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1.  Visual event-related potentials as markers of hyperarousal in Gulf War Illness: evidence against a stress-related etiology 
Psychiatry research  2012;211(3):257-267.
An exaggerated response to emotional stimuli is among the many symptoms widely reported by veterans of the 1991 Persian Gulf War. These symptomologies have been attributed to damage and dysfunction associated with deployment-related exposures. We collected event-related potential data from 22 veterans meeting Haley criteria for Gulf War (GW) Syndromes 1-3 and from 8 matched GW veteran controls, who were deployed but not symptomatic, while they performed a visual three-condition oddball task where images authenticated to be associated with the 1991 Persian Gulf War were the distractor stimuli. Hyperarousal reported by ill veterans was significantly greater than that by control veterans, but this was not paralleled by higher amplitude P3a in their ERP responses to GW-related distractor stimuli. Whereas previous studies of PTSD patients have shown higher amplitude P3b responses to target stimuli that are placed amid trauma-related nontarget stimuli, ill veterans in this study showed P3b amplitudes to target stimuli—placed amid GW-related nontarget stimuli—that were significantly lower than those of the control group. Hyperarousal scores reliably predicted P3b, but not P3a, amplitudes. Although many factors may contribute to P3b amplitude differences—most notably depression and poor sleep quality, symptoms that are prevalent in the GW syndrome groups—our findings in context of previous studies on this population are consistent with the contention that dysfunction in cholinergic and dopaminergic neurotransmitter systems, and in white matter and basal ganglia may be contributing to impairments in GW veterans.
doi:10.1016/j.pscychresns.2012.08.004
PMCID: PMC3578115  PMID: 23149040
ERPs; P3a; P3b; cholinergic; dopaminergic
2.  Striatal-Limbic Activation is Associated with Intensity of Anticipatory Anxiety 
Psychiatry research  2012;204(2-3):123-131.
Anxiety experienced in anticipation of impending aversive events induces striatal-limbic activation. However, previous functional magnetic imaging (fMRI) studies of anticipatory anxiety have utilized post-test measures of anxiety, making a direct association between neural activation and distress problematic. This paradigm was designed to assess the BOLD response to an aversive conditioned stimulus while simultaneously measuring subjective anxiety. Fifteen male healthy subjects (45.5±8.5 years old) were studied. A high threat conditioned stimulus (CS) was paired with either an unpredictable, highly aversive (painful) or a non-aversive (non-painful) unconditioned stimulus and compared to a low threat CS paired with a predictable, non-aversive stimulus. Neural response was assessed with fMRI, and subjective anxiety (1 to 4) was recorded upon the presentation of each CS. High subjective ratings of real-time anticipatory anxiety (2, 3, and 4), relative to low anticipatory anxiety (1), elicited increased activation in the bilateral striatum, bilateral orbital frontal cortex, left anterior insula, and anterior cingulate cortex (ACC) and decreased activation in the posterior cingulate cortex (PCC). The amplitude of BOLD signal change generally paralleled the subjective rating of anxiety. Real-time measures of anticipatory anxiety confirm previous reports, using post-test measures of anxiety, of striatal-limbic activation during anticipatory anxiety while simultaneously demonstrating an increase in BOLD response in parallel with heightened anxiety.
doi:10.1016/j.pscychresns.2012.10.001
PMCID: PMC3562596  PMID: 23137803
striatal-limbic system; striatum; anticipatory anxiety; functional magnetic resonance imaging
3.  Event-Related Potential Patterns Associated with Hyperarousal in Gulf War Illness Syndrome Groups 
Neurotoxicology  2012;33(5):1096-1105.
An exaggerated response to emotional stimuli is one of several symptoms widely reported by veterans of the 1991 Persian Gulf War. Many have attributed these symptoms to post-war stress; others have attributed the symptoms to deployment-related exposures and associated damage to cholinergic, dopaminergic, and white matter systems. We collected event-related potential (ERP) data from 20 veterans meeting Haley criteria for Gulf War Syndromes 1–3 and from 8 matched Gulf War veteran controls, who were deployed but not symptomatic, while they performed an auditory three-condition oddball task with gunshot and lion roar sounds as the distractor stimuli. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans; different ERP profiles emerged to account for their hyperarousability. Syndromes 2 and 3, who have previously shown brainstem abnormalities, show significantly stronger auditory P1 amplitudes, purported to indicate compromised cholinergic inhibitory gating in the reticular activating system. Syndromes 1 and 2, who have previously shown basal ganglia dysfunction, show significantly weaker P3a response to distractor stimuli, purported to indicate dysfunction of the dopaminergic contribution to their ability to inhibit distraction by irrelevant stimuli. All three syndrome groups showed an attenuated P3b to target stimuli, which could be secondary to both cholinergic and dopaminergic contributions or disruption of white matter integrity.
doi:10.1016/j.neuro.2012.06.001
PMCID: PMC3470732  PMID: 22691951
Gulf War Illness; hyperarousal; ERPs; P1; P3a; P3b; cholinergic; dopaminergic
4.  FMRI Reveals Abnormal Central Processing of Sensory and Pain Stimuli in Ill Gulf War Veterans 
Neurotoxicology  2012;33(3):261-271.
Many veterans chronically ill from the 1991 Gulf War exhibit symptoms of altered sensation, including chronic pain. In this study of 55 veterans of a Construction Battalion previously examined in 1995–1996 and 1997–1998, brain activation to innocuous and noxious heat stimuli was assessed in 2008–2009 with a quantitative sensory testing fMRI protocol in control veterans and groups representing three syndrome variants. Testing outside the scanner revealed no significant differences in warm detection or heat pain threshold among the four groups. In the fMRI study, Syndrome 1 and Syndrome 2, but not Syndrome 3, exhibited hypo-activation to innocuous heat and hyper-activation to noxious heat stimuli compared to controls. The results indicate abnormal central processing of sensory and painful stimuli in 2 of 3 variants of Gulf War illness and call for a more comprehensive study with a larger, representative sample of veterans.
doi:10.1016/j.neuro.2012.01.014
PMCID: PMC3358633  PMID: 22327017
functional MRI; neuroimaging; innocuous heat; noxious heat; sensory; pain; Brain Diseases; Gulf War Illness
5.  Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging 
Physical exercise, particularly aerobic exercise, is documented as providing a low cost regimen to counter well-documented cognitive declines including memory, executive function, visuospatial skills, and processing speed in normally aging adults. Prior aging studies focused largely on the effects of medium to long term (>6 months) exercise training; however, the shorter term effects have not been studied. In the present study, we examined changes in brain blood flow, cognition, and fitness in 37 cognitively healthy sedentary adults (57–75 years of age) who were randomized into physical training or a wait-list control group. The physical training group received supervised aerobic exercise for 3 sessions per week 1 h each for 12 weeks. Participants' cognitive, cardiovascular fitness and resting cerebral blood flow (CBF) were assessed at baseline (T1), mid (T2), and post-training (T3). We found higher resting CBF in the anterior cingulate region in the physical training group as compared to the control group from T1 to T3. Cognitive gains were manifested in the exercise group's improved immediate and delayed memory performance from T1 to T3 which also showed a significant positive association with increases in both left and right hippocampal CBF identified earlier in the time course at T2. Additionally, the two cardiovascular parameters, VO2 max and rating of perceived exertion (RPE) showed gains, compared to the control group. These data suggest that even shorter term aerobic exercise can facilitate neuroplasticity to reduce both the biological and cognitive consequences of aging to benefit brain health in sedentary adults.
doi:10.3389/fnagi.2013.00075
PMCID: PMC3825180  PMID: 24282403
aging; CBF; exercise; memory; MRI
6.  Regionally Selective Atrophy after Traumatic Axonal Injury 
Archives of neurology  2010;67(11):1336-1344.
Objectives
To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.
Design
Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.
Setting
Inpatient traumatic brain injury unit
Patients or Other Participants
Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.
Main Outcome Measure
Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.
Results
Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.
Conclusion
Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.
doi:10.1001/archneurol.2010.149
PMCID: PMC3465162  PMID: 20625067
7.  Perfusion deficit to cholinergic challenge in veterans with Gulf War Illness 
Neurotoxicology  2010;32(2):242-246.
A highly plausible etiology for Gulf War Illness (GWI) is that the neural damage and cognitive deficits are associated with excessive exposure to cholinesterase-inhibiting cholinergic stimulants. Our previous SPECT study provided strong indication that cerebral blood flow (CBF) in veterans with GWI may be different from those of unaffected control veterans. The present study confirmed and extended previous findings that patients with GWI have abnormal response to an inhibitory cholinergic challenge, physostigmine infusion, when compared to age-gender-education matched control veterans. The MRI-based arterial spin labeling (ASL) and phase-contrast techniques have several key advantages over SPECT, including shorter experiment duration, complete non-invasiveness, and higher spatial and temporal resolutions, and therefore may provide a cost-effective biomarker for characterization of GWI.
doi:10.1016/j.neuro.2010.12.004
PMCID: PMC3049842  PMID: 21147163
Arterial spin labeling MRI; Phase-contrast MRI; Physostigmine; Brain diseases; Cerebral blood flow; Gulf War Illness
8.  Assessing Spatial Relationships between Axonal Integrity, Regional Brain Volumes, and Neuropsychological Outcomes after Traumatic Axonal Injury 
Journal of Neurotrauma  2010;27(12):2121-2130.
Abstract
Diffuse traumatic axonal injury (TAI) is a type of traumatic brain injury (TBI) characterized predominantly by white matter damage. While TAI is associated with cerebral atrophy, the relationship between gray matter volumes and TAI of afferent or efferent axonal pathways remains unknown. Moreover, it is unclear if deficits in cognition are associated with post-traumatic brain volumes in particular regions. The goal of this study was to determine the relationship between markers of TAI and volumes of cortical and subcortical structures, while also assessing the relationship between cognitive outcomes and regional brain volumes. High-resolution magnetic resonance imaging scans were performed in 24 patients with TAI within 1 week of injury and were repeated 8 months later. Diffusion tensor imaging (DTI) tractography was used to reconstruct prominent white matter tracts and calculate their fractional anisotropy (FA) and mean diffusivity (MD) values. Regional brain volumes were computed using semi-automated morphometric analysis. Pearson's correlation coefficients were used to assess associations between brain volumes, white matter integrity (i.e., FA and MD), and neuropsychological outcomes. Post-traumatic volumes of many gray matter structures were associated with chronic damage to related white matter tracts, and less strongly associated with measures of white matter integrity in the acute scans. For example, left and right hippocampal volumes correlated with FA in the fornix body (r = 0.600, p = 0.001; r = 0.714, p < 0.001, respectively). In addition, regional brain volumes were associated with deficits in corresponding neuropsychological domains. Our results suggest that TAI may be a primary mechanism of post-traumatic atrophy, and provide support for regional morphometry as a biomarker for cognitive outcome after injury.
doi:10.1089/neu.2010.1429
PMCID: PMC2996819  PMID: 20874032
atrophy; diffuse axonal injury; diffusion tensor imaging; traumatic brain injury; volumetric magnetic resonance imaging
9.  Deficits in Functional Connectivity of Hippocampal and Frontal Lobe Circuits after Traumatic Axonal Injury 
Archives of neurology  2011;68(1):74-84.
Objective
To examine the functional connectivity (fc) of hippocampal and selected frontal lobe circuits among patients with traumatic axonal injury (TAI).
Design
Echo-planar and high-resolution T1-weighted images were acquired using 3 Tesla scanners. Regions of interest (ROI) were drawn bilaterally for the hippocampus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC), and were used to extract time series data. BOLD data from each ROI were used as reference functions for correlating with all other brain voxels. Interhermispheric fc was assessed for each participant by correlating homologous regions using a Pearson correlation coefficient. Patient functional and neurocognitive outcomes were assessed approximately 6 months post-injury.
Setting
Patients were recruited within days of their injury while in an inpatient traumatic brain injury unit. Imaging and neurocognitive assessments were conducted in an outpatient research facility.
Participants
25 consecutive patients with brain injuries consistent with TAI and acute subcortical white matter abnormalities were studied. Sixteen healthy volunteers of similar age and gender were recruited.
Main Outcome Measures
Interhemispheric fc for each ROI was compared between patients and controls. Spatial patterns of fc were examined for each of the three ROIs. Connectivity measures were examined for associations with functional and neurocognitive outcomes.
Results
Patients showed significantly lower interhemispheric fc for the hippocampus and ACC. Healthy controls demonstrate stronger and more focused fc for hippocampi and ACC, and a more focused recruitment of the default mode network for the DLPFC ROI. The interhemispheric fc for the hippocampus was correlated to delayed recall of verbal information.
Conclusions
Our findings suggest that traumatic axonal injury impacts interhemispheric neural activity, as patients with TAI show disrupted interhemipsheric fc. These results suggest more careful investigation of interhemisheric connectivity is warranted, as it demonstrated a modest association with outcome in chronic TBI.
doi:10.1001/archneurol.2010.342
PMCID: PMC3100186  PMID: 21220676
10.  Downregulation of Protein 4.1R, a Mature Centriole Protein, Disrupts Centrosomes, Alters Cell Cycle Progression, and Perturbs Mitotic Spindles and Anaphase▿  
Molecular and Cellular Biology  2008;28(7):2283-2294.
Centrosomes nucleate and organize interphase microtubules and are instrumental in mitotic bipolar spindle assembly, ensuring orderly cell cycle progression with accurate chromosome segregation. We report that the multifunctional structural protein 4.1R localizes at centrosomes to distal/subdistal regions of mature centrioles in a cell cycle-dependent pattern. Significantly, 4.1R-specific depletion mediated by RNA interference perturbs subdistal appendage proteins ninein and outer dense fiber 2/cenexin at mature centrosomes and concomitantly reduces interphase microtubule anchoring and organization. 4.1R depletion causes G1 accumulation in p53-proficient cells, similar to depletion of many other proteins that compromise centrosome integrity. In p53-deficient cells, 4.1R depletion delays S phase, but aberrant ninein distribution is not dependent on the S-phase delay. In 4.1R-depleted mitotic cells, efficient centrosome separation is reduced, resulting in monopolar spindle formation. Multipolar spindles and bipolar spindles with misaligned chromatin are also induced by 4.1R depletion. Notably, all types of defective spindles have mislocalized NuMA (nuclear mitotic apparatus protein), a 4.1R binding partner essential for spindle pole focusing. These disruptions contribute to lagging chromosomes and aberrant microtubule bridges during anaphase/telophase. Our data provide functional evidence that 4.1R makes crucial contributions to the structural integrity of centrosomes and mitotic spindles which normally enable mitosis and anaphase to proceed with the coordinated precision required to avoid pathological events.
doi:10.1128/MCB.02021-07
PMCID: PMC2268423  PMID: 18212055

Results 1-10 (10)