Gulf War Illness (GWI) is a chronic, multisymptom disorder estimated to affect approximately 25-32% of Gulf War veterans (GWVs). Cognitive dysfunction is a common symptom of GWI. On the continuum of cognitive decline, mild cognitive impairment (MCI) is conceptualized as a transitional phase between normal aging and dementia. Individuals with MCI exhibit cognitive decline but have relatively spared activities of daily function and do not meet criteria for dementia. The current study sought to investigate the prevalence of MCI in a convenience sample of 202 GWVs (median age: 52 years; 18% female). Twelve percent of the sample (median age: 48 years) had MCI according to an actuarial neuropsychological criterion, a rate materially higher than expected for this age group. GWVs with MCI also had a smaller hippocampal volume and a thinner parietal cortex, higher rates of current posttraumatic stress disorder and major depressive disorder compared to GWVs without MCI. Because people with MCI are more likely to progress to dementia compared to those with normal cognition, these results may portend future higher rates of dementia among deployed GWVs.

Child abuse (CA), which is linked to posttraumatic stress disorder (PTSD), has been associated with a reduction in both hippocampal and corpus callosum (CC) volume. However, few studies have explored these relationships on psychophysiological variables related to trauma exposure. Therefore, we assessed whether the interaction between CA and hippocampal and CC volume were associated with enhanced fear potentiated psychophysiological response patterns in a sample of Veterans. 147 Veteran participants who were part of a larger study of Gulf War Illness were exposed to startling sounds in no, ambiguous, and high threat conditions and also provided MRI data. The Clinician Administered PTSD Scale and Trauma History Questionnaire were used to measure PTSD and CA respectively. Psychophysiological response was measured by EMG, SCR, and heart rate. Repeated-measures mixed linear models were used to assess the significance of CA by neural structure interactions. CA interacted with both hippocampal and CC volume on psychophysiological response magnitudes, where participants with CA and smaller hippocampal volume had greater EMG (p < 0.01) and SCR (p < 0.05) magnitudes across trials and over threat conditions. Participants with CA and smaller CC volume had greater SCR magnitudes across trials and over threat conditions (p < 0.01). Hippocampal and genu volume mediated CA and psychophysiological response magnitude. CA may impact psychophysiological response via a reduction in hippocampal and CC volume. Volumetric reduction in these structures may indicate a neurofunctional, CA-related increase in threat sensitivity, which could portend increased PTSD susceptibility and adverse interpersonal and social consequences across the lifespan.

Background

We previously reported evidence of reduced cortical gray matter (GM), white matter (WM), and hippocampal volume in Gulf War (GW) veterans with predicted exposure to low-levels of nerve agent according to the 2000 Khamisiyah plume model analysis. Because there is suggestive evidence that other nerve agent exposures may have occurred during the Gulf War, we examined the association between the self-reported frequency of hearing chemical alarms sound during deployment in the Gulf War and regional brain volume in GW veterans.

Methods

Ninety consecutive GW veterans (15 female, mean age: 52±8years) participating in a VA-funded study underwent structural magnetic resonance imaging (MRI) on a 3T scanner. Freesurfer (version 5.1) was used to obtain regional measures of cortical GM, WM, hippocampal, and insula volume. Multiple linear regression was used to determine the association between the self-reported frequencies of hearing chemical alarms during the Gulf War and regional brain volume.

Results

There was an inverse association between the self-reported frequency of hearing chemical alarms sound and total cortical GM (adjusted p=0.007), even after accounting for potentially confounding demographic and clinical variables, the veterans' current health status, and other concurrent deployment-related exposures that were correlated with hearing chemical alarms. Post-hoc analyses extended the inverse relationship between the frequency of hearing chemical alarms to GM volume in the frontal (adjusted p=0.02), parietal (adjusted p=0.01), and occipital (adjusted p=0.001) lobes. In contrast, regional brain volumes were not significantly associated with predicted exposure to the Khamisiyah plume or with Gulf War Illness status defined by the Kansas or Centers for Disease Control and Prevention criteria.

Conclusions

Many veterans reported hearing chemical alarms sound during the Gulf War. The current findings suggest that exposure to substances that triggered those chemical alarms during the Gulf War likely had adverse neuroanatomical effects.

Recent findings suggest the formation of myelin in the central nervous system by oligodendrocytes is a continuous process that can be modified with experience. For example, a recent study showed that immobilization stress increased oligodendrogensis in the dentate gyrus of adult rat hippocampus. Because changes in myelination represents an adaptive form of brain plasticity that has a greater reach in the adult brain than other forms of plasticity (e.g., neurogenesis), the objective of this "proof of concept" study was to examine whether there are differences in myelination in the hippocampi of humans with and without post-traumatic stress disorder (PTSD). We used the ratio of T1-weighted/T2-weighted magnetic resonance image (MRI) intensity to estimate the degree of hippocampal myelination in 19 male veterans with PTSD and 19 matched trauma-exposed male veterans without PTSD (mean age: 43 ± 12 years). We found that veterans with PTSD had significantly more hippocampal myelin than trauma-exposed controls. There was also found a positive correlation between estimates of hippocampal myelination and PTSD and depressive symptom severity. To our knowledge, this is the first study to examine hippocampal myelination in humans with PTSD. These results provide preliminary evidence for stress-induced hippocampal myelin formation as a potential mechanism underlying the brain abnormalities associated with vulnerability to stress.

Study objectives

To investigate whether subjective sleep quality is associated with brain volume independent of comorbid psychiatric conditions.

Design

Cross-sectional.

Setting

Department of Veterans Affairs (VA) Medical Center.

Participants

One hundred forty-four Gulf War Veterans (mean age 45 years; range: 31-70 years; 14% female).

Interventions

None.

Measurements and results

Total cortical, lobar gray matter, and hippocampal volumes were quantified from 1.5 Tesla magnetic resonance images using Freesurfer version 4.5. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). Multiple linear regressions were used to determine the association of sleep quality with total and regional brain volumes. The global PSQI score was positively correlated with lifetime and current posttraumatic stress disorder (PTSD) and current depressive symptoms (P < 0.001) and was higher in veterans with Gulf War Illness, trauma exposure, and those using psychotropic medication (P ≤ 0.03). After adjusting for these comorbid variables, age, intracranial volume, and multiple comparisons, global PSQI was inversely associated with total cortical and frontal gray matter volume (adjusted P ≤ 0.03). Within the frontal lobe, total PSQI was inversely associated with the superior and middle frontal, orbitofrontal, anterior cingulate, and frontal pole volumes (adjusted P ≤ 0.02). Examination of the 3-factor structure of the PSQI revealed that the associations were driven by perceived sleep quality.

Conclusions

Poorer subjective sleep quality was associated with reduced total cortical and regional frontal lobe volumes independent of comorbid psychiatric conditions. Future work will be needed to examine if effective treatment of disturbed sleep leads to improved structural and functional integrity of the frontal lobes.

Posttraumatic stress disorder (PTSD) is associated with smaller volumes of the hippocampus, as has been demonstrated by meta-analyses. Proposed mechanistic relationships are reviewed briefly, including the hypothesis that sleep disturbances mediate the effects of PTSD on hippocampal volume. Evidence for this includes findings that insomnia and restricted sleep are associated with changes in hippocampal cell regulation and impairments in cognition. We present results of a new study of 187 subjects in whom neither PTSD nor poor sleep was associated with lower hippocampal volume. We outline a broad research agenda centered on the hypothesis that sleep changes mediate the relationship between PTSD and hippocampal volume.

Background and purpose

To determine if a voxel-wise "co-analysis" of structural and diffusion tensor magnetic resonance imaging (MRI) together reveals additional brain regions affected in mild cognitive impairment (MCI) and Alzheimer's disease (AD) than voxel-wise analysis of the individual MRI modalities alone.

Methods

Twenty-one patients with MCI, 21 patients with AD, and 21 cognitively normal healthy elderly were studied with MRI. Maps of deformation and fractional anisotropy (FA) were computed and used as dependent variables in univariate and multivariate statistical models.

Results

Univariate voxel-wise analysis of macrostructural changes in MCI showed atrophy in the right anterior temporal lobe, left posterior parietal/precuneus region, WM adjacent to the cingulate gyrus, and dorsolateral prefrontal regions, consistent with prior research. Univariate voxel-wise analysis of microstructural changes in MCI showed reduced FA in the left posterior parietal region extending into the corpus callosum, consistent with previous work. The multivariate analysis, which provides more information than univariate tests when structural and FA measures are correlated, revealed additional MCI-related changes in corpus callosum and temporal lobe.

Conclusion

These results suggest that in corpus callosum and temporal regions macro- and microstructural variations in MCI can be congruent, providing potentially new insight into the mechanisms of brain tissue degeneration.

Introduction: Gulf War Illness (GWI), also called Chronic Multisymptom Illness (CMI), is a multi-faceted condition that plagues an estimated 250,000 Gulf War (GW) veterans. Symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. We previously reported that 12% of a convenience sample of middle aged (median age 52 years) GW veterans met criteria for mild cognitive impairment (MCI), a clinical syndrome most prevalent in older adults (e.g., ≥70 years). The current study sought to replicate and extend this finding. Methods: We used the actuarial neuropsychological criteria and the Montreal Cognitive Assessment (MoCA) to assess the cognitive status of 952 GW veterans. We also examined regional brain volumes in a subset of GW veterans (n = 368) who had three Tesla magnetic resonance images (MRIs). Results: We replicated our previous finding of a greater than 10% rate of MCI in four additional cohorts of GW veterans. In the combined sample of 952 GW veterans (median age 51 years at time of cognitive testing), 17% met criteria for MCI. Veterans classified as MCI were more likely to have CMI, history of depression, and prolonged (≥31 days) deployment-related exposures to smoke from oil well fires and chemical nerve agents compared to veterans with unimpaired and intermediate cognitive status. We also replicated our previous finding of hippocampal atrophy in veterans with MCI, and found significant group differences in lateral ventricle volumes. Discussion: Because MCI increases the risk for late-life dementia and impacts quality of life, it may be prudent to counsel GW veterans with cognitive dysfunction, CMI, history of depression, and high levels of exposures to deployment-related toxicants to adopt lifestyle habits that have been associated with lowering dementia risk. With the Food and Drug Administration’s recent approval of and the VA’s decision to cover the cost for anti-amyloid β (Aβ) therapies, a logical next step for this research is to determine if GW veterans with MCI have elevated Aβ in their brains.

While the BDNF Val66Met polymorphism has been linked to various trauma and anxiety - related psychiatric disorders, limited focus has been on the neural structures that might modulate its relationship with objective measures of threat sensitivity. Therefore, we assessed whether there was an interaction of Val66Met polymorphism with brain area volumes previously associated with anxiety and PTSD, such as the ventromedial prefrontal cortex (vmPFC), insular cortex (IC), and dorsal and ventral anterior cingulate cortices (dACC and vACC), in predicting fear-potentiated psychophysiological response in a clinical sample of Veterans. 110 participants engaged in a fear-potentiated acoustic startle paradigm and provided genetic and imaging data. Fear conditions included no, ambiguous, and high threat conditions (shock). Psychophysiological response measures included electromyogram (EMG), skin conductance response (SCR), and heart rate (HR). PTSD status, trauma history, and demographics were also assessed. There was an interaction of Met allele carrier status with vmPFC, IC, dACC, and vACC volumes for predicting SCR (p < 0.001 for all regions). However, only vmPFC and IC significantly moderated the relationship between Val66Met and psychophysiological response (SCR). The Val66met polymorphism may increase susceptibility to PTSD and anxiety disorders via an interaction with reduced vmPFC and IC volume. Future research should examine whether these relationships might be associated with a differential course of illness longitudinally or response to treatments.

Aims

To examine whether cognitive behavioral therapy for insomnia (CBT-I), delivered by telephone, improves sleep and non-sleep symptoms of Gulf War Illness (GWI).

Main methods

Eighty-five Gulf War veterans (21 women, mean age: 54 years, range 46-72 years) who met the Kansas GWI case definition, the Centers for Disease Control and Prevention (CDC) case definition for Chronic Multisymptom Illness (CMI), and research diagnostic criteria for insomnia disorder were randomly assigned to CBT-I or monitor-only wait list control. Eight weekly sessions of individual CBT-I were administered via telephone by Ph.D. level psychologists to study participants. Outcome measures included pre-, mid-, and post-treatment assessments of GWI and insomnia symptoms, subjective sleep quality, and continuous sleep monitoring with diary. Outcomes were re-assessed 6-months post-treatment in participants randomized to CBT-I.

Key findings

Compared to wait list, CBT-I produced significant improvements in overall GWI symptom severity, individual measures of fatigue, cognitive dysfunction, depression and anxiety, insomnia severity, subjective sleep quality, and sleep diary outcome measures. The beneficial effects of CBT-I on overall GWI symptom severity and most individual GWI symptom measures were maintained 6-months after treatment.

Significance

GWI symptoms have historically been difficult to treat. Because CBT-I, which is associated with low stigma and is increasingly readily available to veterans, improved both sleep and non-sleep symptoms of GWI, these results suggest that a comprehensive approach to the treatment of GWI should include behavioral sleep interventions.