Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner.

Cognitive dysfunction and reactive microglia are hallmarks of traumatic brain injury (TBI), yet whether these cells contribute to cognitive deficits and secondary inflammatory pathology remains poorly understood. Here, we show that removal of microglia from the mouse brain has little effect on the outcome of TBI, but inducing the turnover of these cells through either pharmacologic or genetic approaches can yield a neuroprotective microglial phenotype that profoundly aids recovery. The beneficial effects of these repopulating microglia are critically dependent on interleukin-6 (IL-6) trans-signaling via the soluble IL-6 receptor (IL-6R) and robustly support adult neurogenesis, specifically by augmenting the survival of newborn neurons that directly support cognitive function. We conclude that microglia in the mammalian brain can be manipulated to adopt a neuroprotective and pro-regenerative phenotype that can aid repair and alleviate the cognitive deficits arising from brain injury.

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.

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.

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.

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.

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.

Selective Ablation of BDNF from Microglia Reveals Novel Roles in Self-Renewal and Hippocampal Neurogenesis.

Microglia, the resident immune cells of the CNS, have emerged as key regulators of neural precursor cell activity in the adult brain. However, the microglia-derived factors that mediate these effects remain largely unknown. In the present study, we investigated a role for microglial brain-derived neurotrophic factor (BDNF), a neurotrophic factor with well known effects on neuronal survival and plasticity. Surprisingly, we found that selective genetic ablation of BDNF from microglia increased the production of newborn neurons under both physiological and inflammatory conditions (e.g., LPS-induced infection and traumatic brain injury). Genetic ablation of BDNF from microglia otherwise also interfered with self-renewal/proliferation, reducing their overall density. In conclusion, we identify microglial BDNF as an important factor regulating microglia population dynamics and states, which in turn influences neurogenesis under both homeostatic and pathologic conditions.SIGNIFICANCE STATEMENT (1) Microglial BDNF contributes to self-renewal and density of microglia in the brain. (2) Selective ablation of BDNF in microglia stimulates neural precursor proliferation. (3) Loss of microglial BDNF augments working memory following traumatic brain injury. (4) Benefits of repopulating microglia on brain injury are not mediated via microglial BDNF.

Low-intensity ultrasound restores long-term potentiation and memory in senescent mice through pleiotropic mechanisms including NMDAR signaling.

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS+MB), by transiently opening the blood-brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUSonly), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.

New Trajectory of Clinical and Biomarker Changes in Sporadic Alzheimer's Disease.

Identifying dynamic changes in biomarkers and clinical profiles is essential for understanding the progression of Alzheimer's disease (AD). The relevant studies have primarily relied on patients with autosomal dominant AD; however, relevant studies in sporadic AD are poorly understood. Here, we analyzed longitudinal data from 665 participants (mean follow-up 4.90 ± 2.83 years). By aligning normal cognition (CN) baseline with a clinical diagnosis of mild cognitive impairment (MCI) or AD, we studied the progression of AD using a linear mixed model to estimate the clinical and biomarker changes from stable CN to MCI to AD. The results showed that the trajectory of hippocampal volume and fluorodeoxyglucose (FDG) was consistent with the clinical measures in that they did not follow a hypothetical sigmoid curve but rather showed a slow change in the initial stage and accelerated changes in the later stage from MCI conversion to AD. Dramatic hippocampal atrophy and the ADAS13 increase were, respectively, 2.5 and 1 years earlier than the MCI onset. Besides, cognitively normal people with elevated and normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG. These results reveal that pre-MCI to pre-AD may be a better time window for future clinical trial design.

The Development of a Team-Based, Hybrid Inter-university Graduate Certificate Program Focused on Maternal Child Health Professionals.

INTRODUCTION: Pregnancy, childbirth, and child well-being are identified by Healthy People 2030 as priority topics for improving the health of all Americans. New Mexico is the fifth largest state geographically with most of the state's 33 counties considered rural or frontier. Accessing health care services is challenging in this resource-poor environment. The need to provide maternal and child health (MCH) education in the state was the impetus for developing a graduate certificate in maternal and child public health. METHODS: The hybrid MCH graduate certificate engaged professionals in formal training that included a public health approach to addressing MCH issues in the state's diverse communities. Grant funds paid for the tuition, books and travel for students providing an opportunity to individuals who otherwise could not have pursued graduate education and professional development. RESULTS: Over a 4-year period, two cohorts were recruited, educated, and evaluated. The evaluations reflected an increase in competency knowledge scores for all students. DISCUSSION: This model of MCH education was successful at delivering public health graduate education to MCH practitioners and increasing their knowledge and skills. Listening to students and communities as to what their MCH public health needs are and responding with a flexible educational model provided individuals with information and tools that could be used to improve maternal and child health and reduce health disparities in rural, tribal, and underserved communities.

Compensatory post-diuretic renal sodium reabsorption is not a dominant mechanism of diuretic resistance in acute heart failure.

AIMS: In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. METHODS AND RESULTS: Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13-17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47). CONCLUSION: On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF.

Association Between Anterior Cingulate Cortex Neurochemical Profile and Clinical Remission After Electroconvulsive Treatment in Major Depressive Disorder: A Longitudinal 1H Magnetic Resonance Spectroscopy Study.

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 1H magnetic resonance spectroscopy (1H-MRS). METHOD: Using 1H-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-Åsberg 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 1H-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.

Role of EphA4 in Mediating Motor Neuron Death in MND.

Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation is involved in MND pathogenesis, and inhibition of EphA4 improves functional outcomes. However, the underlying mechanism of EphA4's function in MND is unclear. In this review, we first present results to demonstrate that EphA4 signalling acts directly on motor neurons to cause cell death. We then review the three most likely mechanisms underlying this effect.

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.

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

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

EphA4 Regulates Hippocampal Neural Precursor Proliferation in the Adult Mouse Brain by d-Serine Modulation of N-Methyl-d-Aspartate Receptor Signaling.

The hippocampal dentate gyrus (DG) is a major region of the adult rodent brain in which neurogenesis occurs throughout life. The EphA4 receptor, which regulates neurogenesis and boundary formation in the developing brain, is also expressed in the adult DG, but whether it regulates adult hippocampal neurogenesis is not known. Here, we show that, in the adult mouse brain, EphA4 inhibits hippocampal precursor cell proliferation but does not affect precursor differentiation or survival. Genetic deletion or pharmacological inhibition of EphA4 significantly increased hippocampal precursor proliferation in vivo and in vitro, by blocking EphA4 forward signaling. EphA4 was expressed by mature hippocampal DG neurons but not neural precursor cells, and an EphA4 antagonist, EphA4-Fc, did not activate clonal cultures of precursors until they were co-cultured with non-precursor cells, indicating an indirect effect of EphA4 on the regulation of precursor activity. Supplementation with d-serine blocked the increased precursor proliferation induced by EphA4 inhibition, whereas blocking the interaction between d-serine and N-methyl-d-aspartate receptors (NMDARs) promoted precursor activity, even at the clonal level. Collectively, these findings demonstrate that EphA4 indirectly regulates adult hippocampal precursor proliferation and thus plays a role in neurogenesis via d-serine-regulated NMDAR signaling.

Intraindividual changes in brain GABA, glutamate, and glutamine during monitored abstinence from alcohol in treatment-naive individuals with alcohol use disorder.

Proton magnetic resonance spectroscopy (1 H-MRS) studies have demonstrated abnormal levels of a variety of neurometabolites in treatment-seeking individuals with moderate-severe alcohol use disorder (AUD) following acute withdrawal. In contrast, few studies have investigated neurochemical changes across early abstinence in less severe, treatment-naïve AUD. The present study, which represents the primary report of a research grant from ABMRF/The Alcohol Research Fund, measured dorsal anterior cingulate cortex (dACC) GABA, glutamate, and glutamine levels in treatment-naïve AUD (n = 23) via three 1 H-MRS scans spaced across a planned week of abstinence from alcohol. In addition to AUD participants, 12 light drinkers completed two scans, separated by 48 hours, to ensure that results in AUD were not produced by between-scan differences other than abstinence from alcohol. 1 H-MRS spectra were acquired in dACC at each scan using 2D J-resolved point-resolved spectroscopy. Linear mixed modeling results demonstrated a significant increase in GABA, but not glutamate or glutamine (Ps = .237-.626), levels between scans 1 and 2 (+8.88%, .041), with no difference between scans 2 and 3 (+1.00%, .836), in AUD but not LD (F = 1.24, .290) participants. Exploratory regression analyses tentatively revealed a number of significant prospective associations between changes in glutamine levels and heavy drinking, craving, and withdrawal symptoms. Most notably, the present study demonstrated return from abnormally low to normal GABA levels in treatment-naïve AUD within 3 days of their last drink; the pattern of results was consistent with glutamate and glutamine disturbances being exclusive to relatively more severe AUD.

Reduced lateral orbitofrontal cortex volume and suicide behavior in youth with bipolar disorder.

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.

Brain Glutamate, GABA, and Glutamine Levels and Associations with Recent Drinking in Treatment-Naïve Individuals with Alcohol Use Disorder Versus Light Drinkers.

BACKGROUND: Proton magnetic resonance spectroscopy (1 H-MRS) studies have demonstrated abnormal levels of a variety of neurometabolites in inpatients/outpatients with alcohol use disorder (AUD) following acute alcohol withdrawal relative to healthy controls. In contrast, few studies have compared neurometabolite levels between less severe, treatment-naïve AUD individuals and light drinkers (LD) or related them to recent alcohol consumption. The present study compared neurometabolite levels between treatment-naïve AUD and LD individuals. METHODS: Twenty treatment-naïve individuals with AUD and 20 demographically matched LD completed an 1 H-MRS scan, approximately 2.5 days following their last reported drink. 1 H-MRS data were acquired in dorsal anterior cingulate (dACC) using a 2-dimensional J-resolved point-resolved spectroscopy sequence. dACC neurometabolite levels, with a focus on glutamate, glutamine, and GABA, were compared between AUD and LD participants. The associations between metabolite levels and recent drinking were explored. RESULTS: AUD participants had significantly lower concentrations of GABA (Cohen's d = 0.79, p = 0.017) and glutamine (Cohen's d = 1.12, p = 0.005), but not glutamate (Cohen's d = 0.05, p = 0.893), relative to LD. As previously reported, AUD participants' glutamate and N-acetylaspartate concentrations were inversely associated with their number of heavy drinking days. In contrast, neither number of drinking (mean p = 0.56) nor heavy drinking (mean p = 0.47) days were associated with metabolite concentrations in LD. CONCLUSIONS: The present study demonstrated significantly lower levels of prefrontal γ-aminobutyric acid and glutamine in treatment-naïve individuals with AUD relative to LD. Whether these findings reflect the neurotoxic consequence and/or neuroadaptive response of alcohol consumption versus a predrinking trait, and therefore a more durable neurochemical disturbance, awaits elucidation from longitudinal studies.

Cerebral bioenergetic differences measured by phosphorus-31 magnetic resonance spectroscopy between bipolar disorder and healthy subjects living in two different regions suggesting possible effects of altitude.

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, ß nucleoside triphosphate (ßNTP), 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 ßNTP/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 ßNTP/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.