[Show abstract][Hide abstract] ABSTRACT: Post-traumatic stress disorder (PTSD) is a mental health injury characterised by re-experiencing, avoidance, numbing and hyperarousal. Whilst the aetiology of the disorder is relatively well understood, there is debate about the prevalence of cognitive sequelae that manifest in PTSD. In particular, there are conflicting reports about deficits in executive function and mental flexibility. Even less is known about the neural changes that underlie such deficits. Here, we used magnetoencephalography to study differences in functional connec-tivity during a mental flexibility task in combat-related PTSD (all males, mean age = 37.4, n = 18) versus a military control (all males, mean age = 33.05, n = 19) group. We observed large-scale increases in theta connectivity in the PTSD group compared to controls. The PTSD group performance was compromised in the more attentionally-demanding task and this was characterised by 'late-stage' theta hyperconnectivity, concentrated in network connections involving right parietal cortex. Furthermore, we observed significant correlations with the connectivity strength in this region with a number of cognitive-behavioural outcomes , including measures of attention, depression and anxiety. These findings suggest atypical coordination of neural synchronisation in large scale networks contributes to deficits in mental flexibility for PTSD populations in timed, attentionally-demanding tasks, and this propensity toward network hyperconnectivity may play a more general role in the cogni-tive sequelae evident in this disorder.
PLoS ONE 04/2015; 10(4). DOI:10.1371/journal.pone.0123541 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Awareness to neurocognitive issues after mild traumatic brain injury (mTBI) is increasing, but currently no imaging markers are available for mTBI. Advanced structural imaging recently showed microstructural tissue changes and axonal injury, mild but likely sufficient to lead to functional deficits. Magnetoencephalography (MEG) has high temporal and spatial resolution, combining structural and electrophysiological information, and can be used to examine brain activation patterns of regions involved with specific tasks.
Methods 16 adults with mTBI and 16 matched controls were submitted to neuropsychological testing (Wechsler Abbreviated Scale of Intelligence (WASI); Conners; Alcohol Use Disorders Identification Test (AUDIT); Generalised Anxiety Disorder Seven-item Scale (GAD-7); Patient Health Questionnaire (PHQ-9); Symptom Checklist and Symptom Severity Score (SCAT2)) and MEG while tested for mental flexibility (Intra-Extra Dimensional set-shifting tasks). Three-dimensional maps were generated using synthetic aperture magnetometry beamforming analyses to identify differences in regional activation and activation times. Reaction times and accuracy between groups were compared using 2×2 mixed analysis of variance.
Findings While accuracy was similar, patients with mTBI reaction time was delayed and sequence of activation of brain regions disorganised, with involvement of extra regions such as the occipital lobes, not used by controls. Examination of activation time showed significant delays in the right insula and left posterior parietal cortex in patients with mTBI.
Conclusions Patients with mTBI showed significant delays in the activation of important areas involved in executive function. Also, more regions of the brain are involved in an apparent compensatory effort. Our study suggests that MEG can detect subtle neural changes associated with cognitive dysfunction and thus, may eventually be useful for capturing and tracking the onset and course of cognitive symptoms associated with mTBI.
[Show abstract][Hide abstract] ABSTRACT: Posttraumatic stress disorder (PTSD) is a mental disorder that stems from exposure to one or more traumatic events. While PTSD is thought to result from a dysregulation of emotional neurocircuitry, neurocognitive difficulties are frequently reported. Mental flexibility is a core executive function that involves the ability to shift and adapt to new information. It is essential for appropriate social-cognitive behaviours. Magnetoencephalography (MEG), a neuroimaging modality with high spatial and temporal resolution, has been used to track the progression of brain activation during tasks of mental flexibility called set-shifting. We hypothesized that the sensitivity of MEG would be able to capture the abnormal neurocircuitry implicated in PTSD and this would negatively impact brain regions involved in set-shifting. Twenty-two soldiers with PTSD and 24 matched control soldiers completed a colour-shape set-shifting task. MEG data were recorded and source localized to identify significant brain regions involved in the task. Activation latencies were obtained by analysing the time course of activation in each region. The control group showed a sequence of activity that involved dorsolateral frontal cortex, insula and posterior parietal cortices. The soldiers with PTSD showed these activations but they were interrupted by activations in paralimbic regions. This is consistent with models of PTSD that suggest dysfunctional neurocircuitry is driven by hyper-reactive limbic areas that are not appropriately modulated by prefrontal cortical control regions. This is the first study identifying the timing and location of atypical neural responses in PTSD with set-shifting and supports the model that hyperactive limbic structures negatively impact cognitive function.
[Show abstract][Hide abstract] ABSTRACT: Post-traumatic stress disorder (PTSD) is a serious mental health injury which can manifest after experiencing a traumatic life event. The disorder is characterized by symptoms of re-experiencing, avoidance, emotional numbing and hyper-arousal. Whilst its aetiology and resultant symptomology are better understood, relatively little is known about the underlying cortical pathophysiology, and in particular whether changes in functional connectivity may be linked to the disorder. Here, we used non-invasive neuroimaging with magnetoencephalography to examine functional connectivity in a resting-state protocol in the combat-related PTSD group (n = 23), and a military control group (n = 21). We identify atypical long-range hyperconnectivity in the high-gamma-band resting-state networks in a combat-related PTSD population compared to soldiers who underwent comparable environmental exposure but did not develop PTSD. Using graph analysis, we demonstrate that apparent network connectivity of relevant brain regions is associated with cognitive-behavioural outcomes. We also show that left hippocampal connectivity in the PTSD group correlates with scores on the well-established PTSD Checklist (PCL). These findings indicate that atypical synchronous neural interactions may underlie the psychological symptoms of PTSD, whilst also having utility as a potential biomarker to aid in the diagnosis and monitoring of the disorder.
[Show abstract][Hide abstract] ABSTRACT: It is well known that we continuously filter incoming sensory information, selectively allocating attention to what is important while suppressing distracting or irrelevant information. Yet questions remain about spatiotemporal patterns of neural processes underlying attentional biases toward emotionally significant aspects of the world. One index of affectively biased attention is an emotional variant of an attentional blink (AB) paradigm, which reveals enhanced perceptual encoding for emotionally salient over neutral stimuli under conditions of limited executive attention. The present study took advantage of the high spatial and temporal resolution of magnetoencephalography (MEG) to investigate neural activation related to emotional and neutral targets in an AB task. MEG data were collected while participants performed a rapid stimulus visual presentation task in which two target stimuli were embedded in a stream of distractor words. The first target (T1) was a number and the second (T2) either an emotionally salient or neutral word. Behavioural results replicated previous findings of greater accuracy for emotionally salient than neutral T2 words. MEG source analyses showed that activation in orbitofrontal cortex, characterized by greater power in the theta and alpha bands, and dorsolateral prefrontal activation were associated with successful perceptual encoding of emotionally salient relative to neutral words. These effects were observed between 250 and 550 ms, latencies associated with discrimination of perceived from unperceived stimuli. These data suggest that important nodes of both emotional salience and frontoparietal executive systems are associated with the emotional modulation of the attentional blink.
PLoS ONE 04/2014; 9(4):e93753. DOI:10.1371/journal.pone.0093753 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Activation of polymorphonuclear neutrophils (PMN) is thought to contribute to traumatic brain injury (TBI). Because hypertonic fluids can inhibit PMN activation, we studied whether hypertonic fluid resuscitation can reduce PMN activation in TBI patients.
Trauma patients with severe TBI were resuscitated with 250 ml of either 7.5% hypertonic saline (HS; n=22), HS + 6% dextran-70 (HSD; n=22), or 0.9% normal saline (NS; n=39) and blood samples were collected on hospital admission and 12 and 24 h after resuscitation. PMN activation (CD11b, CD62L, CD64) and degranulation (CD63, CD66b, CD35) markers and oxidative-burst activity as well as spontaneous PMN apoptosis were measured by flow cytometry.
Relative to healthy controls, TBI patients showed increased PMN activation and decreased apoptosis of PMN. In the HS group, but not in the HSD group, markers of PMN adhesion (CD11b, CD64) and degranulation (CD35, CD66b) were significantly lower than in the NS group. These effects were particularly pronounced 12 h after resuscitation. Treatment with HS and HSD inhibited PMN oxidative burst responses compared to NS-treated patients. HS alone partially restored apoptosis. Despite these differences, the groups did not differ in clinical outcome parameters such as mortality and Extended Glasgow Outcome Scale.
This study demonstrates that pre-hospital resuscitation with HS can partially restore normal PMN activity and the apoptotic behavior or PMNs, while resuscitation with HSD was largely ineffective. Although the results are intriguing, additional research will be required to translate these effects of HS into treatment strategies that improve clinical outcome in TBI patients.
[Show abstract][Hide abstract] ABSTRACT: The objectives of this review are to assess the current state of hypertonic saline as a prehospital resuscitation fluid in hypotensive trauma patients, particularly after the 3 major Resuscitation Outcomes Consortium trauma trials in the US and Canada were halted due to futility. Hemorrhage and traumatic brain injury are the leading causes of death in both military and civilian populations. Prehospital fluid resuscitation remains controversial in civilian trauma, but small-volume resuscitation with hypertonic fluids is of utility in military scenarios with prolonged or delayed evacuation times. A large body of pre-clinical and clinical literature has accumulated over the past 30 years on the hemodynamic and, most recently, the anti-inflammatory properties of hypertonic saline, alone or with dextran-70. This review assesses the current state of hypertonic fluid resuscitation in the aftermath of the failed Resuscitation Outcomes Consortium trials.
[Show abstract][Hide abstract] ABSTRACT: Posttraumatic inflammation and excessive neutrophil activation cause multiple organ dysfunction syndrome (MODS), a major cause of death among hemorrhagic shock patients. Traditional resuscitation strategies may exacerbate inflammation; thus, novel fluid treatments are needed to reduce such posttraumatic complications. Hypertonic resuscitation fluids inhibit inflammation and reduce MODS in animal models. Here we studied the anti-inflammatory efficacy of hypertonic fluids in a controlled clinical trial. Trauma patients in hypovolemic shock were resuscitated in a prehospital setting with 250 mL of either 7.5% hypertonic saline (HS; n = 9), 7.5% hypertonic saline + 6% dextran 70 (HSD; n = 8), or 0.9% normal saline (NS; n = 17). Blood samples were collected on hospital admission and 12 and 24 h after resuscitation. Multicolor flow cytometry was used to quantify neutrophil expression of cell-surface activation/adhesion (CD11b, CD62L, CD64) and degranulation (CD63, CD66b, CD35) markers as well as oxidative burst activity. Circulating concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVACM-1), P- and E-selectins, myeloperoxidase (MPO), and matrix metalloproteinase 9 (MMP-9) were assessed by immunoassay. Multiple organ dysfunction syndrome, leukocytosis, and mortality were lower in the HS and HSD groups than in the NS group. However, these differences were not statistically significant. Hypertonic saline prevented priming and activation and neutrophil oxidative burst and CD11b and CD66b expression. Hypertonic saline also reduced circulating markers of neutrophil degranulation (MPO and MMP-9) and endothelial cell activation (sICAM-1, sVCAM-1, soluble E-selectin, and soluble P-selectin). Hypertonic saline + 6% dextran 70 was less capable than HS of suppressing the upregulation of most of these activation markers. This study demonstrates that initial resuscitation with HS, but neither NS nor HSD, can attenuate posttraumatic neutrophil and endothelial cell activation in hemorrhagic shock patients. These data suggest that hypertonic resuscitation without dextran may inhibit posttraumatic inflammation. However, despite this effect, neither HS nor HSD reduced MODS in trauma patients with hemorrhagic shock.
[Show abstract][Hide abstract] ABSTRACT: Fluid resuscitation can often exacerbate injury sustained during hemorrhagic shock and is associated with altered immuno-inflammatory events. Early monocyte dysregulation and excessive proinflammatory cytokine production are thought to play a key role in the development of post-traumatic multiorgan dysfunction in resuscitated trauma patients. Compared with standard isotonic crystalloid resuscitation using 0.9% normal saline (NS), 7.5% hypertonic saline with 6% dextran-70 (HSD) has been shown in experimental studies to reduce shock/resuscitation-induced inflammatory reactions and lessen organ dysfunction. However, the immunomodulatory capacity of HSD, has not been evaluated in clinical human trials. In this prospective, randomized controlled trial we show that a single (250 mL) bolus infusion of HSD in hemorrhagic trauma patients restores the balance between pro and antiinflammatory mediators in the early post-resuscitative period. Flow cytometric single-cell analyses revealed that, compared to standard resuscitation with NS, which selectively expands the proinflammatory CD14+CD16+ monocyte phenotype, initial treatment with HSD elicits selective depletion of CD14+CD16+ cells and down-regulates monocytic adhesion molecule expression. Moreover, HSD significantly inhibits intracellular TNF--production by CD14+CD16+ monocytes, while upregulating both IL-10 and IL-1ra by CD14++CD16– monocytes. This differential profile of monocytic cytokine expression in response to HSD appears to be mediated, at least partly, by attenuation of post-resuscitation noradrenergic-stimulated signaling pathways. These findings demonstrate that HSD promotes a more balanced early inflammatory response in resuscitated hemorrhagic shock patients.
[Show abstract][Hide abstract] ABSTRACT: The leading causes of death for trauma patients in civilian and combat settings are traumatic brain injury and uncontrolled hemorrhage, respectively. This study examines the hemostatic activity of an ideal amphipathic peptide (IAP) attached to a biocompatible surface.
Procoagulant properties of IAP attached to a surface were first tested, in vitro, using factor Xa and thrombin generation assays and thromboelastography. Rabbits and swine were used for in vivo studies. Injuries were performed using scalpel blade 11, and free bleeding was allowed for five seconds. While bleeding, IAP coupled to a hydrogel or QuikClot were applied to the wound and the time was recorded until bleeding stopped.
Results show that when IAP is attached to a surface, both factor IXa and factor Xa activities are promoted. Thromboelastography shows that surface-attached IAP results in earlier onset and stronger clot formation. In rabbits, the incorporation of IAP onto a biocompatible hydrogel reduces bleeding times by 40% (p < 0.03). In pigs, bleeding times are reduced 30% to 50% (p < 0.02) by surface-coupled IAP. Finally, using a rabbit liver laceration model, the properties of surface-coupled IAP are less damaging when compared with QuikClot, a currently used material in external hemorrhagic injuries.
This study provides a relevant proof of concept for the development of IAP coupled to a biocompatible surface as a hemostatic agent, that is potentially safer than the commercially available QuikClot.
[Show abstract][Hide abstract] ABSTRACT: In this study, we validated a thromboelastography (TEG) method to evaluate the hemostatic effects of 3 peptides. The first peptide is an ideal amphipathic peptide composed of 22 leucine and lysine in a ratio of 2:1. At a very low concentration, the peptide had a procoagulant effect shown by decreases in reaction time (R) and coagulation time (K) but was impaired by a decrease in maximum amplitude (MA). At higher concentrations, the peptide had an anticoagulant effect. The α angle was minimally affected by the peptide. The second peptide is melittin derived from bee venom. Melittin showed procoagulant effects reflected by a decrease in clotting time but led to lower MA. The third peptide derived from fibrinogen γ chain promoted hemostasis only at an optimal concentration and became anticoagulant at a higher concentration. The hemostatic mechanisms of each peptide were discussed. Our study would facilitate further development of peptides for either hemorrhage control or thrombosis treatment.
[Show abstract][Hide abstract] ABSTRACT: Shock-wave exposure from improvised explosive devices (IEDs) has been implicated as a possible contributing factor to neurological impairment reported in combat veterans. However, evidence-based substantiation of this implication, particularly for low-level exposure in the absence of external signs of trauma, remain elusive. Accordingly, we constructed an open-ended shock tube producing a short-duration, low-amplitude shockwave. Low-level (11.5 kPa static overpressure) complex shock-wave exposure in rats resulted in no histological evidence of lung injury. By contrast, delayed cytoskeletal proteolysis of αII-spectrin was detected in the cortex and hippocampus by 12 h post-injury. Cell death was minimal and localized predominantly in the corpus callosum and periventricular regions. These regions, with presumably different density interfaces, exhibit biological responses to shockwaves consistent with interface turbulence described by Richtmyer-Meshkov instability. Evoked compound action potential (CAP) recordings from the corpus callosum showed a significant increase in the duration of CAP responses at 14 and 30 days post-injury, and a gradual depression in the unmyelinated fiber amplitude. Shielding the head attenuated αII-spectrin cytoskeletal breakdown, thus directly implicating low-level shock-wave exposure as a cause of brain injury in the rat. Despite anatomical and scaling differences in rats compared to humans, the results suggest the potential for undiagnosed traumatic brain pathologies occurring in combat veterans following shock-wave exposure.
Journal of neurotrauma 12/2010; 28(3):343-57. DOI:10.1089/neu.2009.1050 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Wound sealants provide an excellent alternative for closing surgical and non-surgical wounds, as well as stopping external bleeding for prehospital trauma injuries. Numerous biomaterials have been investigated to address specific requirements for their use as suitable wound sealants. This article focuses on the development of new wound sealant biomaterials and recent advances in the surgical applications of wound sealants. In the past 5 years, many new sealant materials had been reported, including keratin, mussel-adhesive proteins, dendrimers and in situ-forming hydrogels. Fibrin sealants remain the most clinically studied for a variety of surgical procedures, while clinical experience with wound sealants for orthopedic surgery is limited. Both liquid and solid wound sealants have been developed and found effective by possessing strong adhesive properties. Biocompatible and biodegradable wound sealants hold much promise in eventually replacing sutures in most surgical procedures.
Expert Review of Medical Devices 09/2010; 7(5):639-59. DOI:10.1586/erd.10.40 · 1.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To promote and understand the structure–property relationship for hemostasis, we modified melittin (MLT) using a four-arm poly(ethylene glycol) (PEG) with N-hydroxysuccinimide ester. The PEGylation was character-ized by FTIR, MALDI-MS, NMR, a bicinchoninic acid assay, circular dichroism, hemolysis assay, and thromboelastography. Changes in the reaction conditions affected the extent of the modification, the numbers of MLT conjugated to PEG arms, and possible PEGylation sites. The reaction at pH 9.2 with a high MLT/PEG ratio, resulted in the highest modification. Reactions in dimethylsulfoxide (DMSO) resulted in more multi-arm coupled MLT, reaching a maximum of four MLT per PEG. The helicity of the modified peptide, relative to the native peptide, was essentially maintained in DMSO, but substantially lost at pH 9.2. PEGylation reduced the hemolytic effects of MLT and subsequently changed its coagulation profiles. The overall hemostatic effects of MLT modified in DMSO indicate that this may be a convenient approach to the PEGylation of biomolecules for biomedical applications.
Journal of Bioactive and Compatible Polymers 02/2010; 25(1). DOI:10.1177/0883911509354230 · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) initiates interrelated inflammatory and coagulation cascades characterized by wide-spread cellular activation, induction of leukocyte and endothelial cell adhesion molecules and release of soluble pro/antiinflammatory cytokines and thrombotic mediators. Resuscitative care is focused on optimizing cerebral perfusion and reducing secondary injury processes. Hypertonic saline is an effective osmotherapeutic agent for the treatment of intracranial hypertension and has immunomodulatory properties that may confer neuroprotection. This study examined the impact of hypertonic fluids on inflammatory/coagulation cascades in isolated head injury.
Using a prospective, randomized controlled trial we investigated the impact of prehospital resuscitation of severe TBI (GCS < 8) patients using 7.5% hypertonic saline in combination with 6% dextran-70 (HSD) vs 0.9% normal saline (NS), on selected cellular and soluble inflammatory/coagulation markers. Serial blood samples were drawn from 65 patients (30 HSD, 35 NS) at the time of hospital admission and at 12, 24, and 48-h post-resuscitation. Flow cytometry was used to analyze leukocyte cell-surface adhesion (CD62L, CD11b) and degranulation (CD63, CD66b) molecules. Circulating concentrations of soluble (s)L- and sE-selectins (sL-, sE-selectins), vascular and intercellular adhesion molecules (sVCAM-1, sICAM-1), pro/antiinflammatory cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL-10)], tissue factor (sTF), thrombomodulin (sTM) and D-dimers (D-D) were assessed by enzyme immunoassay. Twenty-five healthy subjects were studied as a control group.
TBI provoked marked alterations in a majority of the inflammatory/coagulation markers assessed in all patients. Relative to control, NS patients showed up to a 2-fold higher surface expression of CD62L, CD11b and CD66b on polymorphonuclear neutrophils (PMNs) and monocytes that persisted for 48-h. HSD blunted the expression of these cell-surface activation/adhesion molecules at all time-points to levels approaching control values. Admission concentrations of endothelial-derived sVCAM-1 and sE-selectin were generally reduced in HSD patients. Circulating sL-selectin levels were significantly elevated at 12 and 48, but not 24 h post-resuscitation with HSD. TNF-alpha and IL-10 levels were elevated above control throughout the study period in all patients, but were reduced in HSD patients. Plasma sTF and D-D levels were also significantly lower in HSD patients, whereas sTM levels remained at control levels.
These findings support an important modulatory role of HSD resuscitation in attenuating the upregulation of leukocyte/endothelial cell proinflammatory/prothrombotic mediators, which may help ameliorate secondary brain injury after TBI.
Journal of Neuroinflammation 01/2010; 7(1):5. DOI:10.1186/1742-2094-7-5 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An ideal amphipathic peptide (IAP), composed of simply lysine and leucine residues in a 1:2 ratio (K(7)L(15)), specifically prolongs in vitro coagulation assays that use phospholipids, such as the activated partial thromboplastin time (APTT). The main hypothesis of the present work is that IAP's anticoagulant effect occurs by competing with phospholipid membranes in in vitro coagulation reactions. We verified this hypothesis by employing different phospholipid-dependent coagulation assays, such as the APTT, the dilute prothrombin time (dPT) and the dilute Russell viper venom time (dRVVT) with both low and high amounts of phospholipids. We show that coagulation times are prolonged by IAP in a concentration-dependent manner, and that this prolongation is abrogated by adding excess phospholipid, demonstrating a phospholipid dependence for this inhibition. Using an ELISA-based binding assay, we show IAP inhibits the binding of one of the vitamin K-dependent coagulation factors, factor X, to phospholipid membranes. This is further confirmed with fluorescence spectroscopy, where the interaction of IAP and factor X is inhibited by phospholipid. In summary, this work demonstrates that IAP can act as an anticoagulant by impairing the interaction of coagulation factors with phospholipid membranes and provides a paradigm for the development of novel anticoagulants.
Biochemical and Biophysical Research Communications 12/2009; 391(2):1197-202. DOI:10.1016/j.bbrc.2009.12.031 · 2.28 Impact Factor