Associations between perinatal risk and physical health in pre-adolescence in the Adolescent Brain Cognitive Development (ABCD) Study®: the unexpected relationship with sleep disruption.

BACKGROUND: To investigate relationships among different physical health problems in a large, sociodemographically diverse sample of 9-to-10-year-old children and determine the extent to which perinatal health factors are associated with childhood physical health problems. METHODS: A cross-sectional study was conducted utilizing the Adolescent Brain Cognitive Development℠ (ABCD) Study (n = 7613, ages 9-to-10-years-old) to determine the associations among multiple physical health factors (e.g., prenatal complications, current physical health problems). Logistic regression models controlling for age, sex, pubertal development, household income, caregiver education, race, and ethnicity evaluated relationships between perinatal factors and childhood physical health problems. RESULTS: There were significant associations between perinatal and current physical health measures. Specifically, those who had experienced perinatal complications were more likely to have medical problems by 9-to-10 years old. Importantly, sleep disturbance co-occurred with several physical health problems across domains and developmental periods. CONCLUSION: Several perinatal health factors were associated with childhood health outcomes, highlighting the importance of understanding and potentially improving physical health in youth. Understanding the clustering of physical health problems in youth is essential to better identify which physical health problems may share underlying mechanisms. IMPACT: Using a multivariable approach, we investigated the associations between various perinatal and current health problems amongst youth. Our study highlights current health problems, such as sleep problems at 9-to-10 years old, that are associated with a cluster of factors occurring across development (e.g., low birth weight, prenatal substance exposure, pregnancy complications, current weight status, lifetime head injury). Perinatal health problems are at large, non-modifiable (in this retrospective context), however, by identifying which are associated with current health problems, we can identify potential targets for intervention and prevention efforts.

Elevated circulating soluble interleukin-2 receptor (sCD25) level is associated with prefrontal excitatory-inhibitory imbalance in individuals with chronic pain: A proton MRS study.

Aberrant neuronal excitability in the anterior cingulate cortex (ACC) is implicated in cognitive and affective pain processing. Such excitability may be amplified by activated circulating immune cells, including T lymphocytes, that interact with the central nervous system. Here, we conducted a study of individuals with chronic pain using magnetic resonance spectroscopy (MRS) to investigate the clinical evidence for the interaction between peripheral immune activation and prefrontal excitatory-inhibitory imbalance. In thirty individuals with chronic musculoskeletal pain, we assessed markers of peripheral immune activation, including soluble interleukin-2 receptor alpha chain (sCD25) levels, as well as brain metabolites, including Glx (glutamate + glutamine) to GABA+ (γ-aminobutyric acid + macromolecules/homocarnosine) ratio in the ACC. We found that the circulating level of sCD25 was associated with prefrontal Glx/GABA+. Greater prefrontal Glx/GABA+ was associated with higher pain catastrophizing, evaluative pain ratings, and anxiodepressive symptoms. Further, the interaction effect of sCD25 and prefrontal Glx/GABA+ on pain catastrophizing was significant, indicating the joint association of these two markers with pain catastrophizing. Our results provide the first evidence suggesting that peripheral T cellular activation, as reflected by elevated circulating sCD25 levels, may be linked to prefrontal excitatory-inhibitory imbalance in individuals with chronic pain. The interaction between these two systems may play a role as a potential mechanism underlying pain catastrophizing. Further prospective and treatment studies are needed to elucidate the specific role of the immune and brain interaction in pain catastrophizing.

Comparing the effectiveness of game literacy education and game coding education in improving problematic internet gaming.

Objective: Problematic internet gaming by adolescents has been thought to be associated with low self-esteem, depression, anxiety, and attention problems. We hypothesized that both game literacy and coding education would effectively improve problematic internet use. However, game coding education would be more effective in enhancing self-esteem and social anxiety in adolescents than game literacy education. Methods: A total of 733 adolescent volunteers were included and randomly assigned to either the game coding education or game literacy education programs. Both programs consisted of eight sessions, each lasting 45 minutes, over four weeks. The coding education sessions included game planning and development lessons and allowed students to create the game's characters, stages, and tutorials directly using Scratch, a free coding program. Game literacy education sessions included lessons on enjoying gaming with a healthy rationale and etiquette. Data on demographics, gaming patterns, and psychological status, including positive/negative perceptions of online games, depression, social anxiety, and self-esteem, were collected. Results: Both game coding and game literacy education significantly improved YIAS scores compared to baseline, and there was no significant difference in the YIAS scores between the two groups after the interventions. In the hierarchical logistic regression analysis of all participants, higher YIAS scores, stronger negative perceptions of gaming, and lower attention problem scores at baseline predicted lower levels of internet gaming addiction after interventions. In the hierarchical logistic regression analysis among individuals with game coding education, higher YIAS scores, stronger negative perceptions of gaming, lower attention problem scores, and higher self-esteem scores at baseline predicted lower levels of internet gaming addiction after intervention. In addition, game coding education greatly improved negative perceptions of games, self-esteem, and social anxiety compared to game literacy education. Conclusion: Both game literacy and game coding education effectively mitigate internet game addiction. However, game coding education effectively mitigated problematic internet gaming by improving negative perceptions of games, self-esteem, and social anxiety in adolescents. We found that the application of knowledge by students in creating their own games was more effective than simply developing a conceptual understanding of the games.

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.

Exploring the Link between Altitude of Residence and Smoking Patterns in the United States.

INTRODUCTION: Smoking-related diseases affect 16 million Americans, causing approximately 480,000 deaths annually. The prevalence of cigarette smoking varies regionally across the United States, and previous research indicates that regional rates of smoking-related diseases demonstrate a negative association with altitude. The purpose of this study was to determine the relationship between altitude and the prevalence of cigarette smoking by county (N = 3106) in the United States. We hypothesized that smoking prevalence among adults would be negatively associated with mean county altitude. METHODS: A multivariate linear regression was performed to examine the relationship between county-level mean altitude and county smoking rate. Covariates were individually correlated with 2020 smoking data, and significant associations were included in the final model. RESULTS: The multivariate linear regression indicated that the county-level smoking rates are significantly reduced at high altitudes (p < 0.001). The model accounted for 89.5% of the variance in smoking prevalence, and for each 1000-foot increase in altitude above sea level, smoking rates decreased by 0.143%. Based on multivariate linear regression, the following variables remained independently and significantly associated: race, sex, educational attainment, socioeconomic status, unemployment, physical inactivity, drinking behavior, mental distress, and tobacco taxation. CONCLUSIONS: Our results indicate that smoking rates are negatively associated with altitude, which may suggest that altitude affects the pharmacokinetics, pharmacodynamics, and mechanistic pathways involved in cigarette use. Further research is needed to explore the relationship between altitude and smoking and how altitude may serve as a protective factor in the acquisition and maintenance of tobacco use disorders.

Glutamate measurements using edited MRS.

PURPOSE: To demonstrate J-difference coediting of glutamate using Hadamard encoding and reconstruction of Mescher-Garwood-edited spectroscopy (HERMES). METHODS: Density-matrix simulations of HERMES (TE 80 ms) and 1D J-resolved (TE 31-229 ms) of glutamate (Glu), glutamine (Gln), γ-aminobutyric acid (GABA), and glutathione (GSH) were performed. HERMES comprised four sub-experiments with editing pulses applied as follows: (A) 1.9/4.56 ppm simultaneously (ONGABA /ONGSH ); (B) 1.9 ppm only (ONGABA /OFFGSH ); (C) 4.56 ppm only (OFFGABA /ONGSH ); and (D) 7.5 ppm (OFFGABA /OFFGSH ). Phantom HERMES and 1D J-resolved experiments of Glu were performed. Finally, in vivo HERMES (20-ms editing pulses) and 1D J-resolved (TE 31-229 ms) experiments were performed on 137 participants using 3 T MRI scanners. LCModel was used for quantification. RESULTS: HERMES simulation and phantom experiments show a Glu-edited signal at 2.34 ppm in the Hadamard sum combination A+B+C+D with no overlapping Gln signal. The J-resolved simulations and phantom experiments show substantial TE modulation of the Glu and Gln signals across the TEs, whose average yields a well-resolved Glu signal closely matching the Glu-edited signal from the HERMES sum spectrum. In vivo quantification of Glu show that the two methods are highly correlated (p < 0.001) with a bias of ∼10%, along with similar between-subject coefficients of variation (HERMES/TE-averaged: ∼7.3%/∼6.9%). Other Hadamard combinations produce the expected GABA-edited (A+B-C-D) or GSH-edited (A-B+C-D) signal. CONCLUSION: HERMES simulation and phantom experiments show the separation of Glu from Gln. In vivo HERMES experiments yield Glu (without Gln), GABA, and GSH in a single MRS scan.

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.

Detailed assessment of suicidal ideation in youth with bipolar disorder versus major depressive disorder.

OBJECTIVES: There is a critical need to better understand the factors underlying the increased suicide risk for youth with bipolar disorder (BD) in order to develop targeted prevention efforts. This study aimed to examine differences in characteristics of suicide ideation (SI) in youth with BD compared to youth with major depressive disorder (MDD) that may be associated with increased suicide risk. METHODS: One hundred and fifty-one participants (92 MDD and 59 BD), ages 13-21, completed a diagnostic interview and clinical assessments. Lifetime symptoms of SI and SA were assessed using the Columbia Suicide Severity Rating Scale. Ordinal logistic regression models were used to investigate whether the diagnostic group predicted the severity and intensity of the most severe or most common SI with the age of onset, age, and gender as covariates. RESULTS: Compared to MDD youth, BD youth were more likely to report experiencing more severe SI, p = 0.039, experiencing the most severe SI more frequently, p = 0.002, having less control of the most severe SI, p = 0.012, and that deterrents were less likely to stop them from acting on the most severe SI, p = 0.006. CONCLUSION: This study highlights differences in the severity and intensity of SI in youth with BD and suggests that youth with BD have greater difficulty inhibiting thoughts of SI which may lead to less resistance to suicide action. Findings underscore the need for a more detailed assessment of SI in youth with BD to better understand SI as a proximal risk factor for future SA and a potential target for intervention.

Differential alterations in brain structural network organization during addiction between adolescents and adults.

BACKGROUND: The adolescent brain may be susceptible to the influences of illicit drug use. While compensatory network reorganization is a unique developmental characteristic that may restore several brain disorders, its association with methamphetamine (MA) use-induced damage during adolescence is unclear. METHODS: Using independent component (IC) analysis on structural magnetic resonance imaging data, spatially ICs described as morphometric networks were extracted to examine the effects of MA use on gray matter (GM) volumes and network module connectivity in adolescents (51 MA users v. 60 controls) and adults (54 MA users v. 60 controls). RESULTS: MA use was related to significant GM volume reductions in the default mode, cognitive control, salience, limbic, sensory and visual network modules in adolescents. GM volumes were also reduced in the limbic and visual network modules of the adult MA group as compared to the adult control group. Differential patterns of structural connectivity between the basal ganglia (BG) and network modules were found between the adolescent and adult MA groups. Specifically, adult MA users exhibited significantly reduced connectivity of the BG with the default network modules compared to control adults, while adolescent MA users, despite the greater extent of network GM volume reductions, did not show alterations in network connectivity relative to control adolescents. CONCLUSIONS: Our findings suggest the potential of compensatory network reorganization in adolescent brains in response to MA use. The developmental characteristic to compensate for MA-induced brain damage can be considered as an age-specific therapeutic target for adolescent MA users.

Effect of cannabinoids on brain metabolites: A review of animal and human studies.

Cannabis has been widely used medically and recreationally for centuries. With a renewed interest in the therapeutic use of cannabinoids, which are active components of Cannabis sativa, it has become important to understand the cannabinoids' neurobiological mechanisms related to both therapeutic and harmful effects. This review summarizes the effects of two major cannabinoids, delta-9-tetrahydrocannabinol and cannabidiol, on brain metabolites. We focus on human studies applying ¹H-magnetic resonance spectroscopy (MRS) and animal studies using more invasive and direct methods to measure brain metabolites associated with glutamatergic neurotransmission or glial and neuronal functions. Although studies are limited in number, current evidence suggests that two major cannabinoids, which are thought to have differential effects on the brain, may alter the brain metabolite levels in distinct ways from each other. Potential limitations of present studies of cannabinoids on brain metabolites and suggestions regarding future studies are also discussed. We believe that issues clarified in this review may contribute to the design of future studies of cannabinoids on brain metabolites. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Acute and chronic neuropsychiatric symptoms in novel coronavirus disease 2019 (COVID-19) patients: A qualitative review.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a global pandemic by the World Health Organization (WHO) on March 11th, 2020. It has had unprecedented adverse effects on healthcare systems, economies, and societies globally. SARS-CoV-2 is not only a threat to physical health but has also been shown to have a severe impact on neuropsychiatric health. Many studies and case reports across countries have demonstrated insomnia, depressed mood, anxiety, post-traumatic stress disorder (PTSD), and cognitive change in COVID-19 patients during the acute phase of the infection, as well as in apparently recovered COVID-19 patients. The goal of this narrative review is to synthesize and summarize the emerging literature detailing the neuropsychiatric manifestations of COVID-19 with special emphasis on the long-term implications of COVID-19.

Examination of gamma-aminobutyric acid and glutamate-glutamine levels in association with impulsive behavior in adolescent marijuana users.

BACKGROUND: Adolescent marijuana (MJ) use has been associated with alterations in brain structure and function as well as behavior. Examination of neurochemical correlates such as GABA (gamma-aminobutyric acid) and Glx (glutamate + glutamine) in MJ users remains limited. Impulsivity, identified as a risk factor and consequence of MJ use, has been associated with GABA and Glx levels in healthy and clinical populations. However, this relationship has not been investigated in MJ users. In this study, we examined levels of GABA and Glx in the anterior cingulate cortex (ACC) and its relationship with impulsive behavior in MJ-using adolescents and healthy controls. METHODS: Healthy control subjects (HC; N = 21) and MJ-using adolescents (N = 18) completed a metabolite-edited 1H MRS exam to measure ACC GABA and Glx levels, a structured clinical interview to assess MJ use, and the Barratt Impulsivity Scale (BIS-11) to evaluate impulsive behavior. RESULTS: Adolescent MJ users had significantly lower tissue-corrected GABA (with macromolecules; GABA+) levels (p = 0.029) compared to HC's. No significant between-group differences were observed in ACC Glx levels. Assessment of impulsive behavior demonstrated no significant between-group differences in motor, non-planning, attention, and total impulsivity scores. Additionally, impulsivity measures and tissue-corrected GABA+ or Glx levels were not significantly correlated in either group. CONCLUSION: Lower GABA levels in MJ users may indicate alterations in excitatory-inhibitory mechanisms critical for neurodevelopment. Although no significant relationships were observed between impulsive measures and GABA or Glx levels in both groups, further investigations are needed examining the relationship between neurochemical correlates, behavior, and adolescent MJ use.

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.

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.

A Comprehensive Overview of the Physical Health of the Adolescent Brain Cognitive Development Study Cohort at Baseline.

Physical health in childhood is crucial for neurobiological as well as overall development, and can shape long-term outcomes into adulthood. The landmark, longitudinal Adolescent Brain Cognitive Development StudySM (ABCD study®), was designed to investigate brain development and health in almost 12,000 youth who were recruited when they were 9-10 years old and will be followed through adolescence and early adulthood. The overall goal of this paper is to provide descriptive analyses of physical health measures in the ABCD study at baseline, including but not limited to sleep, physical activity and sports involvement, and body mass index. Further this summary will describe how physical health measures collected from the ABCD cohort compare with current normative data and clinical guidelines. We propose this data set has the potential to facilitate clinical recommendations and inform national standards of physical health in this age group. This manuscript will also provide important information for ABCD users and help guide analyses investigating physical health including new avenues for health disparity research as it pertains to adolescent and young adult development.

Effects of cytidine-5'-diphosphate choline on gray matter volumes in methamphetamine-dependent patients: A randomized, double-blind, placebo-controlled study.

BACKGROUND: Cytidine-5'-diphosphate choline (CDP-choline) has been suggested to exert neuroprotective and neuroreparative effects and may be beneficial for patients with stimulant dependence. This randomized, double-blind, placebo-controlled study in methamphetamine (MA) dependence investigated effects of CDP-choline on the brain structures and their associations with craving and MA use. METHODS: MA users (n = 44) were randomized to receive 2 g/day of CDP-choline (n = 22) or placebo (n = 22) for 8 weeks. Patients underwent brain magnetic resonance imaging (MRI) at baseline and 8-week follow-up. Healthy individuals (n = 27) were also examined using brain MRI at the same interval. Voxel-based morphometry analysis was conducted to examine changes in gray matter (GM) volumes and their associations with craving and MA use. RESULTS: Craving for MA was significantly reduced after the 8 week-treatment with CDP-choline (p = 0.01), but not with the placebo treatment (p = 0.10). There was no significant difference in the total number of MA-negative urine samples between the two groups (p = 0.19). With CDP-choline treatment, GM volumes in the left middle frontal gyrus (p = 0.001), right hippocampus (p = 0.009), and left precuneus (p = 0.001) were significantly increased compared to the placebo and control groups. Increased GM volumes in the left middle frontal gyrus with CDP-choline treatment were associated with reduced craving for MA (Spearman's ρ = -0.56, p = 0.03). In addition, the right hippocampal volume increases were positively associated with the total number of MA-negative urine results in the CDP-choline group (Spearman's ρ = 0.67, p = 0.006). CONCLUSION: Our findings suggest that CDP-choline may increase GM volumes of MA-dependent patients, which may be related to decreases in MA use and craving.

Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression.

BACKGROUND: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. METHODS: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. RESULTS: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. CONCLUSIONS: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.

Sex-based changes in rat brain serotonin and behavior in a model of altitude-related vulnerability to treatment-resistant depression.

RATIONALE: Rates of depression and suicide increase with altitude. In our animal model, rats housed at moderate altitude vs. at sea level exhibit increased depressive symptoms in the forced swim test (FST) and lack of response to selective serotonin reuptake inhibitors (SSRIs). Depression and SSRI resistance are linked to disrupted serotonergic function, and hypobaric hypoxia may reduce the oxygen-dependent synthesis of serotonin. We therefore tested brain serotonin in rats housed at altitude. METHODS: Sprague-Dawley rats were housed at altitude (4,500 ft, 10,000 ft) vs. sea level for 7-36 days. Brain serotonin was measured by ELISA, or behavior evaluated in the FST, sucrose preference (SPT), or open-field tests (OFT). RESULTS: After 2 weeks at 4,500 ft or 10,000ft vs. sea level, serotonin levels decreased significantly at altitude in the female prefrontal cortex, striatum, hippocampus, and brainstem, but increased with altitude in the male hippocampus and brainstem. Female brain serotonin decreased from 7 to 36 days at 4,500 ft, but males did not vary. At 2 weeks and 24 days, females at altitude exhibit lower brain serotonin and increased depressive symptoms in the FST and SPT, with motor behavior unaltered. In males, serotonin, passive coping in the FST and OFT immobility increased with altitude at 2 weeks, but not at 24 days. Male SPT behavior did not change with altitude. CONCLUSIONS: Females may be more vulnerable to depressive symptoms at altitude, while males may be resilient. Chronic hypoxic stress at altitudes as low as 4,500 ft may cause a brain serotonin imbalance to worsen vulnerability to depression and SSRI resistance, and potentially worsen suicide risk.

Effect of moderate altitude on human cerebral metabolite levels: A preliminary, multi-site, proton magnetic resonance spectroscopy investigation.

Epidemiological studies show that altitude-of-residence is an independent risk factor for worsening rates of mood disorders, substance abuse, and suicide. Proton (1H) magnetic resonance spectroscopy (MRS) studies in rodent models of moderate-to-high altitude exposure have documented significant alterations in total creatine, glutamate, and myo-inositol, neurometabolites involved in bioenergetic homeostasis and neuronal/glial cell function. This preliminary study utilized 3 Tesla 1H MRS to study anterior cingulate cortex (ACC) and parietal-occipital cortex (POC) neurochemistry in healthy subjects residing in Utah (n = 19), Massachusetts (n = 10), and South Carolina (n = 10), to test the hypothesis that individuals residing at moderate altitude (Utah; 1,372 m) would show neurometabolite alterations vs. subjects living at sea level. Expressed as ratios to total N-acetyl aspartate (NAA), Utah participants showed lower ACC (p = 0.03) and POC (p < 0.01) total creatine, a trend towards lower ACC glutamate (p = 0.06), and lower POC myo-inositol (p = 0.02). Study limitations include small sample sizes and uncorrected multiple comparisons. To our knowledge, this is the first MRS investigation to identify potential neurochemical differences in individuals residing at moderate altitudes vs. sea level, warranting future 1H MRS studies in larger cohorts and across a range of altitudes-of-residence.