P-gp and, therefore, are actively transported away from the brain. In addition, trospium chloride has not been detected in cerebrospinal fluid assays and does not appear to have significant CNS penetration. This article reviews the properties of anticholinergics that affect BBB penetration and active transport out of the CNS, discusses issues of increased BBB permeability in patients with OAB, and examines the clinical implications of BBB penetration on adverse events associated with anticholinergics.

Patients face two major difficulties following limb loss: phantom limb pain (PLP) in the residual limb and limited functionality in the prosthetic limb. Many studies have focused on decreasing PLP with mirror therapy, yet few have examined the same visual ameliorating effect with a virtual or prosthetic limb. Our study addresses the following key questions: (1) does PLP decrease through observation of a 3D limb in a virtual integration environment (VIE) and (2) can consistent surface electromyography (sEMG) signals from the VIE drive an advanced modular prosthetic limb (MPL)? Recorded signals from the residual limb were correlated to the desired motion of the phantom limb, and changes in PLP were scored during each VIE session. Preliminary results show an overall reduction in PLP and a trend toward improvement in signal-to-motion accuracy over time. These signals allowed MPL users to perform a wide range of hand motions.

BACKGROUND:After amputation, the sensorimotor cortex reorganizes, and these alterations might influence motor functions of the remaining extremities. OBJECTIVE:The authors examined how amputation of the dominant or nondominant upper or lower extremity alters deftness in the intact limbs. METHODS:The participants were 32 unilateral upper- or lower-extremity amputees and 6 controls. Upper-extremity deftness was tested by coin rotation (finger deftness) and pegboard (arm, hand, and finger deftness) tasks. RESULTS:Following right-upper- or right-lower-extremity amputation, the left hand's finger movements were defter than the left-hand fingers of controls. In contrast, with left-upper- or left-lower-extremity amputation, the right hand's finger performance was the same as that of the controls. CONCLUSIONS:Although this improvement might be related to increased use (practice), the finding that right-lower-extremity amputation also improved the left hand's finger deftness suggests an alternative mechanism. Perhaps in right-handed persons the left motor cortex inhibits the right side of the body more than the right motor cortex inhibits the left side, and the physiological changes induced by right-sided amputation reduced this inhibition.

The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition-and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07-2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted.