The Relationship Between Traumatic Brain Injury and Rates of Chronic Symptomatic Illness in 202 Gulf War Veterans

The Relationship Between Traumatic Brain Injury and Rates of Chronic Symptomatic Illness in 202... Abstract Introduction Although not a “signature injury” of Operation Desert Shield/Desert Storm (i.e., Gulf War, GW), some GW veterans have a history traumatic brain injury (TBI). For example, a previous study found that 12.2% of the GW veterans from the Fort Devens Cohort Study had self-reported TBIs. The present study sought to build upon this finding by examining the relationship between TBI and chronic symptomatic illness in a different sample of GW veterans. Materials and Methods Participants were 202 GW veterans recruited from 2014 to 2018 at the San Francisco Veterans Affairs Medical Center as part of a VA-funded study on the effects of predicted exposure to low levels of sarin and cyclosarin on brain structure and function. The Ohio State University TBI identification method was used to determine lifetime history of TBI. The Kansas Gulf War Military History and Health Questionnaire was used to assess symptoms and to determine cases of Kansas Gulf War Illness (GWI) and Centers for Disease Control and Prevention (CDC) Chronic Multisymptom Illness (CMI). Results Nearly half (47%) the sample had a history of TBI, but only 7% of the TBIs were sustained in injuries that occurred during the GW. Most of the TBIs were sustained in injuries that occurred prior to (73%) or after (34%) the GW. History of TBI was not associated with higher rates of symptomatic illness when it was narrowly defined (i.e., Kansas GWI cases or cases of severe CMI). History of TBI was only associated with higher rates of symptomatic illness when it is broadly defined (i.e., CDC CMI or mild-moderate CMI). There was suggestive evidence that veterans who sustained TBIs during the GW (only seven in the present sample) have poorer functional outcomes compared with GW veterans with non-GW related TBIs. Conclusions While TBIs were uncommon during the GW, many GW veterans sustained TBIs prior or after the GW. Because TBI and GWI/CMI share some overlapping symptoms, history of TBI may appear to be associated with increased rates of chronic symptomatic illness in GW veterans if chronic symptomatic illness is defined broadly (i.e., CDC CMI or mild-moderate CMI). History of pre-GW TBI did not affect the veterans’ response to exposures/experiences from the GW; however, there was suggestive evidence that veterans who sustained TBIs during the GW may have poorer functional outcomes that GW veterans without TBI or even GW veterans with non-GW-related TBIs. Future, better powered studies with randomly and systematically select participants from the larger population of GW veterans will need to confirm this finding. INTRODUCTION Unlike the recent military operations in the Persian Gulf region (i.e., Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND)), traumatic brain injury (TBI) was not considered to be common in the 1990–1991 Gulf War (GW). Instead, the “signature injury” associated with the service in the GW is a chronic, symptomatic illness that has come to be known as GW Illness (GWI) or chronic multisymptom illness (CMI).1 Approximately 25–32% of GW veterans suffer from GWI/CMI, which is characterized by varying symptoms but typically includes some combination of fatigue, musculoskeletal pain, cognitive and/or mood dysfunction, respiratory, gastrointestinal, and dermatologic complaints.2–6 Routine clinical laboratory tests of veterans suffering from GWI/CMI tend to be remarkable and the search for a GWI/CMI biomarker has largely been unsuccessful.7 Decades after the end of the GW, GWI/CMI remains a controversial topic with no established treatment and no uniform case definition. This prompted the Department of Veterans Affairs (VA) to ask the Institute on Medicine (IOM) in 2014 to help develop a case definition for the disorder.8 After comprehensively reviewing, evaluating, and summarizing the available scientific and medical literature regarding symptoms among the GW veterans, the IOM expert panel found merits in the Kansas GWI case definition5 and the Centers for Disease Control and Prevention (CDC) CMI case definition.2 The Kansas GWI case definition requires moderately severe or multiple chronic symptoms in at least three of six domains, including fatigue/sleep problems, pain, neurological/cognitive/mood symptoms, respiratory symptoms, gastrointestinal symptoms, and skin symptoms. The Kansas GWI case definition also excludes cases that have established diagnoses that might interfere with the accurate reporting of symptoms and/or might produce similar symptoms. The CDC CMI case definition requires one or more symptoms that have been ongoing for at least 6 mo in two of three domains (i.e., fatigue, musculoskeletal pain, and mood-cognitive symptoms). Depending on how each defining symptoms is rated (e.g., mild, moderate, or severe), CDC CMI can be further categorized as mild-moderate or severe. However, unlike the Kansas GWI definition, the CDC CMI case definition does not have any exclusionary criterion. Despite the fact that TBI was uncommon during the GW, we know that some GW veterans have a history of TBI. For example, Yee et al9 reported that 12.2% of the GW veterans from the Fort Devens Cohort Study self-reported a history of TBI. The study also found self-reported TBI to be related to increased rates of health symptoms, CMI, and poorer health-related quality of life.9 One objective of this study was to investigate the frequency of TBI in another cohort of GW veterans. Because Yee et al used retrospective self-report data to quantify TBI, it is possible that they missed veterans who were unaware that they had a TBI. Therefore, the current study also sought to expand on the findings of Yee et al by using a standardized, structured interview to elicit the GW veterans’ lifetime history of TBI (i.e., the Ohio State University TBI Identification Method10). The Yee et al study classified GW veterans’ symptoms according to the CDC CMI case definition; however, they did not specify severe cases versus moderate-mild CMI cases. Research has shown that CMI may be overly inclusive if it is not specified by symptom severity.11 Therefore, the another aim of this was to build upon the findings of Yee et al by examining the relationship between TBI and chronic symptomatic illness as defined by the CDC CMI case definition, severe and moderate-mild cases of CMI, and the Kansas GWI case definition. To examine the rate of TBI in GW veterans and the relationship between TBI and chronic symptomatic illness defined by various case definitions, secondary analyses were conducted in a sample of 202 GW veterans who were originally recruited to participate in an imaging study on the effects of potential exposure to low levels of the nerve agents on brain function and brain structure. In March 1991, U.S. combat engineers destroyed a munition storage depot at Khamisiyah, Iraq. It was later discovered that the storage depot contained organophosphorus nerve agents sarin and cyclosarin and potentially 100,000 military personnel were exposed by the airborne plume generated by the demolition.12 METHOD Participants Two hundred and two GW veterans were recruited from 2014 to 2018 at the San Francisco Veterans Affairs Medical Center (SF VAMC) as part of a VA-funded study on the effects of predicted exposure to low levels of sarin and cyclosarin on brain structure and function. After the GW ended, the Department of Defense (DoD) and the Central Intelligence Agency (CIA) tried to model possible sarin and cyclosarin exposures over a 4-d period based on simulated meteorological conditions and analyses of likely chemical agent dispersal. Military personnel attached with units located in areas covered by the estimated zone of exposure were considered potentially exposed to low levels of sarin/cyclosarin.12 Although the parent imaging study focused on the population of GW veterans with predicted exposure to the Khamisiyah plume, GW veterans without predicted Khamisiyah exposure were also recruited to serve as un-exposed controls. All participants signed informed consent approved by the Institutional Review Boards of the University of California, San Francisco and the San Francisco Veterans Affairs Medical Center. Measures The following measures were assessed by clinical interviews conducted by a Ph.D. level psychologist: the veterans’ history of TBI, diagnoses of current major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), lifetime histories of psychotic or bipolar disorders, alcohol and/or drug abuse or dependence. The following measures were assessed by the veterans’ responses to self-report questionnaires: Kansas GWI5 status, CDC CMI status,2 chronic symptomatic illness severity, and symptoms of depression. Clinical Interview Assessments History of TBI was assessed using the Ohio State University TBI Identification Method (OSU TBI-ID) Short Form.10 The OSU TBI-ID is a structured interview designed to elicit self- or proxy-reports of TBI occurring over a person’s lifetime. Veterans were classified as having “improbable” (i.e., no) TBI if they reported no head or neck injuries, and/or never having been hospitalized or treated in the emergency room following a head or neck injury, and/or never having been nearby a blast or explosion. Veterans who reported a head or neck injury and/or being nearby when a blast or explosion occurred were also classified as “improbable” TBI cases if they did not experience a loss of consciousness (LOC), memory lapse, or alteration of conscious (AOC, e.g., feeling dizzy, dazed, or confused). Veterans who reported memory lapse(s) and/or AOCs as a result of a head or neck injury and/or being nearby when a blast or explosion occurred were classified as having “possible” TBI. Veterans were classified as “mild” TBI cases if they experienced LOC < 30 min due to a head or neck injury and/or being nearby when a blast or explosion occurred. Moderate and moderate-severe TBI was exclusionary for the primary imaging study (the initial phone screen asked about LOCs and duration of LOCs); however, two veterans reported LOCs between 30 and 24 h as a result of a head or neck injury and/or being nearby when a blast or explosion occurred (i.e., moderate TBI) during the OSU TBI-ID interview. No veteran had moderate/severe TBI (i.e., reported LOC that exceeded 24 h). The published inter-rater reliability intraclass correlation coefficients for the seven OSU TBI domains range from 0.84 to 0.95. The Structured Clinical Interview for DSM-IV Diagnosis (SCID)13 was used to diagnose current MDD and to rule out individuals with a lifetime history of psychotic or bipolar disorders and alcohol or drug abuse or dependence within the previous 12 mo. An interview version of the Life Stressor Checklist-Revised,14 which assesses 21 stressful life events (e.g., experiencing or witnessing serious accidents, illnesses, sudden death, and physical and sexual assault), was used to determine exposure to traumatic events. The Clinician Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS)15 was used to diagnose current PTSD. The CAPS has demonstrated moderate inter-rater reliability (κ > 0.58).16 QUESTIONNAIRES Kansas Military History and Health Questionnaire The Kansas Gulf War Military History and Health Questionnaire5 was used to ascertain Kansas GWI case status5 and CDC CMI case status,2 as described below. In addition to questions about symptomatic illnesses, the Kansas Military History and Health Questionnaire also asked about demographic information, education, and military service branch, time periods, and locations in which they served during the GW, and their health and medical histories. Classification of Kansas GW Illness cases The Kansas GWI definition is based on an empirically identified pattern of symptoms found to significantly distinguish GW veterans from veterans who had served during the same time period but did not deploy to the Persian Gulf theater. It requires cases to have multiple and/or moderate-to-severe chronic symptoms in at least three of six defined symptom domains (fatigue/sleep problems, somatic pain, neurologic/cognitive/mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin abnormalities).5 Qualifying symptoms must have persisted over the 6-mo period preceding the study. Additionally, veterans are excluded as Kansas GWI cases if they report being diagnosed with medical or psychiatric conditions that could explain their symptoms or interfere with their ability to report them. Classification of CDC CMI Cases The CDC CMI criteria require veterans to endorse one or more symptoms that had been ongoing for at least 6 mo in two of three symptom categories.2 The symptom categories include: (1) musculoskeletal pain (e.g., joint pain/stiffness, muscle pain), (2) mood-cognition problems (e.g., feeling depressed, moody, anxious, having trouble sleeping, difficulty remembering or concentrating, trouble with word finding), and (3) fatigue. CDC CMI can be further categorized as “severe” if the veteran rates each defining symptom as severe or “mild-moderate” for milder complaints.11 Because the mild form of CMI can be broad and overly inclusive,17 the present study also examined the relationship between history of TBI and rates of mild-moderate versus severe CMI. Index of Chronic Symptomatic Illness Severity The symptom portion of the Kansas Gulf War Military History and Health Questionnaire,5 which includes 30 questions about various symptoms and abnormalities based on the Kansas GWI and CDC CMI case definitions, was used to operationalize the severity of the veterans’ chronic symptomatic illness. If a veteran endorsed a particular symptom, s/he was asked to rate the symptom’s severity. In this way, the symptom portion of the questionnaire is a 4-point Likert scale, (e.g., 0 = no symptom; 3 = symptom is severe). A chronic symptomatic illness severity score was derived by summing the answers to the 30 symptom questions. This yielded a score that ranged from 0 to 90, with higher scores indicating more symptoms and greater symptom severity. Depression Symptoms The Beck Depression Inventory (BDI),18 a 21-item self-report instrument assessing the common cognitive symptoms of depression, considered a valid and reliable instrument for depression screening in the general population, was used to assess depression symptoms. The BDI measures the severity of depressive symptoms occurring over the previous week. The items are rated on a 4-point severity scale (0–3) and are summed to give a total score (range 0–63). A higher score on the BDI denotes more severe depression. Predicted Exposure to Low-Levels of Sarin and Cyclosarin The predicted exposure status of GW veterans who participated in the parent imaging study was obtained from the Directorate of Health Risk Management, US Army Center for Health Promotion and Preventive Medicine. Eighty-eight of the 202 GW veterans had predicted exposure to low levels of sarin and cyclosarin from the Khamisiyah demolition. Analyses IBM SPSS Statistics version 24 was used for all analyses. Chi-square tests of independence were used to compare categorical variables (e.g., rates of CDC CMI and Kansas GWI) and Student’s t-tests were used to examine continuous variables (e.g., symptom severity index). The analyses were carried out in three stages. First, the data were analyzed as a function of TBI history (i.e., TBI versus No TBI). To assess the confound of predicted exposure to the Khamisiyah plume, the data were analyzed separately in subsets of veterans with and without predicted Khamisiyah exposure according to the DOD plume model. Finally, the relationship between TBI severity (i.e., possible versus mild TBI), number of TBIs (i.e., single versus > 1), TBI chronicity relative to the GW (i.e., pre-GW, GW-related, post-GW, pre- and post-GW) and various health outcome measures (e.g., Kansas GWI cases, CDC CMI cases, current diagnoses of PTSD and MDD, symptomatic illness severity and BDI scores) was examined. Only veterans with a history of TBI were included in the last analysis. Because there were only two veterans with a history of moderate TBI, their data were not included in the analysis of the relationship between TBI severity and rates of Kansas GWI and CDC CMI. However, data from the two moderate TBI veterans are included in Table V, along with data from veterans with possible and mild TBI. An analysis of variance was used to assess the relationship between TBI chronicity and chronic symptomatic illness severity and BDI. Because of the multiple comparisons, to protect against the likelihood of false positives, an alpha level of 0.01 was considered significant for all analyses. RESULTS Demographic Results The study sample was 82% male, had a mean age of 53.6 yr, and a mean education attainment of 15.6 yr (summarized in Table I). This sample of GW veterans had a slightly higher rate of current PTSD (14%) but a comparable rate of MDD (9%) as determined by structured clinical interview compared with other GW veteran samples.19,20 Table II presents additional information about the nature of TBIs reported by the GW veterans. Most veterans with histories of TBI in the sample had possible (51%) or mild (47%) TBI. Because moderate TBI was exclusionary for the parent imaging study, only two veterans in the current sample had moderate TBI. (The OSU-TBI clinical screening interview uncovered that the severity of these two veterans’ TBI was moderate rather than mild). A little more than half (51.5%) of the veterans with histories of TBI reported more than one TBI. Only 7% of the TBIs were related to injuries sustained during the GW. Most of the veterans with histories of TBI sustained their TBIs in injuries that occurred prior to (73%) or after (34%) the GW. Thirteen percent reported TBIs both before and after the GW. Table I. Demographic and Clinical Characteristics of Study Sample Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Table I. Demographic and Clinical Characteristics of Study Sample Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Table II. Characteristics of TBI TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) aExperienced head/neck injury and/or was nearby explosion/blast that resulted in memory loss and/or feeling dazed. bExperienced head/neck injury and/or was nearby explosion/blast that resulted in loss of consciousness (LOC) ≤30 min. cExperienced head/neck injury and/or was nearby explosion/blast that resulted in LOC between 30 min and 24 h. Table II. Characteristics of TBI TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) aExperienced head/neck injury and/or was nearby explosion/blast that resulted in memory loss and/or feeling dazed. bExperienced head/neck injury and/or was nearby explosion/blast that resulted in loss of consciousness (LOC) ≤30 min. cExperienced head/neck injury and/or was nearby explosion/blast that resulted in LOC between 30 min and 24 h. Relationship Between History of TBI, Kansas GWI, and CDC CMI Case Status Table III summarizes the demographic and clinical characteristics of the sample dichotomized by history of TBI. There were no significant differences in demographics, rates of Kansas GWI, or diagnoses of current PTSD, or MDD between the groups with (i.e., possible, mild, and moderate) and without (i.e., improbable) history of TBI. However, the group with TBI had a higher rate of CDC CMI compared with the group without TBI (86% vs. 65%, χ2 = 11.56, df = 1, p = 0.001). Although these differences were not significant at the set alpha level of p = 0.01, there were also differences in chronic symptomatic illness severity index (t = 2.31, df = 200, p = 0.02), BDI scores (t = 2.35, df = 200, p = 0.02), and history of alcohol abuse/dependence (χ2 = 3.88, df = 1, p < 0.05) between the two groups. Table III. Demographic and Clinical Characteristics by TBI Status No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 Significant differences at set alpha level of p ≤ 0.01 are bolded. adf = 1, p = 0.001. bdf = 1, p = 0.004. cdf = 200, p = 0.02. ddf = 1, p < 0.05. Table III. Demographic and Clinical Characteristics by TBI Status No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 Significant differences at set alpha level of p ≤ 0.01 are bolded. adf = 1, p = 0.001. bdf = 1, p = 0.004. cdf = 200, p = 0.02. ddf = 1, p < 0.05. Relationship Between History of TBI and CMI Case Status by Symptom Severity As noted earlier, CDC CMI can be further categorized as “severe” if the defining symptoms are rated as severe or “mild-moderate” for milder complaints.11 There was a higher rate of mild-moderate CMI (77% vs. 58%, χ2 = 8.47, df = 1, p = 0.004), but not severe CMI (8% vs. 7% χ2 = 0.18, df = 1, p = 0.67) among veterans with a history of TBI compared with veterans without history of TBI (see Table III). Relationship Between Kansas GWI and CMI Case Status in Veterans Without Predicted Sarin/Cyclosarin Exposure Table IV summarizes the percentages of Kansas GWI and CDC CMI cases dichotomized by TBI history in the entire study sample and as a function of predicted sarin/cyclosarin exposure status. In all groups, there was a higher rate of CDC CMI among veterans with histories of TBI, although this difference was not significant at the set alpha level of p = 0.01 level in the smaller (n = 88) sarin-exposed group. There were also trends (p ≤ 0.04) of higher rates of mild-moderate CDC CMI among veterans with a history of TBI in compared veterans without TBI. In contrast, there was no difference in the rates of Kansas GWI or severe CMI as a function of history of TBI. Table IV. Relationship Between History of TBI, Kansas GWI, and CMI Case Status in the Entire Study Sample and as a Function of Predicted Sarin Exposure Status Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Significant differences at set alpha level of p ≤ 0.01 are bolded. aDifferent from TBI−: χ2 = 11.56, df = 1, p = 0.001. bDifferent from TBI−: χ2 = 8.47, df = 1, p = 0.004. cDifferent from TBI−: χ2 = 6.88, df = 1, p = 0.009. dDifferent from TBI−-: χ2 = 4.18, df = 1, p = 0.04. eDifferent from TBI−: χ2 = 4.95, df = 1, p = 0.03. fDifferent from TBI−: χ2 = 4.56, df = 1, p = 0.03. Table IV. Relationship Between History of TBI, Kansas GWI, and CMI Case Status in the Entire Study Sample and as a Function of Predicted Sarin Exposure Status Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Significant differences at set alpha level of p ≤ 0.01 are bolded. aDifferent from TBI−: χ2 = 11.56, df = 1, p = 0.001. bDifferent from TBI−: χ2 = 8.47, df = 1, p = 0.004. cDifferent from TBI−: χ2 = 6.88, df = 1, p = 0.009. dDifferent from TBI−-: χ2 = 4.18, df = 1, p = 0.04. eDifferent from TBI−: χ2 = 4.95, df = 1, p = 0.03. fDifferent from TBI−: χ2 = 4.56, df = 1, p = 0.03. Relationship Between Health Outcome Measures and TBI Severity, Number of TBI, and TBI Chronicity Table V summarizes the relationship between various health outcomes and TBI severity, number of TBIs, and TBI chronicity relative to the GW. Because only two veterans in the sample had a history of moderate TBI, their data were not included in the statistical analysis of the relationship between TBI severity and rates of Kansas GWI and CDC CMI. However, their data are shown in Table V, along with that of the possible and mild TBI cases. Table V. Relationship Between Health Outcome Measures TBI Severity, Number of TBI, and TBI Chronicity TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) Significant differences at set alpha level of p < 0.01 are bolded. Excluded from statistical analyses because there were only two veterans with moderate TBI. bDifferent from >1 TBI: χ2= 5.05, df = 1, p = 0.03. cDifferent from pre-GW, post-GW: χ2= 12.75, df = 3, p = 0.005. dDifferent from pre-GW, post-GW: χ2= 12.86, df = 3, p = 0.005. eMain effect of TBI chronicity (F3,96 = 3.16, p = 0.03), Tukey’s post hoc test revealed a difference between pre- and GW-related TBI (p < 0.05). Table V. Relationship Between Health Outcome Measures TBI Severity, Number of TBI, and TBI Chronicity TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) Significant differences at set alpha level of p < 0.01 are bolded. Excluded from statistical analyses because there were only two veterans with moderate TBI. bDifferent from >1 TBI: χ2= 5.05, df = 1, p = 0.03. cDifferent from pre-GW, post-GW: χ2= 12.75, df = 3, p = 0.005. dDifferent from pre-GW, post-GW: χ2= 12.86, df = 3, p = 0.005. eMain effect of TBI chronicity (F3,96 = 3.16, p = 0.03), Tukey’s post hoc test revealed a difference between pre- and GW-related TBI (p < 0.05). TBI severity had no significant effect on rates of Kansas GWI (χ2 = 0.07, df = 1, p = 0.79), CDC CMI (χ2 = 0.18, df = 1, p = 0.67), mild-moderate CMI (χ2 = 0.01, df = 1, p = 0.93), severe CMI (χ2 = 0.42, df = 1, p = 0.52), current diagnoses of PTSD (χ2 = 0.47, df = 1, p = 0.79), current diagnosis of MDD (χ2 = 0.32, df = 1, p = 0.57), chronic symptomatic illness severity index (t = 0.47, df = 93, p = 0.64), or BDI scores (t = 0.41, df = 93, p = 0.68). Number of TBIs also did not have a significant effect on the rates of Kansas GWI (χ2 = 0.25, df = 1, p = 0.62), CDC CMI (χ2 = 2.11, df = 1, p = 0.15), mild-moderate CMI (χ2 = 0.09, df = 1, p = 0.76), current PTSD (χ2 = 1.31, df = 1, p = 0.25), current MDD (χ2 = 0.50, df = 1, p = 0.48), chronic symptomatic illness severity index (t = 1.25, df = 93, p = 0.22), or BDI scores (t = 0.69, df = 93, p = 0.49). There were more severe CMI cases among veterans with single TBI compared with those with >1 TBIs (χ2 = 5.05, df = 1, p = 0.03); however, this was not significant at the set alpha level of p< 0.01. There was no relationship between TBI chronicity and rates of Kansas GWI (χ2 = 3.60, df = 3, p = 0.31), CDC CMI (χ2 = 4.31, df = 3, p = 0.23), mild-moderate CMI (χ2 = 6.45, df = 3, p = 0.09), or BDI scores (F3,93 = 1.97, p = 0.12). However, veterans with GW-related TBIs had higher rates of severe CMI (χ2 = 12.75, df = 3, p = 0.005) and MDD (χ2 = 12.86, df = 3, p = 0.005) compared with veterans who sustained TBIs before or after the GW (see Table V). Although not significant at the set alpha level of p< 0.01, there was an effect of TBI chronicity on symptomatic severity index (F3,96 = 3.16, p = 0.03). DISCUSSION Although TBI was not common during the GW, some GW veterans have a history of TBI. Yee et al9 previously reported that 12.2% of the GW veterans from the Devens Cohort Study self-reported a history of TBI. Nearly half (47%) of the GW veterans in this sample of 202 participants, originally recruited for a neuroimaging study on the effects of predicted exposure to sarin/cyclosarin on brain function and brain structure, had a history of TBI. One possible explanation for the difference in this and the Yee et al’s study is that the sample of GW veterans in this study, some of whom were recruited for their predicted Khamisiyah exposure, had higher risk factors for TBI than the GW veterans from the Ft. Devens Cohort. However, it may also be possible that the difference in rates of TBI is, at least in part, related to the different methods used to ascertain histories of TBI. Yee and colleagues used retrospective self-reports, which may have missed some GW veterans who were unaware that they had a TBI. In contrast, the present study used the OSU TBI-ID method,10 which was designed to elicit recall of all injuries receiving medical attention, or that should have, using previously validated methods of injury recall21,22 to optimize personal recall of injuries experienced. The finding that nearly half of the current sample of GW veterans had histories of TBI is in line with reports that the true incidence of TBI is likely far greater than previously recognized23–25 and that military personnel tend to have higher rates of TBI than civilian populations.26,27 The finding that only 7% of the TBIs were associated with injuries that occurred during the GW is consistent with notion that TBIs were uncommon during the GW. In fact, most of the TBIs in this sample were associated with injuries that occurred prior to the GW; 34% of the TBIs were associated with injuries that occurred after the GW. The second aim of this study was to investigate the relationship between TBI and CMI in GW veterans. Compared with veterans without TBI, GW veterans with a history of TBI had higher rates of CDC CMI and greater chronic symptomatic illness severity indices (i.e., more severe symptoms). This is in agreement with Yee et al’s finding that self-reported TBI was related to increased rates of health symptoms and CMI in the Ft. Devens cohort.9 However, Yee et al only classify chronic symptomatic illness according to the CDC CMI case definition. Because the individual symptoms of GWI/CMI can occur in the general population and the mild form of CMI has resulted high prevalence rates in even control populations,17 CDC CMI can be overly inclusive if it is not specified by symptom severity.11 Thus, the current study sought to build upon the findings of Yee et al by examining the relationship between TBI and chronic symptomatic illness according to the Kansas GWI case definition as well as severe and moderate-mild cases of CMI. The results indicate that there were no differences in the rates of Kansas GWI or severe CDC CMI by TBI status; however, there were significantly more CDC CMI cases and mild-moderate CMI cases among veterans with a history of TBI compared with veterans without a history of TBI. Research suggests that a significant minority of individuals with mild TBI report neurobehavioral symptoms years post their TBI injury.28–31 Because these neurobehavioral symptoms (i.e., headaches, balance problems, dizziness, fatigue, depression, anxiety, irritability, and memory and attention difficulties) overlap with some of the chronic symptoms experienced by GW veterans with GWI/CMI, a less restrictive definition of chronic symptomatic illness in GW veterans (e.g., CDC CMI or mild-moderate CMI) will capture more veterans with histories of TBI as “cases” than a more restrictive case definition. Furthermore, there was a similar pattern of results (i.e., more CDC CMI and mild-moderate CMI cases among TBI+ veterans but not more Kansas GWI or severe CMI cases among TBI+ veterans) in the subset of veterans with and without predicted exposure to sarin/cyclosarin. Thus, it is unlikely that predicted exposure to low levels of sarin/cyclosarin confounded these findings. Consistent with reports that patients with TBI are at increased risk for developing depressive symptoms,32 veterans with histories of TBI had higher symptomatic illness severity indices (i.e., more severe symptoms) and higher depressive symptoms than veterans without TBI, although not significant at the set alpha level of p< 0.01. This finding may also explain, at least partially, why self-reported TBI was related to poorer health-related quality of life in GW veterans from the Fort Devens GW veterans.9 Somewhat unexpectedly, there was no relationship between TBI severity (i.e., possible versus mild TBI) and the different health outcome measures examined (i.e., Kansas GWI cases, CDC CMI cases, current diagnoses of PTSD and MDD, symptomatic illness severity and BDI scores). However, this may relate to the limited range of TBI severity in the present sample (e.g., mostly of possible and mild TBI cases with only two moderate TBI cases). Because moderate-severe TBI was exclusionary for the parent imaging study, the present sample was not ideally suited for examining the relationship between TBI severity and health outcomes. Investigation of the effects of TBI chronicity relative to the GW (i.e., pre-GW, GW-related, post-GW, pre- and post-GW) revealed no relationship between pre-GW TBIs and the different health outcomes. Somewhat surprisingly, this suggests that having sustained one or more TBIs before the GW did not influence the veterans’ reactions to exposures/experiences from the GW (i.e., increased their rate of GWI/CMI). However, there was an effect of TBI chronicity on rates of severe CMI and current MDD: more veterans with GW-related TBIs had severe CMI and current MDD compared with veterans whose TBIs were unrelated to the GW. This finding should be considered with the caveat that there were only seven veterans in this category. Nevertheless, it is interesting that this mirrors the high rates of depression seen in OEF/OIF Veterans with mild TBI.33–37 Future, more adequately powered studies will be needed to determine if war-related TBIs are, in fact, associated with poorer functional outcomes in GW veterans. Study Limitations Some study limitations should be noted: First, the study was not originally designed to investigate the relationship between TBI and chronic symptomatic illness. Therefore, the sample lacked a broad range of TBI severity (e.g., moderate-severe TBI was an exclusionary condition for the parent imaging study and only two veterans in the sample had a history of moderate TBI). Consequently, these findings may not reflect the true rate or severity of TBI among GW veterans and require replication in a larger, more general sample of GW veterans. Second, there is evidence that TBI is common among individuals with co-occurring mental health and substance use disorders.38 There is also evidence that TBI may cause decades-lasting vulnerability to psychiatric illness in some individuals39 because axis I and II psychiatric disorders are both common among individuals with TBI.40 Because a lifetime history of psychotic or bipolar disorders and/or drug abuse or dependence in the past 12 mo was also exclusionary for the parent imaging study, this may have biased the current findings. Third, nearly half of the sample had predicted sarin/cyclosarin exposure, which may also have introduced a potential confound. However, there was no difference in the percentage of veterans with and without predicted exposure to sarin/cyclosain in the two TBI groups (44 % vs. 43%) and no difference in the percentage of Kansas GWI and CDC CMI cases in veterans with and without history of TBI with and without predicted sarin/cyclosarin exposure. Fourth, this sample of 202 GW veterans, some of whom had predicted Khamisiyah exposure, all of whom had no contraindications for MRI and the time and means to travel to the San Francisco VA to participate in this research study, may not be representative of the larger GW veteran population. Therefore, it is possible that the results of this study do not generalize to all GW veterans. Finally, the positive TBI screens as determined by the OSU TBI-ID were not followed-up with comprehensive TBI evaluations. CONCLUSIONS Even though TBIs were not common during the GW, many GW veterans have a history of TBI. Most veterans in this sample sustained TBIs in injuries that occurred prior to the GW; however, history of pre-GW TBI did not appear to influence the veterans’ response to exposures/experiences from the GW. That is, veterans with pre-GW TBI were not more likely to have chronic symptomatic illness, PTSD, or MDD. History of TBI was only associated with increased rates of chronic symptomatic illness when chronic symptomatic illness is defined broadly (i.e., CDC CMI or mild-moderate CMI). This is likely because the two conditions (GWI/CMI and TBI) share some overlapping symptoms. History of TBI was not associated with chronic symptomatic illness in GW veterans when it defined by more stringent case definitions (i.e., Kansas GWI or severe-CMI). Therefore, future studies that use broad, inclusive definitions to categorize chronic symptomatic illness in GW veterans should screen for history of TBI. There was also suggestive evidence that GW-related TBI may be associated with poorer functional outcomes in GW veterans. However, because there were only seven veterans with GW-related TBIs in the present sample, future, better powered studies with randomly and systematically select participants from the larger population of GW veterans will need to confirm this finding. Conflict of Interest This material is the result of work supported with resources and the use of facilities at the San Francisco Veterans Affairs Medical Center and was supported by a VA Merit Award Grant (I01 CX0007080) awarded to Dr. Linda Chao. The author reports no declarations of interest. Funding VA grant No. CX000798 entitled “Longitudinal Assessment of Gulf War Veterans with Suspected Sarin Exposure” References 1 Research Advisory Committee on Gulf War Veterans’ Illness (RAC-GWVI) : Gulf War Illness and the Health of Gulf War Veterans: Research Update and Recommendations, 2009-2013 . Boston , U.S. Government Printing Office , 2014 . 2 Fukuda K , Nisenbaum R , Stewart G , et al. : Chronic multisymptom illness affecting Air Force veterans of the Gulf War . JAMA 1998 ; 280 ( 11 ): 981 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Goss Gilroy Inc : Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf . 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Google Scholar CrossRef Search ADS PubMed 37 Eskridge SL , Macera CA , Galarneau MR , et al. : Influence of combat blast-related mild traumatic brain injury acute symptoms on mental health and service discharge outcomes . J Neurotrauma 2013 ; 30 : 1391 – 7 . Google Scholar CrossRef Search ADS PubMed 38 McHugo GJ , Krassenbaum S , Donley S , Corrigan JD , Bogner J , Drake RE : The prevalence of traumatic brain injury among people with co-occurring mental health and substance use disorders . J Head Trauma Rehabil 2017 ; 32 ( 3 ): E65 – 74 . Google Scholar CrossRef Search ADS PubMed 39 Koponen S , Taiminen T , Portin R , et al. : Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study . Am J Psychiatry 2002 ; 159 ( 8 ): 1315 – 21 . Google Scholar CrossRef Search ADS PubMed 40 Koponen S , Taiminen T , Hiekkanen H , Tenovuo O : Axis I and II psychiatric disorders in patients with traumatic brain injury: a 12-month follow-up study . Brain Inj 2011 ; 25 ( 11 ): 1029 – 34 . Google Scholar CrossRef Search ADS PubMed Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Military Medicine Oxford University Press

The Relationship Between Traumatic Brain Injury and Rates of Chronic Symptomatic Illness in 202 Gulf War Veterans

Military Medicine , Volume Advance Article – May 18, 2018

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Association of Military Surgeons of the United States
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Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2018.
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0026-4075
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1930-613X
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10.1093/milmed/usy109
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Abstract

Abstract Introduction Although not a “signature injury” of Operation Desert Shield/Desert Storm (i.e., Gulf War, GW), some GW veterans have a history traumatic brain injury (TBI). For example, a previous study found that 12.2% of the GW veterans from the Fort Devens Cohort Study had self-reported TBIs. The present study sought to build upon this finding by examining the relationship between TBI and chronic symptomatic illness in a different sample of GW veterans. Materials and Methods Participants were 202 GW veterans recruited from 2014 to 2018 at the San Francisco Veterans Affairs Medical Center as part of a VA-funded study on the effects of predicted exposure to low levels of sarin and cyclosarin on brain structure and function. The Ohio State University TBI identification method was used to determine lifetime history of TBI. The Kansas Gulf War Military History and Health Questionnaire was used to assess symptoms and to determine cases of Kansas Gulf War Illness (GWI) and Centers for Disease Control and Prevention (CDC) Chronic Multisymptom Illness (CMI). Results Nearly half (47%) the sample had a history of TBI, but only 7% of the TBIs were sustained in injuries that occurred during the GW. Most of the TBIs were sustained in injuries that occurred prior to (73%) or after (34%) the GW. History of TBI was not associated with higher rates of symptomatic illness when it was narrowly defined (i.e., Kansas GWI cases or cases of severe CMI). History of TBI was only associated with higher rates of symptomatic illness when it is broadly defined (i.e., CDC CMI or mild-moderate CMI). There was suggestive evidence that veterans who sustained TBIs during the GW (only seven in the present sample) have poorer functional outcomes compared with GW veterans with non-GW related TBIs. Conclusions While TBIs were uncommon during the GW, many GW veterans sustained TBIs prior or after the GW. Because TBI and GWI/CMI share some overlapping symptoms, history of TBI may appear to be associated with increased rates of chronic symptomatic illness in GW veterans if chronic symptomatic illness is defined broadly (i.e., CDC CMI or mild-moderate CMI). History of pre-GW TBI did not affect the veterans’ response to exposures/experiences from the GW; however, there was suggestive evidence that veterans who sustained TBIs during the GW may have poorer functional outcomes that GW veterans without TBI or even GW veterans with non-GW-related TBIs. Future, better powered studies with randomly and systematically select participants from the larger population of GW veterans will need to confirm this finding. INTRODUCTION Unlike the recent military operations in the Persian Gulf region (i.e., Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND)), traumatic brain injury (TBI) was not considered to be common in the 1990–1991 Gulf War (GW). Instead, the “signature injury” associated with the service in the GW is a chronic, symptomatic illness that has come to be known as GW Illness (GWI) or chronic multisymptom illness (CMI).1 Approximately 25–32% of GW veterans suffer from GWI/CMI, which is characterized by varying symptoms but typically includes some combination of fatigue, musculoskeletal pain, cognitive and/or mood dysfunction, respiratory, gastrointestinal, and dermatologic complaints.2–6 Routine clinical laboratory tests of veterans suffering from GWI/CMI tend to be remarkable and the search for a GWI/CMI biomarker has largely been unsuccessful.7 Decades after the end of the GW, GWI/CMI remains a controversial topic with no established treatment and no uniform case definition. This prompted the Department of Veterans Affairs (VA) to ask the Institute on Medicine (IOM) in 2014 to help develop a case definition for the disorder.8 After comprehensively reviewing, evaluating, and summarizing the available scientific and medical literature regarding symptoms among the GW veterans, the IOM expert panel found merits in the Kansas GWI case definition5 and the Centers for Disease Control and Prevention (CDC) CMI case definition.2 The Kansas GWI case definition requires moderately severe or multiple chronic symptoms in at least three of six domains, including fatigue/sleep problems, pain, neurological/cognitive/mood symptoms, respiratory symptoms, gastrointestinal symptoms, and skin symptoms. The Kansas GWI case definition also excludes cases that have established diagnoses that might interfere with the accurate reporting of symptoms and/or might produce similar symptoms. The CDC CMI case definition requires one or more symptoms that have been ongoing for at least 6 mo in two of three domains (i.e., fatigue, musculoskeletal pain, and mood-cognitive symptoms). Depending on how each defining symptoms is rated (e.g., mild, moderate, or severe), CDC CMI can be further categorized as mild-moderate or severe. However, unlike the Kansas GWI definition, the CDC CMI case definition does not have any exclusionary criterion. Despite the fact that TBI was uncommon during the GW, we know that some GW veterans have a history of TBI. For example, Yee et al9 reported that 12.2% of the GW veterans from the Fort Devens Cohort Study self-reported a history of TBI. The study also found self-reported TBI to be related to increased rates of health symptoms, CMI, and poorer health-related quality of life.9 One objective of this study was to investigate the frequency of TBI in another cohort of GW veterans. Because Yee et al used retrospective self-report data to quantify TBI, it is possible that they missed veterans who were unaware that they had a TBI. Therefore, the current study also sought to expand on the findings of Yee et al by using a standardized, structured interview to elicit the GW veterans’ lifetime history of TBI (i.e., the Ohio State University TBI Identification Method10). The Yee et al study classified GW veterans’ symptoms according to the CDC CMI case definition; however, they did not specify severe cases versus moderate-mild CMI cases. Research has shown that CMI may be overly inclusive if it is not specified by symptom severity.11 Therefore, the another aim of this was to build upon the findings of Yee et al by examining the relationship between TBI and chronic symptomatic illness as defined by the CDC CMI case definition, severe and moderate-mild cases of CMI, and the Kansas GWI case definition. To examine the rate of TBI in GW veterans and the relationship between TBI and chronic symptomatic illness defined by various case definitions, secondary analyses were conducted in a sample of 202 GW veterans who were originally recruited to participate in an imaging study on the effects of potential exposure to low levels of the nerve agents on brain function and brain structure. In March 1991, U.S. combat engineers destroyed a munition storage depot at Khamisiyah, Iraq. It was later discovered that the storage depot contained organophosphorus nerve agents sarin and cyclosarin and potentially 100,000 military personnel were exposed by the airborne plume generated by the demolition.12 METHOD Participants Two hundred and two GW veterans were recruited from 2014 to 2018 at the San Francisco Veterans Affairs Medical Center (SF VAMC) as part of a VA-funded study on the effects of predicted exposure to low levels of sarin and cyclosarin on brain structure and function. After the GW ended, the Department of Defense (DoD) and the Central Intelligence Agency (CIA) tried to model possible sarin and cyclosarin exposures over a 4-d period based on simulated meteorological conditions and analyses of likely chemical agent dispersal. Military personnel attached with units located in areas covered by the estimated zone of exposure were considered potentially exposed to low levels of sarin/cyclosarin.12 Although the parent imaging study focused on the population of GW veterans with predicted exposure to the Khamisiyah plume, GW veterans without predicted Khamisiyah exposure were also recruited to serve as un-exposed controls. All participants signed informed consent approved by the Institutional Review Boards of the University of California, San Francisco and the San Francisco Veterans Affairs Medical Center. Measures The following measures were assessed by clinical interviews conducted by a Ph.D. level psychologist: the veterans’ history of TBI, diagnoses of current major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), lifetime histories of psychotic or bipolar disorders, alcohol and/or drug abuse or dependence. The following measures were assessed by the veterans’ responses to self-report questionnaires: Kansas GWI5 status, CDC CMI status,2 chronic symptomatic illness severity, and symptoms of depression. Clinical Interview Assessments History of TBI was assessed using the Ohio State University TBI Identification Method (OSU TBI-ID) Short Form.10 The OSU TBI-ID is a structured interview designed to elicit self- or proxy-reports of TBI occurring over a person’s lifetime. Veterans were classified as having “improbable” (i.e., no) TBI if they reported no head or neck injuries, and/or never having been hospitalized or treated in the emergency room following a head or neck injury, and/or never having been nearby a blast or explosion. Veterans who reported a head or neck injury and/or being nearby when a blast or explosion occurred were also classified as “improbable” TBI cases if they did not experience a loss of consciousness (LOC), memory lapse, or alteration of conscious (AOC, e.g., feeling dizzy, dazed, or confused). Veterans who reported memory lapse(s) and/or AOCs as a result of a head or neck injury and/or being nearby when a blast or explosion occurred were classified as having “possible” TBI. Veterans were classified as “mild” TBI cases if they experienced LOC < 30 min due to a head or neck injury and/or being nearby when a blast or explosion occurred. Moderate and moderate-severe TBI was exclusionary for the primary imaging study (the initial phone screen asked about LOCs and duration of LOCs); however, two veterans reported LOCs between 30 and 24 h as a result of a head or neck injury and/or being nearby when a blast or explosion occurred (i.e., moderate TBI) during the OSU TBI-ID interview. No veteran had moderate/severe TBI (i.e., reported LOC that exceeded 24 h). The published inter-rater reliability intraclass correlation coefficients for the seven OSU TBI domains range from 0.84 to 0.95. The Structured Clinical Interview for DSM-IV Diagnosis (SCID)13 was used to diagnose current MDD and to rule out individuals with a lifetime history of psychotic or bipolar disorders and alcohol or drug abuse or dependence within the previous 12 mo. An interview version of the Life Stressor Checklist-Revised,14 which assesses 21 stressful life events (e.g., experiencing or witnessing serious accidents, illnesses, sudden death, and physical and sexual assault), was used to determine exposure to traumatic events. The Clinician Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS)15 was used to diagnose current PTSD. The CAPS has demonstrated moderate inter-rater reliability (κ > 0.58).16 QUESTIONNAIRES Kansas Military History and Health Questionnaire The Kansas Gulf War Military History and Health Questionnaire5 was used to ascertain Kansas GWI case status5 and CDC CMI case status,2 as described below. In addition to questions about symptomatic illnesses, the Kansas Military History and Health Questionnaire also asked about demographic information, education, and military service branch, time periods, and locations in which they served during the GW, and their health and medical histories. Classification of Kansas GW Illness cases The Kansas GWI definition is based on an empirically identified pattern of symptoms found to significantly distinguish GW veterans from veterans who had served during the same time period but did not deploy to the Persian Gulf theater. It requires cases to have multiple and/or moderate-to-severe chronic symptoms in at least three of six defined symptom domains (fatigue/sleep problems, somatic pain, neurologic/cognitive/mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin abnormalities).5 Qualifying symptoms must have persisted over the 6-mo period preceding the study. Additionally, veterans are excluded as Kansas GWI cases if they report being diagnosed with medical or psychiatric conditions that could explain their symptoms or interfere with their ability to report them. Classification of CDC CMI Cases The CDC CMI criteria require veterans to endorse one or more symptoms that had been ongoing for at least 6 mo in two of three symptom categories.2 The symptom categories include: (1) musculoskeletal pain (e.g., joint pain/stiffness, muscle pain), (2) mood-cognition problems (e.g., feeling depressed, moody, anxious, having trouble sleeping, difficulty remembering or concentrating, trouble with word finding), and (3) fatigue. CDC CMI can be further categorized as “severe” if the veteran rates each defining symptom as severe or “mild-moderate” for milder complaints.11 Because the mild form of CMI can be broad and overly inclusive,17 the present study also examined the relationship between history of TBI and rates of mild-moderate versus severe CMI. Index of Chronic Symptomatic Illness Severity The symptom portion of the Kansas Gulf War Military History and Health Questionnaire,5 which includes 30 questions about various symptoms and abnormalities based on the Kansas GWI and CDC CMI case definitions, was used to operationalize the severity of the veterans’ chronic symptomatic illness. If a veteran endorsed a particular symptom, s/he was asked to rate the symptom’s severity. In this way, the symptom portion of the questionnaire is a 4-point Likert scale, (e.g., 0 = no symptom; 3 = symptom is severe). A chronic symptomatic illness severity score was derived by summing the answers to the 30 symptom questions. This yielded a score that ranged from 0 to 90, with higher scores indicating more symptoms and greater symptom severity. Depression Symptoms The Beck Depression Inventory (BDI),18 a 21-item self-report instrument assessing the common cognitive symptoms of depression, considered a valid and reliable instrument for depression screening in the general population, was used to assess depression symptoms. The BDI measures the severity of depressive symptoms occurring over the previous week. The items are rated on a 4-point severity scale (0–3) and are summed to give a total score (range 0–63). A higher score on the BDI denotes more severe depression. Predicted Exposure to Low-Levels of Sarin and Cyclosarin The predicted exposure status of GW veterans who participated in the parent imaging study was obtained from the Directorate of Health Risk Management, US Army Center for Health Promotion and Preventive Medicine. Eighty-eight of the 202 GW veterans had predicted exposure to low levels of sarin and cyclosarin from the Khamisiyah demolition. Analyses IBM SPSS Statistics version 24 was used for all analyses. Chi-square tests of independence were used to compare categorical variables (e.g., rates of CDC CMI and Kansas GWI) and Student’s t-tests were used to examine continuous variables (e.g., symptom severity index). The analyses were carried out in three stages. First, the data were analyzed as a function of TBI history (i.e., TBI versus No TBI). To assess the confound of predicted exposure to the Khamisiyah plume, the data were analyzed separately in subsets of veterans with and without predicted Khamisiyah exposure according to the DOD plume model. Finally, the relationship between TBI severity (i.e., possible versus mild TBI), number of TBIs (i.e., single versus > 1), TBI chronicity relative to the GW (i.e., pre-GW, GW-related, post-GW, pre- and post-GW) and various health outcome measures (e.g., Kansas GWI cases, CDC CMI cases, current diagnoses of PTSD and MDD, symptomatic illness severity and BDI scores) was examined. Only veterans with a history of TBI were included in the last analysis. Because there were only two veterans with a history of moderate TBI, their data were not included in the analysis of the relationship between TBI severity and rates of Kansas GWI and CDC CMI. However, data from the two moderate TBI veterans are included in Table V, along with data from veterans with possible and mild TBI. An analysis of variance was used to assess the relationship between TBI chronicity and chronic symptomatic illness severity and BDI. Because of the multiple comparisons, to protect against the likelihood of false positives, an alpha level of 0.01 was considered significant for all analyses. RESULTS Demographic Results The study sample was 82% male, had a mean age of 53.6 yr, and a mean education attainment of 15.6 yr (summarized in Table I). This sample of GW veterans had a slightly higher rate of current PTSD (14%) but a comparable rate of MDD (9%) as determined by structured clinical interview compared with other GW veteran samples.19,20 Table II presents additional information about the nature of TBIs reported by the GW veterans. Most veterans with histories of TBI in the sample had possible (51%) or mild (47%) TBI. Because moderate TBI was exclusionary for the parent imaging study, only two veterans in the current sample had moderate TBI. (The OSU-TBI clinical screening interview uncovered that the severity of these two veterans’ TBI was moderate rather than mild). A little more than half (51.5%) of the veterans with histories of TBI reported more than one TBI. Only 7% of the TBIs were related to injuries sustained during the GW. Most of the veterans with histories of TBI sustained their TBIs in injuries that occurred prior to (73%) or after (34%) the GW. Thirteen percent reported TBIs both before and after the GW. Table I. Demographic and Clinical Characteristics of Study Sample Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Table I. Demographic and Clinical Characteristics of Study Sample Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Total Sample (n = 202) Age, years: M (SD) 53.6 (7.8) Females: N (%) 36 (18%) Education: years: M (SD) 15.6 (2.3) Ethnicity: N (%)  Caucasian 148 (73%)  African American 18 (9%)  Latino 21 (10%)  Other 15 (7%) Military Branch in GW: N (%)  Army 126 (62%)  Marines 39 (19%)  Navy 20 (10%)  Air Force 17 (8%) Unit Type in GW: N (%)  Active duty 155 (77%)  National guard/reserve 47 (23%)  Officer during GW: N (%) 52 (26%)  Predicted Khamiyah exposure: N (%) 88 (43%)  Kansas GWI cases: N (%) 78 (39%)  Kansas GWI exclusionary condition(s): N (%) 60 (30%)  CDC CMI cases: N (%) 151 (75%)  CDC CMI cases with Kansas GWI exclusionary condition(s) N (%) 48 (32%)  Symptomatic illness severity score: M (SD) 19.4 (16.7)  Trauma exposure: N (%) 151 (75%)  Current PTSD diagnosis: N (%) 28 (14%)  CAPS: M (SD) 20.4 (21.5)  Current MDD diagnosis: N (%) 19 (9%)  BDI: M (SD) 8.1 (8.2)  History of past alcohol abuse/dependence: N (%) 48 (24%)  History of past substance abuse/dependence: N (%) 16 (8%) TBI history: N (%)  Improbable 105 (52%)  Possible 49 (24%)  Mild 46 (23%)  Moderate 2 (1%) Table II. Characteristics of TBI TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) aExperienced head/neck injury and/or was nearby explosion/blast that resulted in memory loss and/or feeling dazed. bExperienced head/neck injury and/or was nearby explosion/blast that resulted in loss of consciousness (LOC) ≤30 min. cExperienced head/neck injury and/or was nearby explosion/blast that resulted in LOC between 30 min and 24 h. Table II. Characteristics of TBI TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) TBI severity: N (%)  Possiblea 49 (51%)  Mildb 46 (47%)  Moderatec 2 (2%) Number of TBI: N (%)  One 47 (48.5%)  >1 50: (51.5%) TBI chronicity relative to GW: N (%)  Pre-GW 71 (73%)  GW-related 7 (7%)  Post-GW 33 (34%)  Pre- & post-GW 13 (13%) Childhood TBI (>15 yr): N (%) 31 (32%) Nearby explosion/blast: N (%) 59 (61%) aExperienced head/neck injury and/or was nearby explosion/blast that resulted in memory loss and/or feeling dazed. bExperienced head/neck injury and/or was nearby explosion/blast that resulted in loss of consciousness (LOC) ≤30 min. cExperienced head/neck injury and/or was nearby explosion/blast that resulted in LOC between 30 min and 24 h. Relationship Between History of TBI, Kansas GWI, and CDC CMI Case Status Table III summarizes the demographic and clinical characteristics of the sample dichotomized by history of TBI. There were no significant differences in demographics, rates of Kansas GWI, or diagnoses of current PTSD, or MDD between the groups with (i.e., possible, mild, and moderate) and without (i.e., improbable) history of TBI. However, the group with TBI had a higher rate of CDC CMI compared with the group without TBI (86% vs. 65%, χ2 = 11.56, df = 1, p = 0.001). Although these differences were not significant at the set alpha level of p = 0.01, there were also differences in chronic symptomatic illness severity index (t = 2.31, df = 200, p = 0.02), BDI scores (t = 2.35, df = 200, p = 0.02), and history of alcohol abuse/dependence (χ2 = 3.88, df = 1, p < 0.05) between the two groups. Table III. Demographic and Clinical Characteristics by TBI Status No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 Significant differences at set alpha level of p ≤ 0.01 are bolded. adf = 1, p = 0.001. bdf = 1, p = 0.004. cdf = 200, p = 0.02. ddf = 1, p < 0.05. Table III. Demographic and Clinical Characteristics by TBI Status No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 No TBI TBI t or χ2 N 105 97 Age in years: M (SD) 53.8 (8.1) 53.4 (7.5) 0.40 Females: N (%) 20 (19%) 16 (17%) 0.22 Education in years: M (SD) 15.7 (2.3) 15.5 (2.3) 0.72 Predicted Khamiyah exposure: N (%) 46 (44%) 42 (43%) 0.01 Kansas GWI cases: N (%) 37 (35%) 41 (42%) 1.05 Kansas GWI exclusionary condition(s): N (%) 28 (27%) 32 (33%) 0.97 CDC CMI cases: N (%) 68 (65%) 83 (86%) 11.56a  Mild-moderate CMI cases: N (%) 61 (58%) 75 (77%) 8.47b  Severe CMI cases: N (%) 7 (7%) 8 (8%) 0.83 Symptomatic illness severity index score: M (SD) 16.8 (16.0) 22.2 (17.0) 2.31c Current PTSD diagnosis: N (%) 12 (44%) 16 (17%) 1.08 CAPS: M (SD) 17.6 (20.6) 23.1 (22.2) 1.58 Current MDD diagnosis: N (%) 9 (9%) 10 (10%) 0.18 BDI: M (SD) 6.8 (8.1) 9.5 (8.2) 2.35c History of alcohol abuse/dependence: N (%) 19 (18%) 29 (30%) 3.88d History of substance abuse/dependence: N (%) 8 (8%) 8 (8%) 0.03 Significant differences at set alpha level of p ≤ 0.01 are bolded. adf = 1, p = 0.001. bdf = 1, p = 0.004. cdf = 200, p = 0.02. ddf = 1, p < 0.05. Relationship Between History of TBI and CMI Case Status by Symptom Severity As noted earlier, CDC CMI can be further categorized as “severe” if the defining symptoms are rated as severe or “mild-moderate” for milder complaints.11 There was a higher rate of mild-moderate CMI (77% vs. 58%, χ2 = 8.47, df = 1, p = 0.004), but not severe CMI (8% vs. 7% χ2 = 0.18, df = 1, p = 0.67) among veterans with a history of TBI compared with veterans without history of TBI (see Table III). Relationship Between Kansas GWI and CMI Case Status in Veterans Without Predicted Sarin/Cyclosarin Exposure Table IV summarizes the percentages of Kansas GWI and CDC CMI cases dichotomized by TBI history in the entire study sample and as a function of predicted sarin/cyclosarin exposure status. In all groups, there was a higher rate of CDC CMI among veterans with histories of TBI, although this difference was not significant at the set alpha level of p = 0.01 level in the smaller (n = 88) sarin-exposed group. There were also trends (p ≤ 0.04) of higher rates of mild-moderate CDC CMI among veterans with a history of TBI in compared veterans without TBI. In contrast, there was no difference in the rates of Kansas GWI or severe CMI as a function of history of TBI. Table IV. Relationship Between History of TBI, Kansas GWI, and CMI Case Status in the Entire Study Sample and as a Function of Predicted Sarin Exposure Status Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Significant differences at set alpha level of p ≤ 0.01 are bolded. aDifferent from TBI−: χ2 = 11.56, df = 1, p = 0.001. bDifferent from TBI−: χ2 = 8.47, df = 1, p = 0.004. cDifferent from TBI−: χ2 = 6.88, df = 1, p = 0.009. dDifferent from TBI−-: χ2 = 4.18, df = 1, p = 0.04. eDifferent from TBI−: χ2 = 4.95, df = 1, p = 0.03. fDifferent from TBI−: χ2 = 4.56, df = 1, p = 0.03. Table IV. Relationship Between History of TBI, Kansas GWI, and CMI Case Status in the Entire Study Sample and as a Function of Predicted Sarin Exposure Status Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Entire Sample No Sarin Sarin Exposed TBI− TBI+ TBI− TBI+ TBI− TBI+ % Kansas GWI 35 42 31 42 41 43 % CDC CMI 65 86a 59 82c 72 91e % mild-moderate CMI 58 77b 54 73d 63 83f % severe CMI 7 8 5 9 9 7 Significant differences at set alpha level of p ≤ 0.01 are bolded. aDifferent from TBI−: χ2 = 11.56, df = 1, p = 0.001. bDifferent from TBI−: χ2 = 8.47, df = 1, p = 0.004. cDifferent from TBI−: χ2 = 6.88, df = 1, p = 0.009. dDifferent from TBI−-: χ2 = 4.18, df = 1, p = 0.04. eDifferent from TBI−: χ2 = 4.95, df = 1, p = 0.03. fDifferent from TBI−: χ2 = 4.56, df = 1, p = 0.03. Relationship Between Health Outcome Measures and TBI Severity, Number of TBI, and TBI Chronicity Table V summarizes the relationship between various health outcomes and TBI severity, number of TBIs, and TBI chronicity relative to the GW. Because only two veterans in the sample had a history of moderate TBI, their data were not included in the statistical analysis of the relationship between TBI severity and rates of Kansas GWI and CDC CMI. However, their data are shown in Table V, along with that of the possible and mild TBI cases. Table V. Relationship Between Health Outcome Measures TBI Severity, Number of TBI, and TBI Chronicity TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) Significant differences at set alpha level of p < 0.01 are bolded. Excluded from statistical analyses because there were only two veterans with moderate TBI. bDifferent from >1 TBI: χ2= 5.05, df = 1, p = 0.03. cDifferent from pre-GW, post-GW: χ2= 12.75, df = 3, p = 0.005. dDifferent from pre-GW, post-GW: χ2= 12.86, df = 3, p = 0.005. eMain effect of TBI chronicity (F3,96 = 3.16, p = 0.03), Tukey’s post hoc test revealed a difference between pre- and GW-related TBI (p < 0.05). Table V. Relationship Between Health Outcome Measures TBI Severity, Number of TBI, and TBI Chronicity TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) TBI severity No. TBI TBI Chronicity Relative to GW Possible Mild Moderatea Single >1 Pre- GW- Post- Pre- & Post- % Kansas GWI 41 44 50 45 40 41 57 49 62 % CDC CMI 88 85 50 92 81 87 100 88 100 % mild-moderate CMI 77 78 50 77 79 83 57 82 100 % severe CMI 10 7 0 15b 2 4 43c 6 0 % current PTSD 14 20 0 21 13 12 43 24 23 % MDD 12 9 0 13 8 10 43d 9 23 Symptomatic Illness Severity Index 23.3 (17.6) 21.6 (16.5) 7.5 (10.6) 24.7 (18.5) 20.3 (15.2) 21.1 (15.3) 36.3 (17.8)e 23.2 (18.0) 28.7 (13.7) BDI 10.0 (8.5) 9.3 (8.1) 3.0 (4.2) 10.3 (8.6) 9.1 (7.9) 9.4 (7.7) 14.7 (8.1) 10.0 (8.6) 11.9 (6.4) Significant differences at set alpha level of p < 0.01 are bolded. Excluded from statistical analyses because there were only two veterans with moderate TBI. bDifferent from >1 TBI: χ2= 5.05, df = 1, p = 0.03. cDifferent from pre-GW, post-GW: χ2= 12.75, df = 3, p = 0.005. dDifferent from pre-GW, post-GW: χ2= 12.86, df = 3, p = 0.005. eMain effect of TBI chronicity (F3,96 = 3.16, p = 0.03), Tukey’s post hoc test revealed a difference between pre- and GW-related TBI (p < 0.05). TBI severity had no significant effect on rates of Kansas GWI (χ2 = 0.07, df = 1, p = 0.79), CDC CMI (χ2 = 0.18, df = 1, p = 0.67), mild-moderate CMI (χ2 = 0.01, df = 1, p = 0.93), severe CMI (χ2 = 0.42, df = 1, p = 0.52), current diagnoses of PTSD (χ2 = 0.47, df = 1, p = 0.79), current diagnosis of MDD (χ2 = 0.32, df = 1, p = 0.57), chronic symptomatic illness severity index (t = 0.47, df = 93, p = 0.64), or BDI scores (t = 0.41, df = 93, p = 0.68). Number of TBIs also did not have a significant effect on the rates of Kansas GWI (χ2 = 0.25, df = 1, p = 0.62), CDC CMI (χ2 = 2.11, df = 1, p = 0.15), mild-moderate CMI (χ2 = 0.09, df = 1, p = 0.76), current PTSD (χ2 = 1.31, df = 1, p = 0.25), current MDD (χ2 = 0.50, df = 1, p = 0.48), chronic symptomatic illness severity index (t = 1.25, df = 93, p = 0.22), or BDI scores (t = 0.69, df = 93, p = 0.49). There were more severe CMI cases among veterans with single TBI compared with those with >1 TBIs (χ2 = 5.05, df = 1, p = 0.03); however, this was not significant at the set alpha level of p< 0.01. There was no relationship between TBI chronicity and rates of Kansas GWI (χ2 = 3.60, df = 3, p = 0.31), CDC CMI (χ2 = 4.31, df = 3, p = 0.23), mild-moderate CMI (χ2 = 6.45, df = 3, p = 0.09), or BDI scores (F3,93 = 1.97, p = 0.12). However, veterans with GW-related TBIs had higher rates of severe CMI (χ2 = 12.75, df = 3, p = 0.005) and MDD (χ2 = 12.86, df = 3, p = 0.005) compared with veterans who sustained TBIs before or after the GW (see Table V). Although not significant at the set alpha level of p< 0.01, there was an effect of TBI chronicity on symptomatic severity index (F3,96 = 3.16, p = 0.03). DISCUSSION Although TBI was not common during the GW, some GW veterans have a history of TBI. Yee et al9 previously reported that 12.2% of the GW veterans from the Devens Cohort Study self-reported a history of TBI. Nearly half (47%) of the GW veterans in this sample of 202 participants, originally recruited for a neuroimaging study on the effects of predicted exposure to sarin/cyclosarin on brain function and brain structure, had a history of TBI. One possible explanation for the difference in this and the Yee et al’s study is that the sample of GW veterans in this study, some of whom were recruited for their predicted Khamisiyah exposure, had higher risk factors for TBI than the GW veterans from the Ft. Devens Cohort. However, it may also be possible that the difference in rates of TBI is, at least in part, related to the different methods used to ascertain histories of TBI. Yee and colleagues used retrospective self-reports, which may have missed some GW veterans who were unaware that they had a TBI. In contrast, the present study used the OSU TBI-ID method,10 which was designed to elicit recall of all injuries receiving medical attention, or that should have, using previously validated methods of injury recall21,22 to optimize personal recall of injuries experienced. The finding that nearly half of the current sample of GW veterans had histories of TBI is in line with reports that the true incidence of TBI is likely far greater than previously recognized23–25 and that military personnel tend to have higher rates of TBI than civilian populations.26,27 The finding that only 7% of the TBIs were associated with injuries that occurred during the GW is consistent with notion that TBIs were uncommon during the GW. In fact, most of the TBIs in this sample were associated with injuries that occurred prior to the GW; 34% of the TBIs were associated with injuries that occurred after the GW. The second aim of this study was to investigate the relationship between TBI and CMI in GW veterans. Compared with veterans without TBI, GW veterans with a history of TBI had higher rates of CDC CMI and greater chronic symptomatic illness severity indices (i.e., more severe symptoms). This is in agreement with Yee et al’s finding that self-reported TBI was related to increased rates of health symptoms and CMI in the Ft. Devens cohort.9 However, Yee et al only classify chronic symptomatic illness according to the CDC CMI case definition. Because the individual symptoms of GWI/CMI can occur in the general population and the mild form of CMI has resulted high prevalence rates in even control populations,17 CDC CMI can be overly inclusive if it is not specified by symptom severity.11 Thus, the current study sought to build upon the findings of Yee et al by examining the relationship between TBI and chronic symptomatic illness according to the Kansas GWI case definition as well as severe and moderate-mild cases of CMI. The results indicate that there were no differences in the rates of Kansas GWI or severe CDC CMI by TBI status; however, there were significantly more CDC CMI cases and mild-moderate CMI cases among veterans with a history of TBI compared with veterans without a history of TBI. Research suggests that a significant minority of individuals with mild TBI report neurobehavioral symptoms years post their TBI injury.28–31 Because these neurobehavioral symptoms (i.e., headaches, balance problems, dizziness, fatigue, depression, anxiety, irritability, and memory and attention difficulties) overlap with some of the chronic symptoms experienced by GW veterans with GWI/CMI, a less restrictive definition of chronic symptomatic illness in GW veterans (e.g., CDC CMI or mild-moderate CMI) will capture more veterans with histories of TBI as “cases” than a more restrictive case definition. Furthermore, there was a similar pattern of results (i.e., more CDC CMI and mild-moderate CMI cases among TBI+ veterans but not more Kansas GWI or severe CMI cases among TBI+ veterans) in the subset of veterans with and without predicted exposure to sarin/cyclosarin. Thus, it is unlikely that predicted exposure to low levels of sarin/cyclosarin confounded these findings. Consistent with reports that patients with TBI are at increased risk for developing depressive symptoms,32 veterans with histories of TBI had higher symptomatic illness severity indices (i.e., more severe symptoms) and higher depressive symptoms than veterans without TBI, although not significant at the set alpha level of p< 0.01. This finding may also explain, at least partially, why self-reported TBI was related to poorer health-related quality of life in GW veterans from the Fort Devens GW veterans.9 Somewhat unexpectedly, there was no relationship between TBI severity (i.e., possible versus mild TBI) and the different health outcome measures examined (i.e., Kansas GWI cases, CDC CMI cases, current diagnoses of PTSD and MDD, symptomatic illness severity and BDI scores). However, this may relate to the limited range of TBI severity in the present sample (e.g., mostly of possible and mild TBI cases with only two moderate TBI cases). Because moderate-severe TBI was exclusionary for the parent imaging study, the present sample was not ideally suited for examining the relationship between TBI severity and health outcomes. Investigation of the effects of TBI chronicity relative to the GW (i.e., pre-GW, GW-related, post-GW, pre- and post-GW) revealed no relationship between pre-GW TBIs and the different health outcomes. Somewhat surprisingly, this suggests that having sustained one or more TBIs before the GW did not influence the veterans’ reactions to exposures/experiences from the GW (i.e., increased their rate of GWI/CMI). However, there was an effect of TBI chronicity on rates of severe CMI and current MDD: more veterans with GW-related TBIs had severe CMI and current MDD compared with veterans whose TBIs were unrelated to the GW. This finding should be considered with the caveat that there were only seven veterans in this category. Nevertheless, it is interesting that this mirrors the high rates of depression seen in OEF/OIF Veterans with mild TBI.33–37 Future, more adequately powered studies will be needed to determine if war-related TBIs are, in fact, associated with poorer functional outcomes in GW veterans. Study Limitations Some study limitations should be noted: First, the study was not originally designed to investigate the relationship between TBI and chronic symptomatic illness. Therefore, the sample lacked a broad range of TBI severity (e.g., moderate-severe TBI was an exclusionary condition for the parent imaging study and only two veterans in the sample had a history of moderate TBI). Consequently, these findings may not reflect the true rate or severity of TBI among GW veterans and require replication in a larger, more general sample of GW veterans. Second, there is evidence that TBI is common among individuals with co-occurring mental health and substance use disorders.38 There is also evidence that TBI may cause decades-lasting vulnerability to psychiatric illness in some individuals39 because axis I and II psychiatric disorders are both common among individuals with TBI.40 Because a lifetime history of psychotic or bipolar disorders and/or drug abuse or dependence in the past 12 mo was also exclusionary for the parent imaging study, this may have biased the current findings. Third, nearly half of the sample had predicted sarin/cyclosarin exposure, which may also have introduced a potential confound. However, there was no difference in the percentage of veterans with and without predicted exposure to sarin/cyclosain in the two TBI groups (44 % vs. 43%) and no difference in the percentage of Kansas GWI and CDC CMI cases in veterans with and without history of TBI with and without predicted sarin/cyclosarin exposure. Fourth, this sample of 202 GW veterans, some of whom had predicted Khamisiyah exposure, all of whom had no contraindications for MRI and the time and means to travel to the San Francisco VA to participate in this research study, may not be representative of the larger GW veteran population. Therefore, it is possible that the results of this study do not generalize to all GW veterans. Finally, the positive TBI screens as determined by the OSU TBI-ID were not followed-up with comprehensive TBI evaluations. CONCLUSIONS Even though TBIs were not common during the GW, many GW veterans have a history of TBI. Most veterans in this sample sustained TBIs in injuries that occurred prior to the GW; however, history of pre-GW TBI did not appear to influence the veterans’ response to exposures/experiences from the GW. That is, veterans with pre-GW TBI were not more likely to have chronic symptomatic illness, PTSD, or MDD. History of TBI was only associated with increased rates of chronic symptomatic illness when chronic symptomatic illness is defined broadly (i.e., CDC CMI or mild-moderate CMI). This is likely because the two conditions (GWI/CMI and TBI) share some overlapping symptoms. History of TBI was not associated with chronic symptomatic illness in GW veterans when it defined by more stringent case definitions (i.e., Kansas GWI or severe-CMI). Therefore, future studies that use broad, inclusive definitions to categorize chronic symptomatic illness in GW veterans should screen for history of TBI. There was also suggestive evidence that GW-related TBI may be associated with poorer functional outcomes in GW veterans. However, because there were only seven veterans with GW-related TBIs in the present sample, future, better powered studies with randomly and systematically select participants from the larger population of GW veterans will need to confirm this finding. Conflict of Interest This material is the result of work supported with resources and the use of facilities at the San Francisco Veterans Affairs Medical Center and was supported by a VA Merit Award Grant (I01 CX0007080) awarded to Dr. Linda Chao. The author reports no declarations of interest. Funding VA grant No. CX000798 entitled “Longitudinal Assessment of Gulf War Veterans with Suspected Sarin Exposure” References 1 Research Advisory Committee on Gulf War Veterans’ Illness (RAC-GWVI) : Gulf War Illness and the Health of Gulf War Veterans: Research Update and Recommendations, 2009-2013 . Boston , U.S. Government Printing Office , 2014 . 2 Fukuda K , Nisenbaum R , Stewart G , et al. : Chronic multisymptom illness affecting Air Force veterans of the Gulf War . JAMA 1998 ; 280 ( 11 ): 981 – 8 . Google Scholar CrossRef Search ADS PubMed 3 Goss Gilroy Inc : Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf . 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Brain Inj 2011 ; 25 ( 11 ): 1029 – 34 . Google Scholar CrossRef Search ADS PubMed Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Journal

Military MedicineOxford University Press

Published: May 18, 2018

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