Evaluation of Prefrontal γ-Aminobutyric Acid and Glutamate Levels in Individuals With Major Depressive Disorder Using Proton Magnetic Resonance Spectroscopy.

Importance: Major depressive disorder (MDD) is one of the most prevalent illnesses worldwide. Perturbations of the major inhibitory and excitatory neurotransmitters, γ-aminobutyric acid (GABA) and glutamate (Glu), respectively, as well as Glx (Glu or glutamine [Gln]) have been extensively reported in a multitude of brain areas of individuals with depression, but few studies have examined changes in Gln, the metabolic counterpart of synaptic Glu. Objective: To investigate changes in GABA, Glx, Glu, and Gln levels in a voxel in the left dorsolateral prefrontal cortex of participants with no, past, and current MDD using proton magnetic resonance spectroscopy (1H-MRS). Design, Setting, and Participants: This community-based study used a cross-sectional design using 3-T 1H-MRS in participants not taking MDD medication recruited from the community. The sample consisted of 251 healthy controls, 98 participants with a history of past MDD, and 47 participants who met the diagnostic criteria for current MDD. Diagnostic groups were comparable regarding age, education, income, and diet. Data were collected from March 2014 to October 2021, and data were analyzed from October 2021 to June 2022. Main Outcomes and Measures: GABA, Glx, Glu, and Gln concentrations in the left dorsolateral prefrontal cortex. Results: Of 396 included participants, 258 (65.2%) were female, and the mean (SD) age was 25.0 (4.7) years. Compared with healthy controls, those with past MDD and current MDD had lower GABA concentrations (mean [SEM] concentration: healthy controls, 2.70 [0.03] mmol/L; past MDD, 2.49 [0.05] mmol/L; current MDD, 2.54 [0.07] mmol/L; 92 with past MDD vs 236 healthy controls: r = 0.18; P = .002; 44 with current MDD vs 236 healthy controls: r = 0.13; P = .04). Compared with healthy controls, those with past MDD also had lower Glu concentrations (mean [SEM] concentration: healthy controls, 7.52 [0.06] mmol/L; past MDD, 7.23 [0.11] mmol/L; 93 with past MDD vs 234 healthy controls: r = 0.16; P = .01) and higher Gln concentrations (mean [SEM] concentration: healthy controls, 1.63 [0.04] mmol/L; past MDD, 1.84 [0.07] mmol/L; 66 with past MDD 153 healthy controls: r = 0.17; P = .04). Conclusions and Relevance: In a large, mostly medication-free community sample, reduced prefrontal GABA concentrations were associated with past MDD, consistent with histopathologic studies reporting reduced glial cell and GABA cell density in the prefrontal cortex in individuals with depression. Patients with MDD also demonstrated increased Gln levels, indicative of increased synaptic Glu release, adding to previous evidence for the Glu hypothesis of MDD.

Associations between heart rate variability, peripheral inflammatory markers and major depressive disorder.

BACKGROUND: Measures for the irregularity of the heartbeat, for example respiratory sinus arrhythmia, have been implicated as a measure for restorative functions of the vegetative nervous system. METHODS: In the current observational study, we investigated 265 subjects, 70 of whom had a lifetime history of major depression, with a plethysmographic heartbeat monitor, blood sampling, as well as a range of psychiatric questionnaires. RESULTS: Subjects with a history of MDE had significantly reduced respiratory sinus arrhythmia (RSA) as compared to never-depressed controls; in the whole sample, higher RSA went with lower anxiety/fear variables, especially in subscores related to cardiac symptoms as well as being afraid of dying. A reduced RSA was also associated with an increased concentration of cytokines (TNFa, IL1a, IL6, IFNg) and thyroid-stimulating hormone in the serum, pointing to a possible triangular relationship between immune system, vegetative nervous system, and emotional dysregulation. LIMITATIONS: We used a plethysmographic device for the measurement of heartbeat instead of an electrocardiogram, and had a single time point only. CONCLUSIONS: This data corroborate the idea that a disequilibrium of the vegetative nervous, especially if accompanied by a dysregulation system in immune function, can increase the risk for depression. Conversely, vagal stimulation and anti-inflammatory treatments may support the treatment with antidepressants.

Cerebral perfusion in depression: Relationship to sex, dehydroepiandrosterone sulfate and depression severity.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disease burden and shows a marked sexual dimorphism. Previous studies reported changes in cerebral perfusion in MDD, an association between perfusion and dehydroepiandrosterone sulfate (DHEAS) levels, and large sex differences in perfusion. This study examines whether perfusion and DHEAS might mediate the link between sex and depressive symptoms in a large, unmedicated community sample. METHODS: The sample included 203 healthy volunteers and 79 individuals with past or current MDD. Depression severity was assessed with the Hamilton Depression Scale (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS). 3 T MRI perfusion data were collected with a pseudocontinuous arterial spin labelling sequence and DHEAS was measured in serum by LC-MS/MS. RESULTS: Large sex differences in perfusion were observed (p < 0.001). Perfusion was negatively correlated with DHEAS (r = -0.23, p < 0.01, n = 250) and with depression severity (HAM-D: r = -0.17, p = 0.01, n = 242; partial Spearman correlation, controlling for age and sex), but not with anxiety. A significant sex*perfusion interaction on depression severity was observed. In women, perfusion showed more pronounced negative correlations with depressive symptoms, with absent or, in the case of the MADRS, opposite effects observed in men. A mediation analysis identified DHEAS and perfusion as mediating variables influencing the link between sex and the HAM-D score. CONCLUSION: Perfusion was linked to depression severity, with the strongest effects observed in women. Perfusion and the neurosteroid DHEAS appear to mediate the link between sex and HAM-D scores, suggesting that inter-individual differences in perfusion and DHEAS levels may contribute to the sexual dimorphism in depression.

Negative association between left prefrontal GABA concentration and BDNF serum concentration in young adults.

BACKGROUND: The brain's major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the brain-derived neurotrophic factor (BDNF) play important roles in several stress-related disorders. Magnetic resonance spectroscopy (MRS) allows for non-invasive quantification of GABA concentration in the brain. We investigated the relationship between GABA concentration in the left dorsolateral prefrontal cortex (DLPFC) and BDNF concentration in the serum in a community-based sample of young subjects. METHODS: For the GABA measurement a single voxel MR spectrum was assessed in the prefrontal lobe (25 × 40 × 30 mm) using the MEGA-PRESS method in 276 subjects. BDNF serum concentrations were assessed with an ELISA kit. For 147 subjects we had both MRS and BDNF serum data, and for 79 subjects we had genotype data on the BDNF rs6265 polymorphism. Depressive psychopathology was assessed using Beck's Depression Inventory (BDI), Montgomery-Asberg Depression Rating Scale (MADRS) and Structured Clinical Interviews for Diagnostic and Statistical Manual of Mental Disorders (SCID) for DSM-IV. RESULTS: GABA concentration in the left DLPFC was negatively associated with BDNF serum concentration (r = -.264, p = .001). This correlation remained significant if corrected for sex (r = -.264, p = .001). BDNF serum concentration was also positively associated with volumes and surface areas of the left prefrontal cortex (p = .048, p = .005). There were no significant associations or interaction with depressive psychopathology (BDI, MADRS, SCID) or rs6265. CONCLUSION: The results of this study suggest that GABA, BDNF and prefrontal brain volumes are interrelated, but do not show a strong association to depressive psychopathology, possibly due to the mild forms of psychiatric conditions present in our community-based sample.

Association between prefrontal glutamine levels and neuroticism determined using proton magnetic resonance spectroscopy.

There is growing evidence for GABA and glutamate-glutamine dysfunction in the pathogenesis of mood and anxiety disorders. It is important to study this pathology in the early phases of the illness in order to develop new approaches to secondary prevention. New magnetic resonance spectroscopy (MRS) measures allow determining glutamine, the principal metabolite of synaptic glutamate that is directly related to glutamate levels in the synaptic cleft, as well as glutamate and GABA. In contrast to previous investigations, this study used community-based recruitment methods and a combined categorical and dimensional approach to psychopathology. In the study protocol, neuroticism was defined as the primary outcome. Neuroticism shares a large proportion of its genetic variance with mood and anxiety disorders. We examined young adult participants recruited from the general population in a cross-sectional study using 3-T 1H-MRS with one voxel in the left dorsolateral prefrontal cortex (DLPFC). The total sample of N = 110 (61 females) included 18 individuals suffering from MDD and 19 individuals suffering from DSM-IV anxiety disorders. We found that glutamine and glutamine-to-glutamate ratio were correlated with neuroticism in the whole sample (r = 0.263, p = 0.005, and n = 110; respectively, r = 0.252, p = 0.008, and n = 110), even when controlling for depression and anxiety disorder diagnoses (for glutamine: beta = 0.220, p = 0.047, and n = 110). Glutamate and GABA were not significantly correlated with neuroticism (r = 0.087, p = 0.365, and n = 110; r = -0.044, p = 0.645, and n = 110). Lack of self-confidence and emotional instability were the clinical correlates of glutamate-glutamine dysfunction. In conclusion, this study suggests that prefrontal glutamine is increased in early phases of mood and anxiety disorders. Further understanding of glutamate-glutamine dysfunction in stress-related disorders may lead to new therapeutic strategies to prevent and treat these disorders.

Age-dependent and -independent changes in attention-deficit/hyperactivity disorder (ADHD) during spatial working memory performance.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) has been associated with spatial working memory as well as frontostriatal core deficits. However, it is still unclear how the link between these frontostriatal deficits and working memory function in ADHD differs in children and adults. This study examined spatial working memory in adults and children with ADHD, focussing on identifying regions demonstrating age-invariant or age-dependent abnormalities. METHODS: We used functional magnetic resonance imaging to examine a group of 26 children and 35 adults to study load manipulated spatial working memory in patients and controls. RESULTS: In comparison to healthy controls, patients demonstrated reduced positive parietal and frontostriatal load effects, i.e., less increase in brain activity from low to high load, despite similar task performance. In addition, younger patients showed negative load effects, i.e., a decrease in brain activity from low to high load, in medial prefrontal regions. Load effect differences between ADHD and controls that differed between age groups were found predominantly in prefrontal regions. Age-invariant load effect differences occurred predominantly in frontostriatal regions. CONCLUSIONS: The age-dependent deviations support the role of prefrontal maturation and compensation in ADHD, while the age-invariant alterations observed in frontostriatal regions provide further evidence that these regions reflect a core pathophysiology in ADHD.

Effects of Steroid Hormones on Sex Differences in Cerebral Perfusion.

Sex differences in the brain appear to play an important role in the prevalence and progression of various neuropsychiatric disorders, but to date little is known about the cerebral mechanisms underlying these differences. One widely reported finding is that women demonstrate higher cerebral perfusion than men, but the underlying cause of this difference in perfusion is not known. This study investigated the putative role of steroid hormones such as oestradiol, testosterone, and dehydroepiandrosterone sulphate (DHEAS) as underlying factors influencing cerebral perfusion. We acquired arterial spin labelling perfusion images of 36 healthy adult subjects (16 men, 20 women). Analyses on average whole brain perfusion levels included a multiple regression analysis to test for the relative impact of each hormone on the global perfusion. Additionally, voxel-based analyses were performed to investigate the sex difference in regional perfusion as well as the correlations between local perfusion and serum oestradiol, testosterone, and DHEAS concentrations. Our results replicated the known sex difference in perfusion, with women showing significantly higher global and regional perfusion. For the global perfusion, DHEAS was the only significant predictor amongst the steroid hormones, showing a strong negative correlation with cerebral perfusion. The voxel-based analyses revealed modest sex-dependent correlations between local perfusion and testosterone, in addition to a strong modulatory effect of DHEAS in cortical, subcortical, and cerebellar regions. We conclude that DHEAS in particular may play an important role as an underlying factor driving the difference in cerebral perfusion between men and women.

Subcortical glutamate mediates the reduction of short-range functional connectivity with age in a developmental cohort.

Marked changes in brain physiology and structure take place between childhood and adulthood, including changes in functional connectivity and changes in the balance between main excitatory and inhibitory neurotransmitters glutamate (Glu) and GABA. The balance of these neurotransmitters is thought to underlie neural activity in general and functional connectivity networks in particular, but so far no studies have investigated the relationship between human development related differences in these neurotransmitters and concomitant changes in functional connectivity. GABA+/H2O and Glu/H2O levels were acquired in a group of healthy children, adolescents, and adults in a subcortical (basal ganglia) region, as well as in a frontal region in adolescents and adults. Our results showed higher GABA+/Glu with age in both the subcortical and the frontal voxel, which were differentially associated with significantly lower Glu/H2O with age in the subcortical voxel and by significantly higher GABA+/H2O with age in the frontal voxel. Using a seed-to-voxel analysis, we were further able to show that functional connectivity between the putamen (seed) and other subcortical structures was lower with age. Lower subcortical Glu/H2O with age mediated the lower connectivity in the dorsal putamen. Based on these results, and the potential role of Glu in synaptic pruning, we suggest that lower Glu mediates a reduction of local connectivity during human development.