Sex differences in suicidal behaviors and aggression in US Veterans.

Female Veterans are the fastest growing demographic group in the Department of Veterans Affairs. Moreover, suicide rates in female Veterans are increasing, making suicide in female Veterans a topic of vital clinical and research significance. The current study examined the association between suicide, aggression, and mood symptoms by sex. Participants consisted of 264 Veterans (female=54, male=210) ages 18-55. Veterans completed well-validated measures of suicidal behaviors, aggression, anxiety, and depression. Male Veterans reported higher physical aggression, verbal aggression, anger, hostility, and total aggression compared to female Veterans. In male Veterans, lifetime suicidal behavior including ideation and attempts was correlated with total aggression and subscales of physical aggression, verbal aggression, anger, and hostility. However, in female Veterans lifetime suicidal behavior was significantly associated with hostility and anger. There were no between-group differences in measures of suicidal behaviors, anxious or depressive symptoms. These results suggest important differences in the association between aggression and suicidal behavior by sex. These data have significant clinical implications, as males with aggressive traits and females who endorse hostility and anger may be more likely to engage in suicidal behaviors.

Cingulate white matter volume and associated cognitive and behavioral impulsivity in Veterans with a history of suicide behavior.

BACKGROUND: Suicide is one of the leading causes of death for military personnel and Veterans. Neuroimaging studies have revealed abnormalities in white matter tracts and brain connectivity in suicide behavior (SB); however, reports of alterations in white matter volume and its association with related behaviors are limited. The current study examined the relationship between cingulate white matter volume (WMV), impulsivity, and SB in Veterans. METHODS: Fifty-two Veterans, ages 18 to 65, underwent magnetic resonance imaging on a 3T Siemens Verio scanner. Morphometric analysis of brain images was performed to evaluate differences in WMV in cingulate regions of interest. Participants completed the Columbia Suicide Severity Rating Scale to assess lifetime suicide behavior and the Barratt Impulsivity Scale (BIS) and the Continuous Performance Test (CPT) to assess impulsivity. RESULTS: Twenty-nine Veterans had a history of suicidal ideation (SI) and 23 had a history of suicide attempts (SA). Controlling for age, sex, handedness and total white matter volume, reduced WMV was observed in the left rostral anterior cingulate cortex (rACC) in Veterans with SA relative to Veterans with SI, p = .008. Additionally, non-planning on the BIS was negatively correlated with left rACC WMV for Veterans with a history of SA, p = .04. Other subregions of the ACC WMV were negatively correlated with planning and attention impulsivity (BIS) and omission and commission errors (CPT) for attempters. CONCLUSIONS: Reduction in rACC WMV in Veterans with SA was negatively correlated with nonplanning measures. These findings are consistent with ACC involvement in inhibitory processes and build on evidence that SB is associated with neurobiological abnormalities and suggest that white matter changes may be related to actual attempts.

An exploratory proton MRS examination of gamma-aminobutyric acid, glutamate, and glutamine and their relationship to affective aspects of chronic pain.

Veterans experience chronic pain more frequently than civilians. Identification of neurobiological mechanisms underlying the pathophysiology of chronic pain in a veteran population may aid in the development of novel treatment targets. In this pilot proof-of-concept study, veterans with chronic pain (N = 61) and no chronic pain (N = 19) completed clinical interviews, self-report questionnaires inquiring about pain history, interference of pain with daily life, and pain catastrophizing, as well as measures of depressive and anxious symptoms. Veterans also underwent single-voxel proton (1H) magnetic resonance spectroscopy (MRS) at 3 T in the anterior cingulate cortex (ACC) using a two-dimensional (2D) J-resolved point spectroscopy sequence. We found no group difference in neurometabolites between veterans with and without chronic pain; however, pain intensity, negative thinking about pain, and description of pain in affective terms were associated with lower GABA/Cre in the ACC. In addition, the Glu/GABA ratio in the ACC was positively associated with anxiety and depressive symptoms in veterans with chronic pain. Reductions in GABA in the ACC may contribute to increased pain intensity and greater pain catastrophizing in veterans with chronic pain. Furthermore, a disturbance in the excitatory-inhibitory balance may contribute to the anxious and depressive symptoms related to chronic pain. Given the pilot nature of the study, these findings must be considered preliminary.

Functional connectivity of the anterior cingulate cortex in Veterans with mild traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is one of the most prevalent injuries in the military with mild traumatic brain injury (mTBI) accounting for approximately 70-80 % of all TBI. TBI has been associated with diffuse and focal brain changes to structures and networks underlying cognitive-emotional processing. Although the anterior cingulate cortex (ACC) plays a critical role in emotion regulation and executive function and is susceptible to mTBI, studies focusing on ACC resting state functional connectivity (rs-fc) in Veterans are limited. METHODS: Veterans with mTBI (n = 49) and with no history of TBI (n = 25), ages 20-54 completed clinical assessments and an 8-minute resting state functional magnetic resonance imaging (rs-fMRI) on a 3 T Siemens scanner. Imaging results were analyzed with left and right ACC as seed regions using SPM8. Regression analyses were performed with time since injury. RESULTS: Seed-based analysis showed increased connectivity of the left and right ACC with brain regions including middle and posterior cingulate regions, preceneus, and occipital regions in the mTBI compared to the non-TBI group. CONCLUSIONS: The rs-fMRI results indicate hyperconnectivity in Veterans with mTBI. These results are consistent with previous studies of recently concussed athletes showing ACC hyperconnectivity. Enhanced top-down control of attention networks necessary to compensate for the microstructural damage following mTBI may explain ACC hyperconnectivity post-mTBI.

Neurobiological evidence of sexual dimorphism in limbic circuitry of US Veterans.

BACKGROUND: Female Veterans are an increasing patient population in the Department of Veterans Affairs and may have distinct clinical and neurobiological features compared to males. METHODS: Nineteen female and 19 male Veterans who met diagnostic criteria for depression/posttraumatic stress disorder (MDD/PTSD) completed diagnostic interviews, symptom measures, and resting-state neuroimaging. Participants completed clinical measures of mood and aggression in addition to magnetic resonance imaging on a 3.0 Tesla Siemens scanner. RESULTS: Females showed increased functional connectivity between the left and right basolateral amygdala (BLA) and the left and right cerebellar and occipital lobes. Sex differences also were evident in the relationship between affective and clinical symptoms with BLA connectivity. Females showed a correlation between revenge planning and decreased connectivity between the left BLA and left occipital lobe and also a correlation between aggression and decreased connectivity between the right BLA and right mid cingulate, right and left medial frontal lobe, and right frontal lobe. Males evidenced a relationship between increased depressive symptoms and increased connectivity between the left BLA and right and left occipital lobe, left calcarine, and other areas associated with visual memory and processing, and interpretation of sensory information. Additionally, males reported higher levels of physical aggression and revenge planning compared to females. LIMITATIONS: This study included neuroimaging and self-report clinical measures. Further studies will benefit from multimodal measures, including behavioral measures of aggression. CONCLUSIONS: Results suggest that male Veterans report more aggression than females and symptoms of aggression and mood are differentially related to BLA connectivity by sex.

Increased myoinositol in the anterior cingulate cortex of veterans with a history of traumatic brain injury: a proton magnetic resonance spectroscopy study.

Traumatic brain injury (TBI) is one of the most prevalent forms of morbidity in veterans and service members, with mild traumatic brain injury (mTBI) being the most common. The diagnosis of mTBI in veterans is difficult because of mixed etiologies and high comorbidity with other disorders such as posttraumatic stress disorder (PTSD), depression, and substance use. Advanced neuroimaging techniques such as magnetic resonance spectroscopy (MRS) may be useful in identifying neurochemical alterations in TBI, which may aid the development of new targets for therapeutic intervention. Veterans with (n = 53) and without a history of TBI (n = 26) underwent single-voxel proton magnetic resonance spectroscopy (1H MRS) at 3 Tesla in the anterior cingulate cortex (ACC) using a two-dimensional J-resolved point spectroscopy sequence in addition to completing a clinical battery. TBI diagnosis was made using the research version of the Ohio State University TBI Identification Method. An increased myoinositol (mI)/H2O ratio was observed in the ACC of the TBI group compared with the non-TBI group during the chronic stage of TBI (average of 139.7 mo after injury), which may be reflective of astrogliosis. Several metabolites in the ACC demonstrated significant associations with TBI variables, including number of TBI with loss of consciousness (LOC) and time since most severe TBI, suggesting that changes in some metabolites may be potential diagnostic and prognostic indicators.NEW & NOTEWORTHY In this study of veterans, we used a state-of-the-art neuroimaging tool to probe the neurometabolic profile of the anterior cingulate cortex in veterans with traumatic brain injury (TBI). We report significantly elevated myoinositol levels in veterans with TBI compared with those without TBI.

Volume and shape analysis of the Hippocampus and amygdala in veterans with traumatic brain injury and posttraumatic stress disorder.

There is a need to improve the understanding of the neurobiological underpinnings of traumatic brain injury (TBI). Individuals with TBI experience comorbidities such as posttraumatic stress disorder (PTSD) with considerable symptom overlap including depression and hyperarousal, confounding the ability to identify specific TBI-related brain changes. The aims of the current study were to investigate hippocampal and amygdalar volumes in Veterans with TBI with (TBI + PTSD, n = 32) and without (TBI - PTSD, n = 25) PTSD. Shape analysis was employed to reveal any relationship between the hippocampus and depressive symptoms in TBI subgroups. 32 TBI + PTSD, 25 TBI - PTSD, and 25 age-matched healthy male Veterans underwent an MRI scan on a 3 Tesla scanner and a clinical evaluation. The TBI + PTSD and the TBI + hyperarousal (met criteria for the hyperarousal symptom cluster, regardless of PTSD diagnosis) subgroup had trend-level larger left amygdalar volume than the TBI - PTSD subgroup and the TBI - hyperarousal subgroup, respectively. However, there was no significant difference between the TBI group as a whole and healthy controls (HC). There was a significant negative correlation between the Hamilton Rating Scale for Depression score (HAM-D) and left hippocampal volume and a positive correlation between the HAM-D score and left amygdalar volume in the TBI group. Left hippocampal volume was correlated with the HAM-D score only in the TBI + PTSD and not in TBI - PTSD subgroup. Shape analyses revealed a significant correlation between the HAM-D score and the CA1 and subiculum regions of the left hippocampus. Our results suggest that the amygdala may be a neuroanatomical correlate in mediating PTSD-like symptoms in Veterans with TBI. The results of shape analysis suggest that alterations in the CA1 and subiculum subregions of hippocampus may have a role in depression and PTSD.

Reduced gamma-amino butyric acid (GABA) and glutamine in the anterior cingulate cortex (ACC) of veterans exposed to trauma.

BACKGROUND: Trauma-related diagnoses such as posttraumatic stress disorder (PTSD) are prevalent in veterans. The identification of mechanisms related to stress vulnerability and development of PTSD specifically in a veteran population may aid in the prevention of PTSD and identification of novel treatment targets. METHODS: Veterans with PTSD (n = 27), trauma-exposed veterans with no PTSD (TEC, n = 18) and non-trauma-exposed controls (NTEC, n = 28) underwent single-voxel proton (1H) magnetic resonance spectroscopy (MRS) at 3 Tesla in the dorsal anterior cingulate cortex (dACC) using a two-dimensional (2D) J-resolved point spectroscopy sequence in addition to completing a clinical battery. RESULTS: The PTSD and TEC groups demonstrated lower gamma-amino butyric acid (GABA)/H2O (p = 0.02) and glutamine (Gln)/H2O (p = 0.02) in the dACC as compared to the NTEC group. The PTSD group showed a trend towards higher Glu/GABA (p = 0.053) than the NTEC group. Further, GABA/H2O in the dACC correlated negatively with sleep symptoms in the PTSD group (p = 0.03) but not in the TEC and NTEC groups. LIMITATIONS: Cross-sectional study design, concomitant medications, single voxel measurement as opposed to global changes, absence of measure of childhood or severity of trauma and objective sleep measures, female participants not matched for menstrual cycle phase. CONCLUSIONS: Exposure to trauma in veterans may be associated with lower GABA/H2O and Gln/H2O in the dACC, suggesting disruption in the GABA-Gln-glutamate cycle. Further, altered Glu/GABA in the dACC in the PTSD group may indicate an excitatory-inhibitory imbalance. Further, lower GABA/H2O in the ACC was associated with poor sleep in the PTSD group. Treatments that restore GABAergic balance may be particularly effective in reducing sleep symptoms in PTSD.

Increased efficiency of brain connectivity networks in veterans with suicide attempts.

Background: Suicide is a public health concern for United States veterans and civilians. Prior research has shown neurobiological factors in suicide. However, studies of neuroimaging correlates of suicide risk have been limited. This study applied complex weighted network analyses to characterize the neural connectivity in white matter in veterans with suicide behavior. Methods: Twenty-eight veterans without suicide behavior (NS), 29 with a history of suicidal ideation only (SI), and 23 with prior suicide attempt (SA) completed diffusion tensor brain imaging, the Columbia Suicide Severity Rating Scale and Barratt Impulsiveness Scale (BIS). Structural connectivity networks among 82 parcellated brain regions were produced using whole-brain tractography. Global and nodal metrics of network topology have been calculated. Results: SA had shorter characteristic path length and greater global efficiency and mean weighted degree of global network metrics (p < 0.024). SA had more hub nodes than NS and SI. The left posterior cingulate cortex (PCC) showed significantly greater weighted degree in SA relative to others (p < 0.0003). Nonplanning subscale of BIS correlated with the weighted degrees of the left PCC within SA. In rich club connectivity, SA had higher local connections than others (p = 0.001). Conclusion: Veterans with prior suicide attempt had altered connectivity networks characteristics in the white matter. These findings may be distinctive neurobiological markers for individuals with suicide attempt. Strong connectivity in the left PCC may be implicated in impulsivity in veterans with suicide attempt.

Altered Cortical GABA in Female Veterans with Suicidal Behavior: Sex Differences and Clinical Correlates.

Background: Suicide is a public health concern in the civilian and veteran populations. Stressful life events are precipitating factors for suicide. The neurochemical underpinnings of the association between stress/trauma and suicide risk are unclear, especially in regards to sex differences. We hypothesized that gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter may be a neurochemical candidate that is critical in the association between stress and suicide risk in veterans. Methods: Proton magnetic resonance spectroscopy (1H MRS) at 3.0 Tesla was used to measure in vivo neurochemistry in the anterior cingulate cortex (ACC; predominantly the dorsal ACC) of 81 veterans (16 females), including 57 (11 females) who endorsed past suicidal ideation (SI) and/or suicide attempt (SA) and 24 (5 females) with no history of SI and/or SA. Suicidal behavior (SB) was defined as the presence of SI and/or SA. Results: We observed no significant differences in GABA/ Creatine+phosphocreatine (Cr+PCr) between veterans with SB (SB+) and without SB (SB-). However, the female SB+ group showed significantly reduced GABA/Cr+PCr vs. the female SB- group. We observed a trend-level significant negative correlation between GABA/Cr+PCr and the defensive avoidance (DA) subscale on the Trauma Symptom Inventory (TSI) in the SB+ group. In contrast, the SB- group exhibited a positive relationship between the two variables. Furthermore, we found significant negative correlations between GABA/Cr+PCr and Hamilton Rating Scale for Depression (HAM-D) scores as well as between GABA/Cr+PCr and several subscales of the TSI in female veterans. Conclusions: This study suggests that reduced GABA/Cr+ PCr ratio in the ACC, which may be related to altered inhibitory capacity, may underlie suicide risk in female veterans. Further, the negative association between GABA/Cr+PCr and stress symptomatology and depression scores suggests that MRS studies may shed light on intermediate phenotypes of SB.

Alterations in anterior cingulate cortex myoinositol and aggression in veterans with suicidal behavior: A proton magnetic resonance spectroscopy study.

Studies investigating the neurochemical changes that correspond with suicidal behavior (SB) have not yielded conclusive results. Suicide correlates such as aggression have been used to explore risk factors for SB. Yet the neurobiological basis for the association between aggression and SB is unclear. Aggression and SB are both prevalent in veterans relative to civilian populations. The current study evaluated the relationship between brain chemistry in the anterior (ACC) and the posterior cingulate cortex (POC), as well as the relationship between aggression and SB in a veteran population using proton magnetic resonance spectroscopy (1H-MRS). Single-voxel MRS data at 3 Tesla (T) were acquired from the ACC and POC voxels using a 2-dimensional J-resolved point spectroscopy sequence and quantified using the ProFit algorithm. Participants also completed a structured diagnostic interview and a clinical battery. Our results showed that the myoinositol (mI)/H2O ratio in the ACC and POC was significantly higher in veterans who reported SB when compared to veterans who did not. The two groups did not differ significantly with regard to other metabolites. Second, verbal aggression and SB measures positively correlated with mI/H2O in the ACC. Finally, verbal aggression mediated the relationship between mI/H2O in the ACC and SB.

Suicide Behavior and Chronic Pain: An Exploration of Pain-Related Catastrophic Thinking, Disability, and Descriptions of the Pain Experience.

This study examined differences in suicidal ideation (SI) and suicide attempts (SAs) among veterans with chronic pain. Pain-specific variables, including catastrophic thinking, disability, and sensory, affective, and evaluative pain descriptors, were a focus. Structured diagnostic and clinical interviews were conducted to examine SI/SA and mental health. Veterans completed the Structured Clinical Interview for DSM-IV and the Columbia-Suicide Severity Rating Scale to assess Axis I symptoms and suicidal behavior(s). Self-report questionnaires were used to evaluate the participants' subjective experience of chronic pain, which included the McGill Pain Questionnaire, Pain Catastrophizing Scale, and Pain Disability Index. The findings add to previous literature by suggesting pain-related catastrophic thinking specifically is related to elevated risk for SA, whereas affective and sensory pain are associated with SI. The study results support the need to assess pain from a multifaceted perspective and to examine the different experiences of pain, such as sensory and affective constructs, when discussing suicide risk in veterans.

Visual-Spatial Memory and Recall Test (V-SMART): validity and reliability.

OBJECTIVE: Nonverbal memory decline is a concern associated with aging. Visuospatial memory tests often do not distinguish between learning, recall, or retrieval, yet such distinctions may help clarify the nature of memory difficulties. Further, many visuospatial tests rely on abilities not directly related to memory (e.g. graphomotor skill). The present study examined the feasibility and initial psychometric evidence of the Visual-Spatial Memory and Recall Test (V-SMART). METHOD: Ninety-nine adults (71% women) were recruited from two sources: undergraduate students (n = 37) and healthy older adults (n = 62). Volunteers completed a brief battery of cognitive tests. RESULTS: Internal consistency and interrater reliability were strong. Principal Components Analysis supported the hypothesized learning and recall structure, and correlations with other memory tests supported external validity of the V-SMART as a visuospatial learning measure. Correlations with recall scores were less compelling yet likely reflected the intact recall among this generally healthy sample. CONCLUSIONS: These preliminary findings support the V-SMART as a visuospatial memory test. Evidence for validity was acceptable for learning indices; further examination of recall measures is needed.

Orbitofrontal cortical thinning and aggression in mild traumatic brain injury patients.

INTRODUCTION: Although mild traumatic brain injury (mTBI) comprises 80% of all TBI, the morphological examination of the orbitofrontal cortex (OFC) in relation to clinical symptoms such as aggression, anxiety and depression in a strictly mTBI sample has never before been performed. OBJECTIVES: The primary objective of the study was to determine if mTBI patients would show morphological differences in the OFC and if the morphology of this region would relate to clinical symptoms. METHODS: Using structural images acquired in a 3T MRI machine, the cortical thickness and cortical volume (corrected for total brain volume) of the OFC was collected for healthy control (N = 27) subjects and chronic mTBI (N = 55) patients at least one year post injury. Also, during clinical interviews, measures quantifying the severity of clinical symptoms, including aggression, anxiety, and depression, were collected. RESULTS: MTBI subjects displayed increased aggression, anxiety, and depression, and anxiety and depression measures showed a relationship with the number of mTBI in which the subject lost consciousness. The cortical thickness of the right lateral OFC displayed evidence of thinning in the mTBI group; however, after correction for multiple comparisons, this difference was no longer significant. Clinical measures were not significantly related with OFC morphometry. CONCLUSION: This study found increased aggression, anxiety, and depression, in the mTBI group as well as evidence of cortical thinning in the right lateral OFC. The association between clinical symptoms and the number of mTBI with loss of consciousness suggests the number and severity of mTBI may influence clinical symptoms long after injury. Future studies examining other brain regions involved in the production and regulation of affective processes and inclusion of subjects with well-characterized mood disorders could further elucidate the relationship between mTBI, brain morphology, and clinical symptoms.

DSM-5 posttraumatic stress disorder symptoms associated with suicide behaviors in veterans.

A connection between suicidality and posttraumatic stress disorder (PTSD) has been consistently demonstrated; however, the underlying relationship between suicidality and PTSD remains unclear. The aim of this study was to examine patterns of DSM-5 PTSD symptom endorsement that differentiated veteran participants with and without a history of suicide behaviors. We enrolled 95 veterans, 32 of whom reported no suicide ideation (SI) or suicide attempts (SA). The 63 remaining participants reported a history of SI, with 28 of the 63 also reporting a historical SA. Participants completed a standardized diagnostic interview (Structured Clinical Interview for DSM-IV-TR; First, Spitzer, Gibbon, & Williams, 2002), structured interview of suicidal behaviors (Columbia-Suicide Severity Rating Scale; Posner et al., 2011), and selected clinical measures. Veterans who reported SI and/or SA were more likely to meet criteria for PTSD on DSM-5 than were veterans who reported neither SI nor SA. Participants who reported SA were more likely to meet criteria for clusters C and D. Finally, at the symptom level, those who reported SI were more likely to report experiencing feelings of alienation. Those who reported a SA were more likely to report avoidance of thoughts and feelings, inability to recall an important aspect of their trauma, persistent negative beliefs, diminished interest, and feelings of alienation. These findings suggest that targeting specific symptoms of PTSD may aid in treatment of suicidal thoughts and behaviors associated with PTSD.