The influence of season on glutamate and GABA levels in the healthy human brain investigated by magnetic resonance spectroscopy imaging.

Seasonal changes in neurotransmitter systems have been demonstrated in imaging studies and are especially noticeable in diseased states such as seasonal affective disorder (SAD). These modulatory neurotransmitters, such as serotonin, are influencing glutamatergic and GABAergic neurotransmission. Furthermore, central components of the circadian pacemaker are regulated by GABA (the suprachiasmatic nucleus) or glutamate (e.g., the retinohypothalamic tract). Therefore, we explored seasonal differences in the GABAergic and glutamatergic system in 159 healthy individuals using magnetic resonance spectroscopy imaging with a GABA-edited 3D-MEGA-LASER sequence at 3T. We quantified GABA+/tCr, GABA+/Glx, and Glx/tCr ratios (GABA+, GABA+ macromolecules; Glx, glutamate + glutamine; tCr, total creatine) in five different subcortical brain regions. Differences between time periods throughout the year, seasonal patterns, and stationarity were tested using ANCOVA models, curve fitting approaches, and unit root and stationarity tests, respectively. Finally, Spearman correlation analyses between neurotransmitter ratios within each brain region and cumulated daylight and global radiation were performed. No seasonal or monthly differences, seasonal patterns, nor significant correlations could be shown in any region or ratio. Unit root and stationarity tests showed stable patterns of GABA+/tCr, GABA+/Glx, and Glx/tCr levels throughout the year, except for hippocampal Glx/tCr. Our results indicate that neurotransmitter levels of glutamate and GABA in healthy individuals are stable throughout the year. Hence, despite the important correction for age and gender in the analyses of MRS derived GABA and glutamate, a correction for seasonality in future studies does not seem necessary. Future investigations in SAD and other psychiatric patients will be of high interest.

Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort.

Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals. Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, undergoing GHT, and 15 age-matched cisgender women (CW), receiving no therapy, underwent MRSI before and after at least 12 weeks. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (combination of GABA and macromolecules) and Glx (combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus). Linear mixed models analysis revealed a significant measurement by gender identity effect (pcorr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (pcorr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men. Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies. DATA AVAILABILITY STATEMENT: Due to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger@meduniwien.ac.at with any questions or requests.

Escitalopram administration, relearning, and neuroplastic effects: A diffusion tensor imaging study in healthy individuals.

BACKGROUND: Neuroplastic processes are influenced by serotonergic agents, which reportedly alter white matter microstructure in humans in conjunction with learning. The goal of this double-blind, placebo-controlled imaging study was to investigate the neuroplastic properties of escitalopram and cognitive training on white matter plasticity during (re)learning as a model for antidepressant treatment and environmental factors. METHODS: Seventy-one healthy individuals (age=25.6 ± 5.0, 43 females) underwent three diffusion magnetic resonance imaging scans: at baseline, after 3 weeks of associative learning (emotional/non-emotional content), and after relearning shuffled associations for an additional 3 weeks. During the relearning phase, participants received a daily dose of 10 mg escitalopram or placebo orally. Fractional anisotropy (FA), and mean (MD), axial (AD), and radial diffusivity (RD) were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. RESULTS: In a three-way repeated-measures marginal model with sandwich estimator standard errors, we found no significant effects of escitalopram and content on AD, FA, MD, and RD during both learning and relearning periods (pFDR>0.05). When testing for escitalopram or content effects separately, we also demonstrated no significant findings (pFDR>0.05) for any of the diffusion tensor imaging metrics. LIMITATIONS: The intensity of the study interventions might have been too brief to induce detectable white matter changes. DISCUSSION: Previous studies examining the effects of SSRIs on white matter tracts in humans have yielded inconclusive outcomes. Our results indicate that relearning under escitalopram does not affect the white matter microstructures in healthy individuals when administered for 3 weeks.

Neuroplastic effects of a selective serotonin reuptake inhibitor in relearning and retrieval.

Animal studies using selective serotonin reuptake inhibitors (SSRIs) and learning paradigms have demonstrated that serotonin is important for flexibility in executive functions and learning. SSRIs might facilitate relearning through neuroplastic processes and thus exert their clinical effects in psychiatric diseases where cognitive functioning is affected. However, translation of these mechanisms to humans is missing. In this randomized placebo-controlled trial, we assessed functional brain activation during learning and memory retrieval in healthy volunteers performing associative learning tasks aiming to translate facilitated relearning by SSRIs. To this extent, seventy-six participants underwent three MRI scanning sessions: (1) at baseline, (2) after three weeks of daily associative learning and subsequent retrieval (face-matching or Chinese character-noun matching) and (3) after three weeks of relearning under escitalopram (10 mg/day) or placebo. Associative learning and retrieval tasks were performed during each functional MRI (fMRI) session. Statistical modeling was done using a repeated-measures ANOVA, to test for content-by-treatment-by-time interaction effects. During the learning task, a significant substance-by-time interaction was found in the right insula showing a greater deactivation in the SSRI cohort after 21 days of relearning compared to the learning phase. In the retrieval task, there was a significant content-by-time interaction in the left angular gyrus (AG) with an increased activation in face-matching compared to Chinese-character matching for both learning and relearning phases. A further substance-by-time interaction was found in task performance after 21 days of relearning, indicating a greater decrease of performance in the placebo group. Our findings that escitalopram modulate insula activation demonstrates successful translation of relearning as a mechanism of SSRIs in human. Furthermore, we show that the left AG is an active component of correct memory retrieval, which coincides with previous literature. We extend the function of this region by demonstrating its activation is not only stimulus dependent but also time constrained. Finally, we were able to show that escitalopram aids in relearning, irrespective of content.

The Influence of Acute SSRI Administration on White Matter Microstructure in Patients Suffering From Major Depressive Disorder and Healthy Controls.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are predominantly prescribed for people suffering from major depressive disorder. These antidepressants exert their effects by blocking the serotonin transporter (SERT), leading to increased levels of serotonin in the synaptic cleft and subsequently to an attenuation of depressive symptoms and elevation in mood. Although long-term studies investigating white matter (WM) alterations after exposure to antidepressant treatment exist, results on the acute effects on the brain's WM microstructure are lacking. METHODS: In this interventional longitudinal study, 81 participants were included (33 patients and 48 healthy controls). All participants underwent diffusion weighted imaging on 2 separate days, receiving either citalopram or placebo using a randomized, double-blind, cross-over design. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. RESULTS: The repeated-measures ANOVA model revealed significant decreases after SSRI administration in mean diffusivity, axial diffusivity, and radial diffusivity regardless of the group (P < .05, family-wise error [FWE] corrected). Results were predominantly evident in frontal WM regions comprising the anterior corona radiata, corpus callosum, and external capsule and in distinct areas of the frontal blade. No increases in diffusivity were found, and no changes in fractional anisotropy were present. CONCLUSIONS: Our investigation provides the first evidence, to our knowledge, that fast WM microstructure adaptations within 1 hour after i.v. SSRI administration precede elevations in mood due to SSRI treatment. These results add a new facet to the complex mode of action of antidepressant therapy. This study was registered at clinicaltrials.gov with the identifier NCT02711215.

The "sugar dilemma".

Type 2 diabetes mellitus is characterized by insulin resistance and elevated blood glucose levels. Treatment protocols generally include dietary restriction of sugar, as well as drugs aiming at a reduction of blood glucose, mainly by activating the insulin system or supplementing insulin. This established approach does not take into account the outstanding physiological role of glucose as a key molecule in metabolism. Glucose is crucial to meet the high energy demand of the brain, which depends on it as an exclusive nutrient. Insulin independent glucose transporters GLUT1 import glucose into the brain. Reduction of blood glucose, as in current treatment concepts, may lead to energy deficiency in the brain and consecutively to worsening of - possibly already impaired - neurocognitive function. Reduced cell membrane fluidity of the vascular endothelium of the bloodbrain-barrier (BBB) - due to malnutrition and/or aging - is considered a major factor in pathogenesis of the cerebral metabolic syndrome, which is a key step in neurodegeneration. Under this aspect we suggest a novel approach to prophylaxis and treatment focusing on a sufficient supply of glucose to the brain.