Subtle Neurologic Compromise as a Vulnerability Factor for Combat-Related Posttraumatic Stress Disorder

Gurvits, Tamara V.; Metzger, Linda J.; Lasko, Natasha B.; Cannistraro, Paul A.; Tarhan, Alexandra S.; Gilbertson, Mark W.; Orr, Scott P.; Charbonneau, Anna M.; Wedig, Michelle M.; Pitman, Roger K.

doi:10.1001/archpsyc.63.5.571

Cited by 69 publications

(66 citation statements)

References 26 publications

(44 reference statements)

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“…86 Similarly, PTSD, which is highly co-morbid with depression, has been proposed based on a variety of data, to be due in part to a deficit in extinction of fear. [29][30][31][32] A recently published study also demonstrates that there may be spatial memory deficits, for example copying figures and other similar neurological soft signs, in twin subjects with PTSD compared to their identical twin without PTSD, 87 consistent with the correlations seen here between spatial memory performance in the water maze and extinction of fear.…”

Section: Extinction Deficit With Hippocampal Bdnf Deletionssupporting

confidence: 83%

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

et al. 2007

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Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the synaptic plasticity underlying the acquisition and/or consolidation of certain forms of memory. Additionally, a role has been suggested for neurotrophin function within the hippocampus in protection from anxiety and depressive disorders. Understanding the function of this important gene in adult animals has been limited however, because standard knockouts are confounded by gene effects during development. There are no BDNF receptor-specific pharmacological agents, and infusions of neuropeptides or antibodies have other significant limitations. In these studies, we injected a lentivirus expressing Cre recombinase bilaterally into the dorsal hippocampus in adult mice floxed at the BDNF locus to facilitate the sitespecific deletion of the BDNF gene in adult animals. Significant decreases in BDNF mRNA expression are demonstrated in the hippocampi of lenti-Cre-infected animals compared with control lenti-GFP-infected animals. Behaviorally, there were no significant effects of BDNF deletion on locomotion or baseline anxiety measured with startle. In contrast, hippocampalspecific BDNF deletions impair novel object recognition and spatial learning as demonstrated with the Morris water maze. Although there were no effects on the acquisition or expression fear, animals with BDNF deletions show significantly reduced extinction of conditioned fear as measured both with fear-potentiated startle and freezing. These data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.

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Section: Extinction Deficit With Hippocampal Bdnf Deletionssupporting

confidence: 83%

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

et al. 2007

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“…Monozygotic twin studies of Vietnam veterans suggest that subtle ("soft") NDs, which likely resulted from mild inherited alterations in cerebral function, may predispose to PTSD [50]. The 45 neurological signs measured in the Vietnam veterans were similar to the elements of the neurological examination performed in this study.…”

Section: Variablesupporting

confidence: 66%

“…Monozygotic twins were studied where one twin was in combat and the other not. Among twins pairs where the twin who had been in combat developed PTSD, both twins had a higher prevalence of neurological soft signs [50] or gray matter abnormalities in the right hippocampus, pregenual anterior cingulate cortex, and left and right insular cortex [51] than the twin pairs where the combat-exposed twin did not have PTSD. The presence of similar patterns of NDs among both of the monozygotic twins suggests that the observed NDs were genetic in origin.…”

Section: Variablementioning

confidence: 89%

For veterans with mild traumatic brain injury, improved posttraumatic stress disorder severity and sleep correlated with symptomatic improvement

Ruff

Riechers²,

Wang³

et al. 2012

JRRD

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Abstract-This was an observational study of a cohort of 63 Operation Iraqi Freedom/Operation Enduring Freedom veterans with mild traumatic brain injury (mTBI) associated with an explosion. They had headaches, residual neurological deficits (NDs) on neurological examination, and posttraumatic stress disorder (PTSD) and were seen on average 2.5 years after their last mTBI. We treated them with sleep hygiene counseling and oral prazosin. We monitored headache severity, daytime sleepiness using the Epworth Sleepiness Scale, cognitive performance using the Montreal Cognitive Assessment test, and the presence of NDs. We quantitatively measured olfaction and assessed PTSD severity using the PTSD Checklist-Military Version. Nine weeks after starting sleep counseling and bedtime prazosin, the veterans' headache severity decreased, cognitive function as assayed with a brief screening tool improved, and daytime sleepiness diminished. Six months after completing treatment, the veterans demonstrated additional improvement in headache severity and daytime sleepiness and their improvements in cognitive function persisted. There were no changes in the prevalence of NDs or olfaction scores. Clinical improvements correlated with reduced PTSD severity and daytime sleepiness. The data suggested that reduced clinical manifestations following mTBI correlated with PTSD severity and improvement in sleep, but not the presence of NDs or olfaction impairment.

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“…There is a significant genetic component to risk for PTSD (Kendler, 2001), as well as neurological abnormalities in unaffected probands that are suggestive of antecedent genetic or familial risk factors (Gurvits et al, 2006). Functional neuroimaging studies have identified hyperactivity of the amygdala as a neural correlate for the clinical symptoms seen in PTSD Shin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Variation in Mouse Basolateral Amygdala Volume is Associated With Differences in Stress Reactivity and Fear Learning

Yang

Mozhui

Karlsson

et al. 2008

Neuropsychopharmacol

131

106

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A wealth of research identifies the amygdala as a key brain region mediating negative affect, and implicates amygdala dysfunction in the pathophysiology of anxiety disorders. Although there is a strong genetic component to anxiety disorders such as posttraumatic stress disorder (PTSD) there remains debate about whether abnormalities in amygdala function predispose to these disorders. In the present study, groups of C57BL/6 Â DBA/2 (B Â D) recombinant inbred strains of mice were selected for differences in volume of the basolateral amygdala complex (BLA). Strains with relatively small, medium, or large BLA volumes were compared for Pavlovian fear learning and memory, anxiety-related behaviors, depression-related behavior, and glucocorticoid responses to stress. Strains with relatively small BLA exhibited stronger conditioned fear responses to both auditory tone and contextual stimuli, as compared to groups with larger BLA. The small BLA group also showed significantly greater corticosterone responses to stress than the larger BLA groups. BLA volume did not predict clear differences in measures of anxiety-like behavior or depression-related behavior, other than greater locomotor inhibition to novelty in strains with smaller BLA. Neither striatal, hippocampal nor cerebellar volumes correlated significantly with any behavioral measure. The present data demonstrate a phenotype of enhanced fear conditioning and exaggerated glucocorticoid responses to stress associated with small BLA volume. This profile is reminiscent of the increased fear processing and stress reactivity that is associated with amygdala excitability and reduced amygdala volume in humans carrying loss of function polymorphisms in the serotonin transporter and monoamine oxidase A genes. Our study provides a unique example of how natural variation in amygdala volume associates with specific fear-and stress-related phenotypes in rodents, and further supports the role of amygdala dysfunction in anxiety disorders such as PTSD.

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Subtle Neurologic Compromise as a Vulnerability Factor for Combat-Related Posttraumatic Stress Disorder

Cited by 69 publications

References 26 publications

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

For veterans with mild traumatic brain injury, improved posttraumatic stress disorder severity and sleep correlated with symptomatic improvement

Variation in Mouse Basolateral Amygdala Volume is Associated With Differences in Stress Reactivity and Fear Learning

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