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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.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.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.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.

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.

There is a critical need to better understand 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.One-hundred fifty-one participants (92 MDD and 59 BD), ages 13 to 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 diagnostic group predicted the severity and intensity of the most severe or most common SI with age of onset, age, and gender as covariates.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.This study highlights differences in the severity and intensity of SI in youth with BD and suggest 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 more detailed assessment of SI in youth with BD to better understand SI as proximal risk factor for future SA and a potential target for intervention.

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.

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. 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). 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. 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.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development. This paper reports activation patterns for fMRI tasks assessing response inhibition, working memory and reward processing obtained at baseline in the longitudinal ABCD Study, providing a reference for research into adolescent brain development.

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

Background Caloric restriction (CR) without micronutrient deficiency has been shown to increase both lifespan and healthspan. In animals, CR has been demonstrated to increase glutathione (GSH), a neuroprotective antioxidant, in the brain and preserve brain mitochondrial function by altering neuroenergetics. In humans it has been associated with improvements in mood states and cognitive function. However, most CR studies have employed a 30–60% reduction in calories which is likely too stringent for most people to adhere to long-term. Thus, there is an unmet need for nutritional supplements which can mimic the biological effects of CR, without the need for calorie limitations. Aim The purpose of the present randomized, placebo-controlled clinical trial was to use Proton (1H) Magnetic Resonance Spectroscopic (MRS) measurements to determine non-invasively whether a blend of micronutrients, a putative CR mimetic, positively modulates metabolites related to neuroprotection and neuroenergetics in the brain. Methods Healthy middle-aged men and women (N = 63 [33 women]; age: 40–60 years) were randomized in a double-blind manner to 6 weeks supplementation with either the putative CR mimetic or placebo. At baseline and 6 weeks, subjects underwent MRS at 3 T to investigate changes in brain chemistry, including the neurometabolites: GSH, Glutamate (Glu), Glutamine (Gln) and N-Acetylaspartate (NAA). Results GSH, a marker of antioxidant and cellular redox status, increased in the brain of participants in the supplement group. The supplement group also showed an increase in the Glu/Gln ratio, a marker of excitatory neurotransmission and bioenergetics. A trend for an increase in NAA/H2O, a marker of neuronal integrity, was observed in females in the supplement group. Conclusions The present study reveals that 6-weeks daily supplementation with a micronutrient blend elicits positive changes in brain neurochemistry. This is the first study to demonstrate that a putative CR mimetic increases brain GSH concentrations and improves neuroprotection and neuroenergetics in the brain of healthy humans. This study was registered at www.clinicaltrials.gov as NCT02439983.

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.

Creatine monohydrate is actively being researched for its antidepressant effects, yet little is known about the link between dietary creatine and depression risk. This study examines the association between dietary creatine and depression in U.S. adults, using data from the 2005 to 2012 National Health and Nutrition Examination Survey (NHANES). Patient health questionnaire, dietary creatine intake and covariates were obtained on 22,692 NHANES participants ≥20 years of age. Depression prevalence was calculated within quartiles of dietary creatine intake. Adjusted logistic regression models were formulated to determine the relationship between dietary creatine intake and depression risk. Additional covariates included income to poverty ratio, race/ethnicity, sex, age, education level, body mass index, healthcare access, smoking status, physical activity, and antidepressant/anxiolytic medication use. Models were further stratified by sex, age group, and antidepressant/anxiolytic medication use. Depression prevalence was 10.23/100 persons (95% CI: 8.64–11.83) among NHANES participants in the lowest quartile of dietary creatine intake compared with 5.98/100 persons (95% CI: 4.97–6.98) among participants in the highest quartile (p

Rationale Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment. Objective This randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males. Methods Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements. Results The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen’s effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated. Conclusions Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.

Objective: We aimed to understand whether Attention Deficit Hyperactivity Disorder (ADHD) and Internet gaming disorder (IGD) share similar brain functional connectivity (FC) between the frontal and subcortices. Method: We compared changes in clinical symptoms and brain activity using functional magnetic resonance imaging (fMRI) in 26 patients with ADHD but without IGD, 29 patients with ADHD and IGD, and 20 patients with IGD but without ADHD. Results: The functional connectivity (FC) from the cortex to subcortex in both groups was decreased relative to that in age-matched healthy participants. One-year treatment for ADHD and IGD symptoms increased the FC between the cortex and subcortex in all ADHD participants and all IGD participants with good prognoses compared with those in all ADHD participants and all IGD participants with poor prognoses. Conclusion: Patients with ADHD and IGD shared similar brain FC at baseline and FC changes in response to treatment.

Aim Increased oxidative stress in cerebral mitochondria may follow exposure to the systemic hypobaric hypoxia associated with residing at higher altitudes. Because mitochondrial dysfunction is implicated in bipolar disorder (BD) pathophysiology, this may impact the cerebral bioenergetics in BD. In this study, we evaluated the cerebral bioenergetics of BD and healthy control (HC) subjects at two sites, located at sea level and at moderate altitude. Methods Forty‐three veterans with BD and 33 HC veterans were recruited in Boston (n = 22) and Salt Lake City (SLC; n = 54). Levels of phosphocreatine, β nucleoside triphosphate (βNTP), inorganic phosphate, and pH over total phosphate (TP) were measured using phosphorus‐31 magnetic resonance spectroscopy in the following brain regions: anterior cingulate cortex and posterior occipital cortex, as well as bilateral prefrontal and occipitoparietal (OP) white matter (WM). Results A significant main effect of site was found in βNTP/TP (Boston > SLC) and phosphocreatine/TP (Boston < SLC) in most cortical and WM regions, and inorganic phosphate/TP (Boston < SLC) in OP regions. A main effect analysis of BD diagnosis demonstrated a lower pH in posterior occipital cortex and right OP WM and a lower βNTP/TP in right prefrontal WM in BD subjects, compared to HC subjects. Conclusion The study showed that there were cerebral bioenergetic differences in both BD and HC veteran participants at two different sites, which may be partly explained by altitude difference. Future studies are needed to replicate these results in order to elucidate the dysfunctional mitochondrial changes that occur in response to hypobaric hypoxia.

Although the neurotransmitters/modulators glutamate and, more recently, glycine have been implicated in the development and maintenance of Alcohol Use Disorder (AUD) in preclinical research, human proton magnetic resonance spectroscopy ((1)H-MRS) studies have focused solely on the measurement of glutamate. The purpose of the present analysis was to examine the relative associations of brain glutamate and glycine levels with recent heavy drinking in 41 treatment naïve individuals with AUD using (1)H-MRS. The present study is the first that we are aware of to report in vivo brain glycine levels from an investigation of addiction. Dorsal Anterior Cingulate Cortex (dACC) glutamate and glycine concentration estimates were obtained using Two-Dimensional J-Resolved Point Resolved Spectroscopy at 3 Tesla, and past 2-week summary estimates of alcohol consumption were assessed via the Timeline Followback method. Glutamate (β= −0.44, t= −3.09, p= 0.004) and glycine (β= −0.68, t= −5.72, p< 0.001) were each significantly, inversely associated with number of heavy drinking days when considered alone. However, when both variables were simultaneously entered into a single regression model, the effect of glutamate was no longer significant (β= −0.11, t= −0.81, p= 0.42) whereas the effect of glycine remained significant (β= −0.62, t= −4.38, p< 0.001). The present study extends the literature by demonstrating a unique, inverse association of brain glycine levels with recent heavy drinking in treatment naïve individuals with AUD. If replicated and extended, these data could lead to enhanced knowledge of how glycinergic systems change with alcohol consumption and AUD progression leading to pharmacological interventional/preventative strategies that modulate brain glycine levels.

Aims: Suicide rates in the general population in the United States are correlated with altitude. To explore factors contributing to suicide among military veterans, we examined the relationship between veteran state-level suicide rates and altitude for 2014, including firearm-related and nonfirearm-related rates. Methods: Pearson's coefficients were calculated for altitude and each outcome. Mixed linear models were used to determine the association between suicide and altitude while adjusting for demographic confounds. Results: State mean altitude was significantly correlated with total veteran suicide rate (r = 0.678, p

Multiple studies suggest that the risks of depression and suicide increase with increasing altitude of residence, but no studies have assessed whether changing altitude changes these risks. To address this gap, we used data from the Intern Health Study, which follows students from the end of medical school through the first year of residency, recording depression via the 9-item Patient Health Questionnaire (PHQ-9), anxiety via the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), and multiple risk factors for these symptoms. Data from 3,764 medical students representing 46 schools and 282 residencies were available. Odds ratios (OR) representing the effects of altitude on psychiatric symptoms were estimated using generalized linear models. After excluding participants with missing altitude data, 3731 medical students were analyzed. High altitude residence (>900m) was significantly associated with PHQ-9 total score (OR=1.32, 95% CI=1.001-1.75, p

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.

Objectives Structural abnormalities in cortical and subcortical regions, including the orbitofrontal cortex (OFC), are altered during brain development in adolescents with bipolar disorder (BD), which may increase risk for suicide. Few studies have examined the neural substrates of suicidal behavior in BD youth. The aim of the present study was to investigate the relationship between suicide behavior and the OFC in youth with BD. Methods Thirty-seven participants with BD and 26 non-psychiatric controls, ages 13-21 years, completed a diagnostic interview and mood rating scales. Lifetime symptoms of suicide ideation and behavior were examined using the Columbia Suicide Severity Rating Scale. Participants underwent magnetic resonance imaging on a 3T Siemens Verio scanner. Morphometric analysis of brain images was performed using FreeSurfer. Results Eighteen participants with BD had a history of suicide attempt (SA). Bipolar youth with a history of SA showed reduced left lateral OFC volumes compared to controls, but there was no difference between BD attempters and non-attempters. Controls and BD non-attempters had significantly greater OFC cortical thickness than BD attempters. Additionally, there was a significant negative correlation between OFC volumes and suicide lethality, demonstrating that as suicide lethality increased, OFC volume in BD youth was reduced. Conclusions The OFC is involved in decision-making, impulsivity, and reward circuitry which have shown to be impaired in BD. Reduced OFC volume and its association with lethality of suicide suggest that suicide behavior in BD may be related to the emerging neuroanatomical substrates of the disorder, particularly abnormalities of the OFC.

Background and aims Although Internet gaming disorder (IGD) is included as a condition in the fifth edition of Diagnostic and Statistical Manual of Mental Disorders, little is known about its nature or treatment response. This study is a follow-up of 755 patients who received professional treatment for IGD over a 5-year period. Methods The initial recommended treatment course lasted for 8 weeks, with additional care provided as needed. Treatment completion rates in the complete sample, as well as baseline predictors of treatment completion and long-term recovery among the 367 patients who completed the follow-up, are reported. Results Nearly two thirds of patients who initiated treatment for IGD completed the 8-week psychotherapy. Of these, about two thirds who had not recovered completely by the end were offered additional care. Independent predictors of extended treatment were higher baseline scores on the Young Internet Addiction Scale, Beck Depression Inventory (BDI), and Korean-Attention Deficit Hyperactivity Disorder-Rating Scale (K-ADHD-RS). Between 1 and 5 years later, 33.5% of the complete sample was considered as recovered from IGD. Significant predictors of recovery from IGD were older age, earlier admission to the clinic, lower baseline scores on the BDI and K-ADHD-RS, and no offer of extended treatment. Discussion and conclusions The majority of the patients seeking treatment for IGD continued experiencing difficulties and randomized controlled trials of interventions, which are needed to be conducted to improve outcomes. Age, family, social factors, and psychological symptoms should be considered, while designing and evaluating interventions, because they impact initial and sustained response to treatment for IGD.

Key Points Question Are clinical and demographic factors associated with brain glutamate or glutamate plus glutamine (Glx) levels in schizophrenia? Findings In this mega-analysis of 1251 patients with schizophrenia and 1197 healthy volunteers, medial frontal cortex glutamatergic metabolite levels were lower in patients and negatively associated with the dose of antipsychotic medication, although a reduction in glutamate levels with age was not accelerated in patients with schizophrenia compared with healthy individuals. Higher medial frontal cortex and medial temporal lobe glutamate levels were associated with more severe symptoms in patients with schizophrenia. Meaning Lower brain glutamate levels may be associated with antipsychotic exposure rather than with greater age-related decline, whereas higher glutamate levels may serve as a biomarker of illness severity in patients with schizophrenia., Importance Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P, This mega-analysis assesses whether age, symptom severity, level of functioning, and antipsychotic treatment are associated with glutamate or glutamatergic metabolite levels measured with proton magnetic resonance spectroscopy in the medial frontal cortex or medial temporal lobe of patients with schizophrenia.

Background The aim of the study was to assess anterior cingulate cortex (ACC) neurochemical profile of patients with unipolar major depressive disorder (MDD) before and after electroconvulsive therapy (ECT) by using H-1 magnetic resonance spectroscopy (H-1-MRS). Method Using H-1-MRS, the metabolite levels of choline, glutamate + glutamine (Glx), myo-inositol, N-acetylaspartate, and total creatine were measured in ACC before and after 4-week ECT. The Montgomery-angstrom sberg Depression Rating Scale (MADRS) was implemented by blind raters to evaluate the efficacy of the treatment. Electroconvulsive therapy-remitter (ER) and nonremitter groups were compared using the 1-way repeated measures analysis of variance. Results Thirty patients with unipolar MDD (aged 41.3 +/- 10.0 years, 66.7% female) were included in the study. The ER group (n = 16, 53.3%) and NR group did not differ regarding baseline Global Assessment of Functioning and MADRS scores. At the end of 4-week ECT treatment, results did not suggest any significant difference for metabolite levels in ACC. When compared with the NR group, the ER group had higher baseline levels of Glx (8.8 +/- 1.8 vs 6.3 +/- 2.0, P = 0.005) and total creatine (5.3 +/- 0.6 vs 4.7 +/- 0.5, P = 0.010). In addition, elevated baseline Glx (r = -0.68, P = 0.002) was associated with lower MADRS scores at the end treatment. Finally, the change in Glx levels was correlated with change in MADRS scores after ECT (r = 0.47, P = 0.049). Limitations Modest sample size and H-1-MRS at 1.5 Tesla are limitations of the study. Conclusions Results suggested that Glx levels could be a predictor of remission. Studies with larger samples should explore neurochemical correlates of ECT in unipolar MDD.

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.

Metabolite-specific, scalar spin-spin coupling constant (J)-editing 1H MRS methods have become gold-standard for measuring brain γ-amino butyric acid (GABA) levels in human brain. Localized, two-dimensional (2D) 1H MRS technology offers an attractive alternative as it significantly alleviates the problem of severe metabolite signal overlap associated with standard 1D MRS and retains spectroscopic information for all MRS-detectable species. However, for metabolites found at low concentration, a direct, in vivo, comprehensive methods comparison is challenging and has not been reported to date. Here, we document an assessment of comparability between 2D 1H MRS and J-editing methods for measuring GABA in human brain. This clinical study is unique in that it involved chronic administration a GABA-amino transferase (AT) inhibitor (CPP-115), which induces substantial increases in brain GABA concentration, with normalization after washout. We report a qualitative and quantitative comparison between these two measurement techniques. In general, GABA concentration changes detected using J-editing were closely mirrored by the 2D 1H MRS time courses. The data presented are particularly encouraging considering recent 2D 1H MRS methodological advances are continuing to improve temporal resolution and spatial coverage for achieving whole-brain, multi-metabolite mapping.

Treatment-resistant depression, a chronic condition that affects 30% of depressed patients on antidepressants, is highly linked to suicidal behavior. Chronic hypoxia exposure via living at altitude (hypobaric hypoxia) or with chronic hypoxic diseases is demographically linked to increased risk for depression and suicide. We previously demonstrated that housing rats at altitude for a week incrementally increases depression-like behavior in the forced swim test (FST) in females, but not males. In animal models, high altitude exposure reduces brain serotonin, and selective serotonin reuptake inhibitors (SSRIs) can lose efficacy when brain serotonin levels are low. To address whether residence at moderate altitude is detrimental to SSRI function, we examined SSRI efficacy in the FST after a week of housing rats at altitudes of 4500 ft. or 10,000 ft. as compared to at sea level. In females, the tricyclic antidepressant desipramine (positive control) functioned well in all groups, increasing latency to immobility and decreasing immobility, by increasing climbing. However, the SSRIs fluoxetine, paroxetine and escitalopram were ineffective in females in all groups: only paroxetine improved swimming in the FST as expected of a SSRI, while all three unexpectedly reduced climbing. Fluoxetine was also ineffective in male rats. Sertraline was the only SSRI with antidepressant efficacy at altitude in both females and males, increasing swimming, climbing and latency to immobility, and reducing immobility. Hypobaric hypoxia thus appears to be detrimental to efficacy of the SSRIs fluoxetine, paroxetine and escitalopram, but not of sertraline. Unlike the other SSRIs, sertraline can improve both serotonergic and dopaminergic transmission, and may be less impacted by a hypoxia-induced serotonin deficit. A targeted approach may thus be necessary for successful antidepressant treatment in patients with depression who live at altitude or with chronic hypoxic diseases, and that sertraline may be the SSRI of choice for prescription for this population.

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.

Sheth, Chandni, Hendrik Ombach, Paul Olson, Perry F. Renshaw, and Shami Kanekar. Increased anxiety and anhedonia in female rats following exposure to altitude. High Alt Med Biol. 19:81-90, 2018.-Anxiety disorders are chronic, highly prevalent conditions, often comorbid with depression. Both anxiety and depression form major risk factors for suicide. Living at altitude is associated with higher rates of depression and suicide, leading us to address whether anxiety disorders may also be amplified at altitude. Using a novel translational animal model, we previously showed that depression-like behavior increases with altitude of housing in female, but not male rats. We now use this model to examine the effects of altitude on both anxiety-like behavior and anhedonia, a core symptom of depression. After housing for a week at sea level, 4500 or 10,000 ft, rats were evaluated for anxiety in the open-field test or the elevated plus maze, and anhedonia in the sucrose preference test. Another group was tested at baseline. Anxiety-like behavior increased in females housed at altitude. In females, lower sucrose preference was seen in those housed at 10,000 ft versus those at sea level. Males showed no change in anxiety or anhedonia across groups. These data suggest that living at moderate-high altitude may pose a risk factor for those vulnerable to anxiety disorders, with the potential to be particularly detrimental to females at altitude.

LEARNING OBJECTIVES After participating in this activity, learners should be better able to:• Assess epidemiologic evidence that increased altitude of residence is linked to increased risk of depression and suicide• Evaluate strategies to address hypoxia-related depression and suicidal ideation ABSTRACT: Suicide and major depressive disorder (MDD) are complex conditions that almost certainly arise from the influences of many interrelated factors. There are significant regional variations in the rates of MDD and suicide in the United States, suggesting that sociodemographic and environmental conditions contribute. Here, we review epidemiological evidence that increases in the altitude of residence are linked to the increased risk of depression and suicide. We consider the possibility that chronic hypobaric hypoxia (low blood oxygen related to low atmospheric pressure) contributes to suicide and depression, which is suggested by animal models, short-term studies in humans, and the effects of hypoxic medical conditions on suicide and depression. We argue that hypobaric hypoxia could promote suicide and depression by altering serotonin metabolism and brain bioenergetics; both of these pathways are implicated in depression, and both are affected by hypoxia. Finally, we briefly examine treatment strategies to address hypoxia-related depression and suicidal ideation that are suggested by these findings, including creatine monohydrate and the serotonin precursors tryptophan and 5-hydroxytryptophan.

The focus of this review is to provide a synthesis of the current literature on the role of brain choline, as measured by proton magnetic resonance spectroscopy (1H-MRS), in major depressive disorder (MDD). The most recent 1H-MRS literature review took place over 10 years ago and, reflecting the high level of research on this topic, much has been learned since then. Higher brain choline levels have been linked to an increase in depression, and a cholinergic model for MDD development has been postulated. However, current 1H-MRS studies have been inconclusive regarding the role of choline in depression. Data from eighty-six peer-reviewed studies were analyzed for a random-effects model meta-analysis. Two significant findings are reported. Papers that did not report segmentation had a significant, moderate effect size. Higher choline concentrations in the frontal lobe were found in depressed patients, both in those who responded to treatment and those who did not, after treatment with psychiatric medication, repetitive transcranial magnetic stimulation, or electroconvulsive therapy. Findings from this review may add to existing information regarding the role of brain choline in MDD. This may provide a future target for treatment and drug development. It also may serve as a biomarker for treatment progress.

Background Although cognitive deficits in bipolar disorder (BD) have been repeatedly observed, our understanding of these impairments at a mechanistic level remains limited. Few studies that investigated cognitive impairments in bipolar illness have examined the association with brain biochemistry. This pilot study utilized proton magnetic resonance spectroscopy (1H-MRS) to evaluate the relationship between neurocognitive performance and brain metabolites in youth with BD. Methods Thirty participants, twenty depressed BD participants and ten healthy comparison participants, ages 13–21, completed mood and executive function measures. 1H-MRS data were also acquired from the anterior cingulate cortex (ACC) using two-dimensional (2D) J-resolved 1H-MRS sequence. Proton metabolites including N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) were quantified for both groups. Results Participants with BD performed significantly lower on executive functioning measures than comparison participants. There were significant positive correlations between Wisconsin Card Sorting Test (WCST) performance and NAA (p Limitations Small sample size and lack of control for medications. Conclusions These findings build on previous observations of biochemical alterations associated with BD and indicate that executive functioning deficits in bipolar youth are correlated with NAA and GABA. These results suggest that cognitive deficits occur early in the course of illness and may reflect risk factors associated with altered neurochemistry. Further investigation of the relationship between brain metabolites and cognition in BD may lead to important information for developing novel, targeted interventions.