Creatine concentration in the anterior cingulate cortex is associated with greater stress recovery from traumatic events: Preliminary evidence from a US Veteran sample.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric condition characterized by a prolonged stress response to potentially life-threatening events long after the event has passed. Understanding factors related to recovery from traumatic life events may inform novel targets for intervention. There is emerging preclinical evidence that creatine (Cr), a molecule critical to brain bioenergetics, may be a neurobiological marker of stress reactivity and recovery. METHOD: 25 US Veterans (8 female) completed the Life Events Checklist for DSM-5, which assessed different types of traumatic events. Veterans were also asked to rate the subjective stress of each traumatic event on a 1-10 scale currently (Current Stress) and at the time the event occurred (Past Stress). Stress recovery was quantified as the difference between Current and Past Stress. Current PTSD symptoms were also assessed using the PTSD Checklist for DSM-5. Cr concentrations in the anterior cingulate cortex (ACC) were measured in the anterior cingulate cortex using proton magnetic resonance spectroscopy (1H-MRS). RESULTS: Higher levels of Cr were associated with self-reported stress recovery from participants' most traumatic life event. Cr was not related to number of different types of traumatic life events or current PTSD symptoms. LIMITATIONS: The sample size was relatively small. Stress recovery was measured via retrospective self-report. Future experimental work in humans should clarify the protective role of Cr in recovery from trauma. CONCLUSIONS: ACC concentrations of Cr may be an important neurochemical factor related to stress recovery. Future work should investigate Cr as a possible protective factor against the effects of traumatic stress.

A Literature Review of Mental Health Symptom Outcomes in U.S. Veterans and Servicemembers Following Combat Exposure and Military Sexual Trauma.

Combat exposure (CE) and military sexual trauma (MST) are among the most common types of traumatic experiences faced by veterans and active duty servicemembers and, as such, have both garnered increased research focus over the past decades. However, there has not yet been a critical review of the literature to examine the distinct clinical presentations associated with different trauma types. This is particularly important, as understanding distinct clinical profiles could help researchers and clinicians refine treatment approaches based on trauma type. To address this question, we conducted a search of the available literature in PsycINFO and PubMed prior to October 2022. We identified 43 articles evaluating the distinct and overlapping clinical symptoms of CE and MST. Study findings were conceptually organized by psychiatric condition. In general, there was substantial variability in study methodology including sample size, composition, and operationalizations of CE and MST. Despite this variability, notable patterns emerged across studies. Specifically, MST and CE uniquely predicted posttraumatic stress disorder symptoms, MST was more related to depressive symptoms and suicidality than CE, and CE appeared to be more related to alcohol use and other externalizing behaviors. Gender also played a significant role in the relationship between CE, MST, and clinical variables across studies. This review suggests that individuals with a history of MST and CE likely have distinct clinical presentations and more research into these presentations could better inform assessment and treatment. Important methodological gaps in the literature are also discussed.

The role of the hypothalamic-pituitary-adrenal axis in depression across the female reproductive lifecycle: current knowledge and future directions.

The aim of this narrative review is to consolidate knowledge on the role of the hypothalamic-pituitary-adrenal (HPA) axis in depression pathophysiology at different reproductive stages across the female lifespan. Despite growing evidence about the impact of gonadal hormones on mood disorders, no previous review has examined the interaction between such hormonal changes and the HPA axis within the context of depressive disorders in women. We will focus on HPA axis function in depressive disorders at different reproductive stages including the menstrual cycle (e.g., premenstrual dysphoric disorder [PMDD]), perinatally (e.g., postpartum depression), and in perimenopausal depression. Each of these reproductive stages is characterized by vast physiological changes and presents major neuroendocrine reorganization. The HPA axis is one of the main targets of such functional alterations, and with its key role in stress response, it is an etiological factor in vulnerable windows for depression across the female lifespan. We begin with an overview of the HPA axis and a brief summary of techniques for measuring HPA axis parameters. We then describe the hormonal milieu of each of these key reproductive stages, and integrate information about HPA axis function in depression across these reproductive stages, describing similarities and differences. The role of a history of stress and trauma exposure as a contributor to female depression in the context of HPA axis involvement across the reproductive stages is also presented. This review advances the pursuit of understanding common biological mechanisms across depressive disorders among women. Our overarching goal is to identify unmet needs in characterizing stress-related markers of depression in women in the context of hormonal changes across the lifespan, and to support future research in women's mental health as it pertains to pathophysiology, early diagnosis, and treatment targets.

Mild Traumatic Brain Injury and Behavior and Sleep Among 9- and 10-Year Old Children: Initial Findings From the Adolescent Brain Cognitive Development (ABCD) Study.

There has been concern about the potential sequelae of mild traumatic brain injury (mTBI) in children. This study used data from the Adolescent Brain Cognitive DevelopmentSM (ABCD) study to investigate associations between mTBI and behavior and sleep in school-aged children. Generalized additive mixed models were run to examine the association between TBI and parent-reported Child Behavior Checklist and Sleep Disturbance Scale for Children scores. mTBI with or without loss of consciousness (LOC) in 9- and 10-year old children was associated with 1) higher internalizing, externalizing and total problems and 2) greater sleep disturbance scores on the CBCL. The study also demonstrated a higher incidence of mTBI with and without LOC in boys compared to girls. This study shows a statistically significant but modest association between mTBI and behavioral and sleep changes, suggesting that in a non-clinical, sociodemographically diverse community sample of school-aged children mTBI does not result in clinically significant behavioral or psychological sequelae.

Overweight/Obesity-related microstructural alterations of the fimbria-fornix in the ABCD study: The role of aerobic physical activity.

Childhood overweight/obesity has been associated with negative consequences related to brain function and may involve alterations in white matter pathways important for cognitive and emotional processing. Aerobic physical activity is a promising lifestyle factor that could restore white matter alterations. However, little is known about either regional white matter alterations in children with overweight/obesity or the effects of aerobic physical activity targeting the obesity-related brain alterations in children. Using a large-scale cross-sectional population-based dataset of US children aged 9 to 10 years (n = 8019), this study explored the associations between overweight/obesity and microstructure of limbic white matter tracts, and examined whether aerobic physical activity may reduce the overweight/obesity-related white matter alterations in children. The primary outcome measure was restriction spectrum imaging (RSI)-derived white matter microstructural integrity measures. The number of days in a week that children engaged in aerobic physical activity for at least 60 minutes per day was assessed. We found that females with overweight/obesity had lower measures of integrity of the fimbria-fornix, a major limbic-hippocampal white matter tract, than their lean peers, while this difference was not significant in males. We also found a positive relationship between the number of days of aerobic physical activity completed in a week and integrity measures of the fimbria-fornix in females with overweight/obesity. Our results provide cross-sectional evidence of sex-specific microstructural alteration in the fimbria-fornix in children with overweight/obesity and suggest that aerobic physical activity may play a role in reducing this alteration. Future work should examine the causal direction of the relationship between childhood overweight/obesity and brain alterations and evaluate potential interventions to validate the effects of aerobic physical activity on this relationship.

Boldness moderates cognitive performance under acute threat: Evidence from a task-switching paradigm involving cueing for shock.

Understanding factors that influence behavioral performance in high-pressure contexts is relevant to critical occupations such as first responders, military personnel, and frontline medical workers. A recent study by Yancey et al. (2019) demonstrated an association between boldness, a biobehavioral trait reflecting social dominance and fearlessness, and enhanced task-switching performance during threat of shock relative to a no-shock (safe) condition. This study used a sustained threat manipulation in which cues signaling possible shock were present throughout blocks of multiple task trials. Here, we extended this work by evaluating the relationship between boldness and task-switching performance under acute threat of shock conditions, in which cues signaling possible shock occurred during individual task trials, intermingled with safe trials. Participants (N = 79) completed a task-switching procedure involving acute threat of shock in which unwarned noise probes were presented to elicit blink-startle responses. Boldness was associated with better switching performance under threat versus safe conditions, with high-bold participants who exhibited low startle potentiation during threat showing the best performance. These findings provide additional evidence that dispositional boldness is a meaningful individual difference characteristic related to effective performance in high-pressure situations and have implications for personnel selection and assignment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Measurement of gender and sexuality in the Adolescent Brain Cognitive Development (ABCD) study.

The Adolescent Brain Cognitive DevelopmentSM (ABCD) study is a longitudinal study of adolescent brain development and health that includes over 11,800 youth in the United States. The ABCD study includes broad developmental domains, and gender and sexuality are two of these with noted changes across late childhood and early adolescence. The Gender Identity and Sexual Health (GISH) workgroup recommends measures of gender and sexuality for the ABCD study, prioritizing those that are developmentally sensitive, capture individual differences in the experience of gender and sexuality, and minimize participant burden. This manuscript describes the gender and sexuality measures used in ABCD and provides guidance for researchers using these data. Data showing the utility of these measures and longitudinal trends are presented. Including assessment of gender and sexuality in ABCD allows for characterization of developmental trajectories of gender and sexuality, and the broad scope of ABCD data collection allows examination of identity development in an intersectional manner.

Suicide Ideation and Neurocognition Among 9- and 10-Year Old Children in the Adolescent Brain Cognitive Development (ABCD) Study.

OBJECTIVE: During the past decade, the pediatric suicide rate has nearly tripled. Yet, little is known about suicide behavior (SB) in children. Identification of risk factors associated with SB during childhood may be critical to preventing future attempts. The purpose of this study was to examine the relationship between neurocognitive performance and suicide ideation (SI) in children. METHOD: The present study utilized baseline data from 11,875 participants in the Adolescent Brain Cognitive Development (ABCD) study, a longitudinal study that follows 9- and 10-year-old children through late adolescence to examine factors that influence developmental trajectories. Suicidality was assessed by the Kiddie Schedule for Affective Disorder and Schizophrenia (KSADS) suicide module completed by the parent. Neurocognitive ability was assessed using the NIH Toolbox Cognition measures administered to the youth. RESULTS: Children with a history of SI reported by their parent or concordant parent and youth report of SI demonstrated lower performance on the NIH Toolbox Picture Sequence Memory Test compared to children without SI. The difference in performance on the memory task remained significant when including demographic characteristics, family history of suicide, and internalizing symptoms in the model as covariates. CONCLUSIONS: To our knowledge, this is the first study to identify decreased episodic memory in children with SI. These findings are similar to results from adult and adolescent studies which have reported decreased memory performance among suicide attempters. Deficits in episodic memory may impact a child's ability to problem-solve and generate potential future outcomes, which may increase the risk for SB. Early identification of memory deficits in children may inform suicide prevention and intervention efforts.Highlights6% of parents and children reported a history of active suicide ideation in children.Children with a history of suicide ideation had lower episodic memory performance.Early identification of memory deficits may inform suicide intervention efforts.

The Emotional Word-Emotional Face Stroop task in the ABCD study: Psychometric validation and associations with measures of cognition and psychopathology.

Characterizing the interactions among attention, cognitive control, and emotion during adolescence may provide important insights into why this critical developmental period coincides with a dramatic increase in risk for psychopathology. However, it has proven challenging to develop a single neurobehavioral task that simultaneously engages and differentially measures these diverse domains. In the current study, we describe properties of performance on the Emotional Word-Emotional Face Stroop (EWEFS) task in the Adolescent Brain Cognitive Development (ABCD) Study, a task that allows researchers to concurrently measure processing speed/attentional vigilance (i.e., performance on congruent trials), inhibitory control (i.e., Stroop interference effect), and emotional information processing (i.e., difference in performance on trials with happy as compared to angry distracting faces). We first demonstrate that the task manipulations worked as designed and that Stroop performance is associated with multiple cognitive constructs derived from different measures at a prior time point. We then show that Stroop metrics tapping these three domains are preferentially associated with aspects of externalizing psychopathology and inattention. These results highlight the potential of the EWEFS task to help elucidate the longitudinal dynamics of attention, inhibitory control, and emotion across adolescent development, dynamics which may be altered by level of psychopathology.

Proton magnetic resonance spectroscopy (MRS) in individuals with internet gaming.

Background: Various comorbid psychiatric diagnoses, including attention deficit hyperactivity disorder (ADHD), have been reported in individuals with internet gaming disorder (IGD). Prior research has shown alterations in brain metabolites, including N-acetylaspartate (NAA), and combined glutamate and glutamine in patients with ADHD that were similar to those observed in patients with IGD. We hypothesized that the decreased NAA levels in the IGD group would be associated with a history of ADHD. Methods: Forty adults participated in this study. Participants were classified as having a high risk for IGD if they had a total score higher than 21 on the IGD Scale-short form. Proton magnetic resonance spectroscopy (1H-MRS) and high-resolution structural magnetic resonance imaging (MRI) data were acquired using a 3 Tesla Siemens Prisma scanner system. Results: Levels of NAA within the right prefrontal cortex were lower in the IGD group than those observed in the control group. In a multiple linear regression analysis, internet addiction test scores and history of ADHD were shown to predict increased game play. In addition, history of ADHD predicted lower levels of NAA within the right prefrontal cortex. Conclusion: The preliminary results of current study suggest a mediating effect of ADHD on the severity of internet game play as well as the levels of NAA within the dorsolateral prefrontal cortex (DLPFC). The inclusion of ADHD in IGD research is important and deserving of further consideration.

Demographic and mental health assessments in the adolescent brain and cognitive development study: Updates and age-related trajectories.

The Adolescent Brain Cognitive Development (ABCD) Study of 11,880 youth incorporates a comprehensive range of measures assessing predictors and outcomes related to mental health across childhood and adolescence in participating youth, as well as information about family mental health history. We have previously described the logic and content of the mental health assessment battery at Baseline and 1-year follow-up. Here, we describe changes to that battery and issues and clarifications that have emerged, as well as additions to the mental health battery at the 2-, 3-, 4-, and 5-year follow-ups. We capitalize on the recent release of longitudinal data for caregiver and youth report of mental health data to evaluate trajectories of dimensions of psychopathology as a function of demographic factors. For both caregiver and self-reported mental health symptoms, males showed age-related decreases in internalizing and externalizing symptoms, while females showed an increase in internalizing symptoms with age. Multiple indicators of socioeconomic status (caregiver education, family income, financial adversity, neighborhood poverty) accounted for unique variance in both caregiver and youth-reported externalizing and internalizing symptoms. These data highlight the importance of examining developmental trajectories of mental health as a function of key factors such as sex and socioeconomic environment.

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.

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.

Gender differences in the effect of tobacco use on brain phosphocreatine levels in methamphetamine-dependent subjects.

BACKGROUND: A high prevalence of tobacco smoking has been observed in methamphetamine users, but there have been no in vivo brain neurochemistry studies addressing gender effects of tobacco smoking in methamphetamine users. Methamphetamine addiction is associated with increased risk of depression and anxiety in females. There is increasing evidence that selective analogues of nicotine, a principal active component of tobacco smoking, may ease depression and improve cognitive performance in animals and humans. OBJECTIVES: To investigate the effects of tobacco smoking and gender on brain phosphocreatine (PCr) levels, a marker of brain energy metabolism reported to be reduced in methamphetamine-dependent subjects. METHODS: Thirty female and 27 male methamphetamine-dependent subjects were evaluated with phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) to measure PCr levels within the pregenual anterior cingulate, which has been implicated in methamphetamine neurotoxicity. RESULTS: Analysis of covariance revealed that there were statistically significant slope (PCr versus lifetime amount of tobacco smoking) differences between female and male methamphetamine-dependent subjects (p = 0.03). In females, there was also a statistically significant interaction between lifetime amounts of tobacco smoking and methamphetamine in regard to PCr levels (p = 0.01), which suggests that tobacco smoking may have a more significant positive impact on brain PCr levels in heavy, as opposed to light to moderate, methamphetamine-dependent females. CONCLUSION: These results indicate that tobacco smoking has gender-specific effects in terms of increased anterior cingulate high energy PCr levels in methamphetamine-dependent subjects. Cigarette smoking in methamphetamine-dependent women, particularly those with heavy methamphetamine use, may have a potentially protective effect upon neuronal metabolism.

Decreased frontal lobe phosphocreatine levels in methamphetamine users.

BACKGROUND: Mitochondria-related mechanisms have been suggested to mediate methamphetamine (METH) toxicity. However, changes in brain energetics associated with high-energy phosphate metabolism have not been investigated in METH users. Phosphorus-31 ((31)P) magnetic resonance spectroscopy (MRS) was used to evaluate changes in mitochondrial high energy phosphates, including phosphocreatine (PCr) and ß-nucleoside triphosphate (ß-NTP, primarily ATP in brain) levels. We hypothesized that METH users would have decreased high-energy PCr levels in the frontal gray matter. METHODS: Study participants consisted of 51 METH (age=32.8±6.7) and 23 healthy comparison (age=31.1±7.5) subjects. High-energy phosphate metabolite levels were compared between the groups and potential gender differences were explored. RESULTS: METH users had lower ratios of PCr to total pool of exchangeable phosphate (PCr/TPP) in the frontal lobe as compared to the healthy subjects (p=.001). The lower PCr levels in METH subjects were significantly associated with lifetime amount of METH use (p=.003). A sub-analysis for gender differences revealed that female METH users, who had lower daily amounts (1.1±1.0g) of METH use than males (1.4±1.7g), had significantly lower PCr/TPP ratios than male METH users, controlling for the amount of METH use (p=.02). CONCLUSIONS: The present findings suggest that METH compromises frontal lobe high-energy phosphate metabolism in a dose-responsive manner. Our findings also suggest that the abnormality in frontal lobe high-energy phosphate metabolism might be more prominent in female than in male METH users. This is significant as decreased PCr levels have been associated with depressive symptoms, and poor responses to antidepressant treatment have been reported in those with decreased PCr levels.

Cortico-cerebellar abnormalities in adolescents with heavy marijuana use.

There are currently no studies that have evaluated the motor network, including the cerebellum, in adolescent marijuana (MJ) smokers. The current study aimed to evaluate whether there were activation differences in Brodmann's area 4 (BA4), Brodmann's area 6 (BA6), cingulate (CG) and cerebellum between MJ-using adolescents and healthy controls (HC) on a functional magnetic resonance imaging (fMRI) bilateral finger-tapping task. Twenty-four adolescents (aged 18.2 ± 0.7 years) with heavy MJ use and 24 HC (18.0 ± 1.9) had MRI scans on a 3T Siemens scanner, including a standard bilateral fMRI finger-tapping sequence. Imaging data were analyzed using SPM5 in Matlab. As regions of interest, BA4, BA6, cingulate (CG) and cerebellum were selected, and significant clusters of activity were thresholded at p<0.05, corrected. Healthy controls had significantly greater activation than MJ users for the CG and cerebellum. In addition, activation of the cerebellum and CG correlated with lifetime MJ smokes. This is one of the first studies to evaluate cortico-cerebellar circuits in adolescents with heavy MJ use. The study, which used a bilateral finger-tapping fMRI task, provides evidence for both CG and cerebellar dysfunction in MJ abuse and indicates that lifetime MJ use may impact the developing brain.

Neuroimaging correlates of traumatic brain injury and suicidal behavior.

INTRODUCTION: There is an urgent need to define the neurobiological and cognitive underpinnings of suicidal ideation and behavior in veterans with traumatic brain injury (TBI). Separate studies implicate frontal white matter systems in the pathophysiology of TBI, suicidality, and impulsivity. We examined the relationship between the integrity of major frontal white matter (WM) systems on measures of impulsivity and suicidality in veterans with TBI. METHODS: Fifteen male veterans with TBI and 17 matched healthy controls (HC) received clinical ratings, measures of impulsivity and MRI scans on a 3T magnet. Diffusion tensor imaging (DTI) data for the genu and cingulum were analyzed using Freesurfer and FSL. Correlations were performed for fractional anisotropy (FA) (DTI) values and measures of suicidality and impulsivity for veterans with TBI. RESULTS: Significantly decreased in FA values in the left cingulum (P = 0.02), and left (P = 0.02) and total genu (P = 0.01) were observed in the TBI group relative to controls. Measures of impulsivity were significantly greater for the TBI group and total and right cingulum FA positively correlated with current suicidal ideation and measures of impulsivity (P <0.03). CONCLUSION: These data demonstrate a significant reduction in FA in frontal WM tracts in veterans with mild TBI that was associated with both impulsivity and suicidality. These findings may reflect a neurobiological vulnerability to suicidal risk related to white matter microstructure.