Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge

Li, Xiufeng; Spence, Jeffrey S.; Buhner, David M.; Hart, John; Cullum, C. Munro; Biggs, Melanie M.; Hester, Andrea L.; Odegard, Timothy N.; Carmack, Patrick S.; Briggs, Richard W.; Haley, Robert W.

doi:10.1148/radiol.11101715

Cited by 59 publications

(50 citation statements)

References 39 publications

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“…These findings are akin to depression, anxiety, and cognitive dysfunction reported in veterans with GWI David et al, 2002;Li et al, 2011;Odegard et al, 2012). At the structural level, these impairments were associated with persistent reductions in dentate neurogenesis, partial loss of principal neurons, mild neuroinflammation, and reduced hippocampal volume.…”

Section: Discussionmentioning

confidence: 73%

Mood and Memory Deficits in a Model of Gulf War Illness Are Linked with Reduced Neurogenesis, Partial Neuron Loss, and Mild Inflammation in the Hippocampus

Parihar

Hattiangady

Shuai

et al. 2013

Neuropsychopharmacol

156

190

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Impairments in mood and cognitive function are the key brain abnormalities observed in Gulf war illness (GWI), a chronic multisymptom health problem afflicting ∼25% of veterans who served in the Persian Gulf War-1. Although the precise cause of GWI is still unknown, combined exposure to a nerve gas prophylaxis drug pyridostigmine bromide (PB) and pesticides DEET and permethrin during the war has been proposed as one of the foremost causes of GWI. We investigated the effect of 4 weeks of exposure to Gulf war illness-related (GWIR) chemicals in the absence or presence of mild stress on mood and cognitive function, dentate gyrus neurogenesis, and neurons, microglia, and astrocytes in the hippocampus. Combined exposure to low doses of GWIR chemicals PB, DEET, and permethrin induced depressive- and anxiety-like behavior and spatial learning and memory dysfunction. Application of mild stress in the period of exposure to chemicals exacerbated the extent of mood and cognitive dysfunction. Furthermore, these behavioral impairments were associated with reduced hippocampal volume and multiple cellular alterations such as chronic reductions in neural stem cell activity and neurogenesis, partial loss of principal neurons, and mild inflammation comprising sporadic occurrence of activated microglia and significant hypertrophy of astrocytes. The results show the first evidence of an association between mood and cognitive dysfunction and hippocampal pathology epitomized by decreased neurogenesis, partial loss of principal neurons, and mild inflammation in a model of GWI. Hence, treatment strategies that are efficacious for enhancing neurogenesis and suppressing inflammation may be helpful for alleviation of mood and cognitive dysfunction observed in GWI.

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Section: Discussionmentioning

confidence: 73%

Mood and Memory Deficits in a Model of Gulf War Illness Are Linked with Reduced Neurogenesis, Partial Neuron Loss, and Mild Inflammation in the Hippocampus

Parihar

Hattiangady

Shuai

et al. 2013

Neuropsychopharmacol

156

190

View full text Add to dashboard Cite

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“…A recent longitudinal study of American Gulf War veterans has shown alterations of the HPA axis (such as impairment in the response to ACTH to CRF and increased cortisol levels after stimulation) and of the neuroendocrine profile of the veterans (54,98). In addition, chronic and persistent abnormalities of hippocampal blood flow and alterations of levels of the neuronal markers N-acetylaspartate in the basal ganglia and pons have also been documented in Gulf War Veterans (99,102,177).…”

Section: Warmentioning

confidence: 99%

Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology

Schiavone

Jaquet

Trabace

et al. 2013

Antioxidants & Redox Signaling

289

211

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Significance: Severe life stress (SLS), as opposed to trivial everyday stress, is defined as a serious psychosocial event with the potential of causing an impacting psychological traumatism. Recent Advances: Numerous studies have attempted to understand how the central nervous system (CNS) responds to SLS. This response includes a variety of morphological and neurochemical modifications; among them, oxidative stress is almost invariably observed. Oxidative stress is defined as disequilibrium between oxidant generation and the antioxidant response. Critical Issues: In this review, we discuss how SLS leads to oxidative stress in the CNS, and how the latter impacts pathophysiological outcomes. We also critically discuss experimental methods that measure oxidative stress in the CNS. The review covers animal models and human observations. Animal models of SLS include sleep deprivation, maternal separation, and social isolation in rodents, and the establishment of hierarchy in non-human primates. In humans, SLS, which is caused by traumatic events such as child abuse, war, and divorce, is also accompanied by oxidative stress in the CNS. Future Directions: The outcome of SLS in humans ranges from resilience, over post-traumatic stress disorder, to development of chronic mental disorders. Defining the sources of oxidative stress in SLS might in the long run provide new therapeutic avenues.

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“…Accordingly, in addition to being nociceptor populations that are demonstrated to respond to NTPB with maladapted K v 7 and Na v 1.9, they are also candidates for chronic misregulation of muscarinic receptors by anticholinesterases. That vascular nociceptors are the focus for many of the molecular and functional defects associated with NTPB might be reflective of known cholinergic vascular reflex dysfunctions in veterans suffering from GWI (Haley et al, 2009;Liu et al, 2010;Li et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The up-regulation of K v 7 current in vascular nociceptors could have been an adaptation to disturbed cholinergic regulation due to extended exposure to cholinesterase inhibitors. In recent reports, there is evidence of cholinergic vascular reflex anomalies in GWI veterans (Haley et al, 2009;Liu et al, 2010;Li et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Actions of Pyridostigmine Bromide and Insecticides on Muscle and Vascular Nociceptors

Cooper¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)July 2013 (From -To) 15 5e. TASK NUMBER 5f. WORK UNIT NUMBER REPORT TYPE Annual DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) University of Florida AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERGainesville, Fl 32611-5500 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and MaAnd Material Command Fort Detrick, Maryland SPONSOR/MONITOR'S REPORT 21702-5012 NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release: distribution unlimited SUPPLEMENTARY NOTES ABSTRACTWe examined whether chronic exposure to combinations of two neurotoxicants (chlorpyrifos and permethrin) with pyridostigmine bromide (PB) could produce a delayed neuropathic pain condition in rats; and whether corresponding molecular changes would occur in nociceptive neurons coding for pain in skin, muscle or vasculature. Following a 60 day exposure to neurotoxicants/PB (NTPB), we observed molecular dysfunctions in membrane Kv (Kv7) and Nav (Nav1.8, Nav1.9) proteins that persisted 8 weeks after exposure had ended. Functional changes (spontaneous activity, action potential duration) were also documented. Most of the maladaptations were present in vascular nociceptors. The physical location of vascular nociceptive neurons renders them most exposed to concentrations of circulating neurotoxicants/PB as well as to any blood borne secondary influences (endocrine, immune) these agents might induce. As a result, vascular nociceptors could be the first nervous system component damaged by neurotoxicants/PB. An imbalance between Kv 7 and other Na + channel proteins (Nav1.9) could prove to be a basis for a chronic pain condition sourced from a vulnerable subset of vascular nociceptors. A resulting neurovascular reflex dysfunction could cause widespread pain and also contribute to the development of CNS symptoms that have been identified in Gulf War veterans. . The events leading to the development of GWI pain are unknown, but it has been reported that the use of pyridostigmine bromide (PB) and a variety of insecticides/repellants co-var...

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Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge

Cited by 59 publications

References 39 publications

Mood and Memory Deficits in a Model of Gulf War Illness Are Linked with Reduced Neurogenesis, Partial Neuron Loss, and Mild Inflammation in the Hippocampus

Mood and Memory Deficits in a Model of Gulf War Illness Are Linked with Reduced Neurogenesis, Partial Neuron Loss, and Mild Inflammation in the Hippocampus

Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology

Synergistic Actions of Pyridostigmine Bromide and Insecticides on Muscle and Vascular Nociceptors

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