Alcohol use disorder (AUD) has been shown to have harmful cognitive and physiological effects, including altered brain chemistry. Further, although men and women may differ in vulnerability to the neurobiological effects of AUD, the results of existing studies have been conflicting. We examined brain metabolite levels and cognitive functions in a cross-section of men with AUD (AUDm) and women with AUD (AUDw) to determine the degree of abnormalities after extended periods of abstinence (mean, 6 years) and to evaluate gender differences in neuropsychological and metabolite measures. Participants were 40 abstinent individuals with AUD (22 AUDw, 18 AUDm) and 50 age-equivalent non-AUD comparison participants (26 NCw, 24 NCm). Proton magnetic resonance spectroscopy (MRS) was employed at 3 Tesla to acquire metabolite spectra from the dorsal anterior cingulate cortex (dACC). Brain metabolites N-acetyl aspartate (NAA), choline (Cho), myo-Inositol (mI), and glutamate & glutamine (Glx) were examined relative to measures of memory and inhibitory control. Metabolite levels did not differ significantly between AUD and NC groups. Memory and inhibitory-control impairments were observed in the AUD group. There also were significant group-specific associations between metabolite ratios and measures of inhibitory control. There were no group-by-gender interactions for the four metabolite ratios. These findings demonstrate that brain metabolite levels in men and women with AUD, following long-term abstinence, do not differ from individuals without AUD. The data also provide preliminary evidence of sustained associations between metabolite levels and measures of inhibitory control, a functional domain important for curtailing harmful drinking.

Aim There is increasing concern that cannabinoid exposure during adolescence may disturb brain maturation and produce long-term cognitive deficits. However, studies in human subjects have provided limited evidence for such causality. The present study utilized behavioral and neuroimaging endpoints in female non-human primates to examine the effects of acute and chronic exposure during adolescence to the cannabinoid receptor full agonist, AM2389, on cognitive processing and brain function and chemistry. Materials and methods Adolescent female rhesus macaques were trained on a titrating-delay matching-to-sample (TDMTS) touchscreen task that assays working memory. TDMTS performance was assessed before and during chronic exposure to AM2389, following antagonist (rimonabant) administration, and after discontinuation of the chronic regimen. Resting-state fMRI connectivity and magnetic resonance spectroscopy data were acquired prior to drug treatment, during chronic exposure, and following its discontinuation. Voxels were placed in the medial orbitofrontal cortex (mOFC), a region involved in memory processing that undergoes maturation during adolescence. Results TDMTS performance was dose-dependently disrupted by acute AM2389; however, chronic treatment resulted in tolerance to these effects. TDMTS performance also was disrupted by discontinuation of the chronic regimen but surprisingly, not by rimonabant administration during chronic AM2389 treatment. mOFC N-acetylaspartate/creatine ratio decreased after acute and chronic administration but returned to baseline values following discontinuation of chronic treatment. Finally, intra-network functional connectivity (mOFC) increased during the chronic regimen and returned to baseline values following its discontinuation. Conclusion Neural effects of a cannabinergic drug may persist during chronic exposure, notwithstanding the development of tolerance to behavioral effects. However, such effects dissipate upon discontinuation, reflecting the restorative capacity of affected brain processes.

Gamma-aminobutyric acid (GABA) metabolism is implicated in posttraumatic stress disorder (PTSD) and may be altered in prefrontal-limbic brain regions involved in arousal regulation. This study used proton magnetic resonance spectroscopy (MRS) to test the hypothesis that PTSD and trauma-exposed non-PTSD comparison (TENC) adults have significantly different GABA than healthy comparison (HC) subjects in two brain areas implicated in arousal (medial prefrontal cortex, insula) but not in a control brain area (posterior temporal cortex). We also examined whether GABA alterations correlated with hyperarousal and dissociation symptoms. One hundred and fourteen participants (39 PTSD, 34 TENC, 41 HC) underwent 3T MRS of the medial prefrontal, right insular, and right posterior temporal cortices, and the GABA plus macromolecule signal (GABA+) was normalized to creatine (Cr). The Clinician Administered PTSD Scale measured hyperarousal symptoms, including sleep disruption. The Dissociative Experiences Scale assessed dissociation symptoms. PTSD and TENC participants had significantly lower mPFC GABA+/Cr than HC participants, and this deficit was significantly correlated with greater dissociation. Compared with HC, PTSD patients but not TENC had significantly lower insula GABA+/Cr. Total hyperarousal symptoms and sleep disruption were not significantly associated with GABA+/Cr alterations in either region. Our findings point to lower GABA in cortical areas implicated in arousal regulation in PTSD and suggest that GABA alterations are associated with symptoms of trauma-related psychopathology but not always a biomarker of diagnosis. These findings also add to evidence that dissociation has distinct neural correlates within PTSD, including high excitability of medial prefrontal cortex.

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.

Background: Both Major Depressive Disorder (MDD) and Primary Insomnia (PI) have been linked to de ficiencies in cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) thus suggesting a shared neurobiological link be- tween these two conditions. The extent to which comorbid insomnia contributes to GABAergic or glutamatergic de ficiencies in MDD remains unclear. Methods: We used single-voxel proton magnetic resonance spectroscopy ( 1 H MRS) at 4 Tesla to examine GABA+ and Glu relative to creatine (Cr) in the dorsal anterior cingulate cortex (dACC) and in the parieto-occipital cortex (POC) of 51 non -medicated adults with MDD, 24 adults with Primary Insomnia (PI), and 25 age- and sex - matched good sleeper controls (HC). Measures of depression severity and subjective and objective sleep quality were compared with 1 H MRS metabolite measures. Results: MDD subjects exhibited a 15% decrease in Glu/Cr in the dACC compared to HC. Within the MDD group, there was a trend inverse correlation between dACC Glu/Cr and anhedonia ratings. We observed no signi ficant association between measures of sleep quality with dACC Glu/Cr in those with MDD. Limitations: The protocol and data interpretation would have been enhanced by the recruitment of MDD subjects with a broader range of a ffect severity and a more comprehensive assessment of clinical features. Conclusions: These findings support the role of cortical glutamatergic mechanisms in the pathophysiology of MDD. Insomnia severity did not further contribute to the relative de ficiency of glutamatergic measures in MDD.

ABSTRACT Stress is a major risk factor for the development of mental illness, including major depressive disorder (MDD), yet the underlying biological mechanisms remain unclear. Particular challenges lie in disentangling adaptive versus maladaptive responses to repeated stress exposure. Preclinically, stress-induced changes in glutamatergic function have been frequently observed in the medial prefrontal cortex (mPFC), a key region for mediating adaptive stress responses. Here, we examined stress-induced changes in mPFC glutamate using magnetic resonance spectroscopy (MRS) in four human samples varying in perceived stress exposure. Changes in mPFC glutamate following an acute stressor were reliably moderated by recent perceived stress in healthy controls. This adaptive glutamate response was absent in unmedicated individuals with MDD and was associated with excessively pessimistic beliefs as assessed via ecological momentary assessments over a 1-month follow-up period. Taken together, these data provide novel evidence for glutamatergic adaptation to stress in mPFC that is significantly disrupted in MDD.

The increased burden of rare copy number variants (CNVs) in neuropsychiatric disorders is well established but linking mutations in specific genes to underlying disease biology and targeted treatment is challenging. Here we describe 1) the molecular genetic architecture of a complex genomic rearrangement that includes the glycine decarboxylase (GLDC) gene, implicating NMDAR-receptor hypofunction in two individuals with different psychotic disorders, 2) the results of placebo-controlled augmentation trials that targeted the reduced glycine and D-serine levels predicted to result from the GLDC mutation, and 3) efforts to characterize the effect of this mutation on glycine metabolism in the brain using magnetic resonance spectroscopy (MRS).

Major Depressive Disorder (MDD) is a debilitating disorder that interferes with successful daily life and functioning, particularly in women, who have a greater prevalence of MDD compared to men. Gamma-amino butyric acid (GABA), the main inhibitory neurotransmitter in brain has been implicated in the pathophysiology of mood disorders. As prior studies have documented GABAergic alterations associated with MDD, the objective of this study was to investigate brain chemistry, using magnetic resonance spectroscopy (MRS), in women across a clinical spectrum of MDD.

OBJECTIVE:This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate (Glu), glutamine (Gln), and N-acetyl aspartate (NAA), in older age bipolar depression (OABD) to that of psychiatrically healthy comparison subjects using proton (1H) magnetic resonance spectroscopy imaging at 4-Tesla. Metabolite levels were assessed in OABD subjects before and after 8 weeks of lamotrigine therapy with the goal of determining relationships between cerebral energy metabolism, depression symptom severity, and changes in depression symptom response. METHODS:Individuals (n = 21, mean age: 62.0 ± 5.9 years) with bipolar disorder, current episode depressed, and a healthy comparison group (n = 14, mean age: 67.5 ± 8.8 years) were selected. Participants with bipolar disorder, current episode depressed, were treated in open label fashion with lamotrigine monotherapy for 8 weeks. All subjects were scanned with 1H magnetic resonance spectroscopy at 4T at baseline and again after 8 weeks to assess levels of cerebral metabolites in the anterior cingulate cortex and parieto-occipital cortex. Metabolite levels were examined as ratios relative to creatine (Cr). Response to 8 weeks of lamotrigine treatment in the bipolar disorder, current episode depressed group, was assessed as a continuous measure on the Montgomery-Asberg Depression Rating Scale. RESULTS:NAA/Cr ratio in OABD was significantly lower by 14% (95% confidence interval: [1%, 26%]) than in comparison subjects at baseline. However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment. CONCLUSION:Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD.

Functional magnetic resonance imaging (fMRI) studies indicate that the emotional and cognitive symptoms of depression may be linked to aberrant resting-state functional connectivity (rsFC). However, much remains unknown about how abnormalities in higher frequency connectivity contribute to these disturbances. Furthermore, while concurrent evidence suggests glutamatergic abnormalities in the rostral anterior cingulate (rACC) may be implicated in depression and may contribute to disrupted rsFC, no study has examined whether these disturbances are linked in depressed populations.

Objective: The Vagal-Gamma-Aminobutyric Acid (GABA) theory proposes that some yoga postures and breathing practices exert their effects through stimulation of vagal nerves (parasympathetic system) with associated brain GABA increases. To evaluate this theory, we compared results from a 12-week randomized controlled trial (RCT) of yoga in participants with Major Depressive Disorder (MDD) with those of a similar RCT in healthy control participants (HC). Methods: In an RCT, magnetic resonance spectroscopy (MRS) and mood measures were acquired in subjects with MDD (n=15) prior to and following a 12-week yoga intervention. The same measures were obtained in the HC (n=17) group. In both studies, thalamic GABA/Creatine was obtained using MEGAPRESS at 4 Telsa at baseline (Scan-1), post-intervention (Scan-2), and immediately following a yoga session (Scan-3). Clinical scales were completed prior to each scan. Results: The MDD-group had significantly lower GABA compared to the HC at baseline (Scan-1, p=0.001), but not after 12 weeks of yoga, either before (Scan-2, p=0.12) or after a yoga session (Scan-3, p=0.20). Depressive symptoms decreased significantly in the MDD-group (p=0.0001), and anxiety improved in both groups. Conclusion: After a 12-week yoga intervention, MDD-group mood and anxiety measures improved with scores equivalent to those of non-depressed individuals. This study provides the first evidence of brain GABA increases associated with specific yoga postures and breathing practices in MDD. These results suggest potential benefits of specific yoga postures and breathing practices as monotherapy or augmentation to other treatments to reduce anxiety and depression in MDD.

Hippocampus atrophy is implicated in posttraumatic stress disorder (PTSD), and may partly reflect stress-induced glutamate excitotoxicity that culminates in neuron injury and manifests as re-experiencing symptoms and other memory abnormalities. This study used high-field proton magnetic resonance spectroscopy (MRS) to determine whether PTSD is associated with lower hippocampus levels of the neuron marker N-acetyl aspartate (NAA), along with higher levels of glutamate (Glu) and Glu/NAA. We also predicted that metabolite levels would correlate with re-experiencing symptoms and lifetime trauma load. Twenty-four adult PTSD patients and 23 trauma-exposed normal controls (TENC) underwent 4T MRS of the left and right hippocampus. Participants received psychiatric interviews, and completed the Traumatic Life Events Questionnaire to define lifetime trauma load. Relative to TENC participants, PTSD patients exhibited significantly lower NAA in right and left hippocampi, and significantly higher Glu and Glu/NAA in the right hippocampus. Re-experiencing symptoms were negatively correlated with left and right NAA, and positively correlated with right Glu and right Glu/NAA. Trauma load was positively correlated with right Glu/NAA in PTSD patients. When re-experiencing symptoms and trauma load were examined together in relation to right Glu/NAA, only re-experiencing symptoms remained a significant correlate. This represents the first report that PTSD is associated with MRS markers of hippocampus Glu excess, together with indices of compromised neuron integrity. Their robust associations with re-experiencing symptoms affirm that MRS indices of hippocampus neuron integrity and glutamate metabolism may reflect biomarkers of clinically significant disease variation in PTSD.

BACKGROUND: Accumulating evidence suggests the involvement of abnormal glutamateric neurotransmission and N-methyl-D-aspartate receptor hypofunction in the pathophysiology of psychotic disorders. The purpose of this study was to quantify in vivo glutamate (Glu) and glycine (Gly) levels in patients with first-episode psychosis as well as age-matched healthy control subjects with magnetic resonance spectroscopy (MRS). METHODS: The subjects were 46 patients with first-episode psychosis (20 with a schizophrenia spectrum disorder, 26 with bipolar disorder) and 50 age-matched healthy control subjects. Glu and Gly levels were measured in vivo in the anterior cingulate cortex and posterior cingulate cortex of the subjects by using the echo time-averaged proton MRS technique at 4T (i.e., modified point resolved spectroscopy sequence: 24 echo time steps with 20-ms increments). Metabolite levels were quantified using LCModel with simulated basis sets. RESULTS: Significantly higher Glu and Gly levels were found in both the anterior cingulate cortex and posterior cingulate cortex of patients with first-episode psychosis as compared with healthy control subjects. Glu and Gly levels were positively correlated in patients. Patients with a schizophrenia spectrum disorder and bipolar disorder showed similar abnormalities. CONCLUSIONS: Our findings demonstrate abnormally elevated brain Glu and Gly levels in patients with first-episode psychosis by means of echo time-averaged proton MRS at 4T. The findings implicate dysfunction of N-methyl-D-aspartate receptor and glutamatergic neurotransmission in the pathophysiology of the acute early phase of psychotic illnesses.

Little is known about the acute effects of antidepressant treatments on brain glutamate and gamma-amino-butyric acid (GABA) levels, and their association with clinical response. Using proton magnetic resonance spectroscopy (1H-MRS) we examined longitudinally the effects of citalopram on glutamine/glutamate ratios and GABA levels in the pregenual anterior cingulate cortex (pgACC) of individuals with major depressive disorder (MDD). We acquired 1H-MRS scans at baseline and at days 3, 7, and 42 of citalopram treatment in nineteen unmedicated individuals with MDD. Ten age- and sex-matched non-depressed comparison individuals were scanned once. The association between 1) baseline metabolites and 2) change in metabolites from baseline to each time point and clinical response (change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 42) was assessed by longitudinal regression analysis using generalized estimating equations. Contrary to our hypotheses, no significant associations emerged between glutamate metabolites and clinical response; however, greater increases (or smaller decreases) in pgACC GABA levels from baseline to days 3 and 7 of citalopram treatment were significantly associated with clinical response. These findings suggest that an acute change in GABA levels in pgACC predicts, and possibly mediates, later clinical response to citalopram treatment in individuals with MDD.

Objectives: The aims of this study were to assess the effects of an intervention of Iyengar yoga and coherent breathing at five breaths per minute on depressive symptoms and to determine optimal intervention yoga dosing for future studies in individuals with major depressive disorder (MDD). Methods: Subjects were randomized to the high-dose group (HDG) or low-dose group (LDG) for a 12-week intervention of three or two intervention classes per week, respectively. Eligible subjects were 18-64 years old with MDD, had baseline Beck Depression Inventory-II (BDI-II) scores ≥14, and were either on no antidepressant medications or on a stable dose of antidepressants for ≥3 months. The intervention included 90-min classes plus homework. Outcome measures were BDI-II scores and intervention compliance. Results: Fifteen HDG (Mage=38.4±15.1 years) and 15 LDG (Mage=34.7±10.4 years) subjects completed the intervention. BDI-II scores at screening and compliance did not differ between groups (p=0.26). BDI-II scores declined significantly from screening (24.6±1.7) to week 12 (6.0±3.8) for the HDG (-18.6±6.6; p < 0.001), and from screening (27.7±2.1) to week 12 (10.1±7.9) in the LDG (-17.7±9.3; p < 0.001). There were no significant differences between groups, based on response (i.e., >50% decrease in BDI-II scores; p=0.65) for the HDG (13/15 subjects) and LDG (11/15 subjects) or remission (i.e., number of subjects with BDI-II scores <14; p=1.00) for the HDG (14/15 subjects) and LDG (13/15 subjects) after the 12-week intervention, although a greater number of subjects in the HDG had 12-week BDI-II scores ≤10 (p=0.04). Conclusion: During this 12-week intervention of yoga plus coherent breathing, depressive symptoms declined significantly in patients with MDD in both the HDG and LDG. Both groups showed comparable compliance and clinical improvements, with more subjects in the HDG exhibiting BDI-II scores ≤10 at week 12.

Glutamate is the prime excitatory neurotransmitter in the mammalian brain and has been implicated in a wide range of psychiatric conditions. To improve the applicability and clinical reach of magnetic resonance spectroscopy (MRS), research is needed to develop shortened, yet reliable, MRS scanning procedures for standard 1.5–3‐T clinical magnetic resonance imaging (MRI) systems, particularly with young or vulnerable populations unable to tolerate longer protocols. To this end, we evaluated the test–retest reliability of a shortened J‐resolved MRS sequence in healthy adolescents (n = 22) aged 12–14 years. Participants underwent a series of sequential 6‐min MRS scans, with the participants remaining in situ between successive scans. Glutamate and other metabolites were acquired from the rostral anterior cingulate cortex, as glutamatergic function in this region has been implicated in a number of psychiatric illnesses. Thirteen neurochemicals were quantified as ratios to total creatine, and reliability scores were expressed as the percentage difference between the two scans for each metabolite. Test–retest assessment of glutamate was reliable, as scores were less than 10% different (7.1 ± 4.2%), and glutamate values across scans were significantly correlated (Pearson r = 0.680, p < 10−4). Several other neurochemicals demonstrated satisfactory reliability, including choline (Cho) (7.4 ± 5.6%), glutathione (GSH) (8.6 ± 4.1%), myo‐inositol (mI) (6.5 ± 7.1%) and N‐acetylaspartate (NAA) (3.5 ± 3.6%), with test–retest correlations ranging from 0.747 to 0.953. A number of metabolites, however, did not demonstrate acceptable test–retest reliability using the current J‐resolved MRS sequence, ranging from 13.8 ± 13.7% (aspartate, Asp) to 45.9 ± 38.3% (glycine, Gly). Collectively, test–retest analyses suggest that clinically viable quantitative data can be obtained on standard MRI systems for glutamate, as well as the other metabolites, during short scan times in a traditionally challenging brain region.