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IntroductionDeuterium metabolic imaging (DMI) and quantitative exchange label turnover (QELT) are novel MR spectroscopy techniques for non-invasive imaging of human brain glucose and neurotransmitter metabolism with high clinical potential. Following oral or intravenous administration of non-ionizing [6,6’-2H2]-glucose, its uptake and synthesis of downstream metabolites can be mapped via direct or indirect detection of deuterium resonances using2H MRSI (DMI) and1H MRSI (QELT), respectively.The purpose of this study was to compare the dynamics of spatially resolved brain glucose metabolism, i.e., estimated concentration enrichment of deuterium labeled Glx (glutamate+glutamine) and Glc (glucose) acquired repeatedly in the same cohort of subjects using DMI at 7T and QELT at clinical 3T.MethodsFive volunteers (4m/1f) were scanned in repeated sessions for 60 min after overnight fasting and 0.8g/kg oral [6,6’-2H2]-glucose administration using time-resolved 3D2H FID-MRSI with elliptical phase encoding at 7T and 3D1H FID-MRSI with a non-Cartesian concentric ring trajectory readout at clinical 3T.ResultsOne hour after oral tracer administration regionally averaged deuterium labeled Glx4concentrations and the dynamics were not significantly different over all participants between 7T2H DMI and 3T1H QELT data for GM (1.29±0.15 vs. 1.38±0.26 mM, p=0.65 & 21±3 vs. 26±3 µM/min, p=0.22) and WM (1.10±0.13 vs. 0.91±0.24 mM, p=0.34 & 19±2 vs. 17±3 µM/min, p=0.48). Also, the observed time constants of dynamic Glc6data in GM (24±14 vs. 19±7 min, p=0.65) and WM (28±19 vs. 18±9 min, p=0.43) dominated regions showed no significant differences.Between individual2H and1H data points a weak to moderate negative correlation was observed for Glx4concentrations in GM (r=-0.52, p6data GM (r=- 0.61, pConclusionThis study demonstrates that indirect detection of deuterium labeled compounds using1H QELT MRSI at widely available clinical 3T without additional hardware is able to reproduce absolute concentration estimates of downstream glucose metabolites and the dynamics of glucose uptake compared to2H DMI data acquired at 7T. This suggests significant potential for widespread application in clinical settings especially in environments with limited access to ultra-high field scanners and dedicated RF hardware.

ObjectivesNon-invasive, affordable, and reliable mapping of brain glucose metabolism is of critical interest for clinical research and routine application as metabolic impairment is linked to numerous pathologies e.g., cancer, dementia and depression. A novel approach to map glucose metabolism non-invasively in the human brain and separate normal oxidative from pathologic anaerobic pathways has been presented recently on experimental MR scanners using direct or indirect detection of deuterium-labeled glucose and downstream metabolites such as glutamate, glutamine and lactate.The aim of this study was to demonstrate the feasibility to non-invasively detect deuterium labeled downstream glucose metabolites indirectly in the human brain via 3D proton (1H) MR spectroscopic imaging on a clinical 3T MR scanner without additional hardware.Materials and MethodsThis prospective, institutional review board approved study was performed in seven healthy volunteers (mean age, 31±4 years, 5 m/ 2 f) following written informed consent. After overnight fasting and oral deuterium-labeled glucose administration 3D metabolic maps were acquired every ∼4 min with ∼0.24 ml isotropic spatial resolution using real-time motion-, shim- and frequency-corrected echo-less 3D1H-MR Spectroscopic Imaging. Time courses were analyzed using linear regression and non-parametric statistical tests. Deuterium labeled glucose and downstream metabolites were detected indirectly via their respective signal decrease in dynamic1H MR spectra due to deuterium to proton exchange in the molecules.ResultsSixty-five minutes after deuterium-labeled glucose administration, glutamate+glutamine (Glx) signal intensities decreased in gray/white matter (GM,WM) by -15±2%,(p=0.02)/-14±3%,(p=0.02), respectively. Strong negative correlation between Glx and time was observed in GM/WM (r=-0.71ppp=0.02) steeper slopes, indicating faster metabolic activity in GM compared to WM. Other non-labeled metabolites showed no significant changes.ConclusionOur approach translates deuterium metabolic imaging to widely available clinical routine MR scanners without specialized hardware offering a safe, affordable, and versatile (other substances than glucose can be labeled) approach for non-invasive imaging of glucose and neurotransmitter metabolism in the human brain.

Impaired brain glucose metabolism characterizes most severe brain diseases. Recent studies have proposed deuterium (2H)-Magnetic Resonance Spectroscopic Imaging (MRSI) as a reliable, non-invasive, and safe method to quantify the human metabolism of 2H-labeled substrates such as glucose and their downstream metabolism (e.g., aerobic/anaerobic glucose utilization and neurotransmitter synthesis) and address the major drawbacks of positron emission tomography (PET) or carbon (13C)-MRS. Here, for the first time, we show an indirect dynamic proton (1H)-MRSI technique in humans, which overcomes four critical 2H-MRSI limitations. Our innovative approach provides higher sensitivity with improved spatial/temporal resolution and higher chemical specificity to differentiate glutamate (Glu4), glutamine (Gln4), and gamma-aminobutyric acid (GABA2) deuterated at specific molecular positions while allowing simultaneous mapping of both labeled and unlabeled metabolites without the need for specialized hardware. Our novel method demonstrated significant Glu4, Gln4, and GABA2 decreases, with 18% faster Glu4 reduction in the gray matter than white matter after ingestion of deuterated glucose. Thus, robustly detected downstream glucose metabolism utilizing clinically available MR hardware without the need for radioactive tracers and PET.

While the concept of sexual orientation is more clearly defined in cisgender, this is less so in transgender individuals. Both experienced gender and sex hormones have a relation to sexual preferences, arousal in response to erotic stimuli, and thus sexual orientation. In transgender individuals sexual orientation occasionally changes before or during transition, which may involve gender-affirming hormone therapy. Using functional magnetic resonance imaging, we investigated whether the neuronal and behavioral patterns of sexual arousal in transgender individuals moved from the given (before) to their chosen gender after 4.5 months of hormone therapy. To this aim, trans women and men as well as age-matched cisgender controls rated visual stimuli showing heterosexual, lesbian or gay intercourse for subjective sexual arousal. Utilizing a Bayesian framework allowed us to incorporate behavioral findings in cisgender individuals of different sexual orientations. The hypothesized changes in response patterns could indeed be observed in the behavioral responses to the single but not the differentiation between stimulus categories with the strongest results for trans men and lesbian scenes. Activation of the ventral striatum supported our hypothesis only for lesbian scenes in trans women. This prominent role of lesbian stimuli might be explained by their differential responses in cis women and men. We show that correlates of sexual arousal in transgender individuals might change in direction of the chosen gender. Future investigations longer into transition might resolve the discrepancy on behavioral and neuronal levels.

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, and 15 age-matched cisgender women (CW) underwent MRSI before and after at least 12 weeks of GHT. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (a combination of GABA and macromolecules) and Glx (a 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.

Previous evidence indicates that transcranial direct stimulation (tDCS) is a neuromodulatory brain stimulation technique. Easy applicability, low side-effects and negligible costs facilitated its wide–spread application in efforts to modulate brain function, however neuronal mechanisms of tDCS are insufficiently understood. Hence, we investigated the immediate impact of tDCS on the brain’s glucose consumption in a continuous infusion protocol with the radioligand 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET). This novel functional PET (fPET) method is capable to reliably detect area-specific and dynamic absolute glucose demand related to neuronal activity in a single molecular imaging session. Fifteen healthy subjects underwent tDCS at 0.5, 1 and 2 mA (mA) at the bilateral dorsolateral prefrontal cortex (dlPFC, cathodal right) for 10 min during functional [18F]FDG-PET lasting 70 min. Active stimulation compared to sham did not yield significant changes in glucose consumption at any tested stimulation intensity in this paradigm. Exploratory investigation of aftereffects provided hints for increased glucose consumption with a delay of 5 min at 1 mA in the right posterior temporal cortex. This is the first study investigating changes of glucose consumption in the brain during tDCS. The lack of immediately increased glucose consumption indicates that energy demanding processes in the brain such as glutamatergic signaling might not be immediately increased by tDCS. However, our results implicate the need of fPET investigations for medium-term and long-term effects.

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.

An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character–German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.

PURPOSE Recently, a 3D-concentric ring trajectory (CRT)-based free induction decay (FID)-MRSI sequence was introduced for fast high-resolution metabolic imaging at 7 T. This technique provides metabolic ratio maps of almost the entire brain within clinically feasible scan times, but its robustness has not yet been thoroughly investigated. Therefore, we have assessed quantitative concentration estimates and their variability in healthy volunteers using this approach. METHODS We acquired whole-brain 3D-CRT-FID-MRSI at 7 T in 15 min with 3.4 mm nominal isometric resolution in 24 volunteers (12 male, 12 female, mean age 27 ± 6 years). Concentration estimate maps were calculated for 15 metabolites using internal water referencing and evaluated in 55 different regions of interest (ROIs) in the brain. Data quality, mean metabolite concentrations, and their inter-subject coefficients of variation (CVs) were compared for all ROIs. RESULTS Of 24 datasets, one was excluded due to motion artifacts. The concentrations of total choline, total creatine, glutamate, myo-inositol, and N-acetylaspartate in 44 regions were estimated within quality thresholds. Inter-subject CVs (mean over 44 ROIs/minimum/maximum) were 9%/5%/19% for total choline, 10%/6%/20% for total creatine, 11%/7%/24% for glutamate, 10%/6%/19% for myo-inositol, and 9%/6%/19% for N-acetylaspartate. DISCUSSION We defined the performance of 3D-CRT-based FID-MRSI for metabolite concentration estimate mapping, showing which metabolites could be robustly quantified in which ROIs with which inter-subject CVs expected. However, the basal brain regions and lesser-signal metabolites in particular remain as a challenge due susceptibility effects from the proximity to nasal and auditory cavities. Further improvement in quantification and the mitigation of B0 /B1 -field inhomogeneities will be necessary to achieve reliable whole-brain coverage.

The antidepressant effect of selective serotonin reuptake inhibitors (SSRI) is related to increased neuroplasticity during relearning. Stress-induced dendritic atrophy in key brain areas for learning and memory such as the hippocampus and prefrontal cortex is reversed by SSRI treatment. This finding is accompanied by behavioral stabilization. The aim of this study was to investigated serotonergic modulation effects on structural neuroplasticity (cortical thickness, subcortical volumes) during relearning in healthy subjects. Participants performed daily associative learning tasks over 3 weeks followed by a 3-week relearning phase combined with intake of the SSRI escitalopram or placebo. Evidence suggests that SSRIs promote the brains susceptibility to change on the basis of environment factors. We found no effect of SSRI on grey matter measures during relearning. Here, non-findings might be a consequence of the implemented intensity and duration of study interventions. With sparse literature on healthy participants in this field, future studies will have to further elucidate SSRIs properties on relearning and structural neuroplasticity.

BackgroundNeuroplastic processes are influenced by selective serotonergic reuptake inhibitors, while learning in conjunction with the administration of serotonergic agents alters white matter microstructure in humans. The goal of this double-blind, placebo-controlled imaging study was to investigate the influence of escitalopram on white matter plasticity during (re)learning.MethodsSeventy-one healthy individuals (age = 25.6±5.0, 43 females) underwent 3 diffusion magnetic resonance imaging sessions: 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, subjects received daily escitalopram 10 mg or placebo orally. Statistical analysis was performed with statistical parametric mapping (SPM) and using sandwich estimator.ResultsA three-way and two-way rmANOVA was conducted to analyze the effects of escitalopram on AD, FA, MD and RD during the learning and relearning period. We found no significant three-way or two-way interactions for each DTI metrics (pFDR > 0.05), thus neither after 3 nor after 6 weeks we found significant changes in white matter microstructure.ConclusionWe examined neither an effect of escitalopram nor learning (or relearning) interventions on different DTI metrics. The duration and intensity of study interventions (i.e. administration of escitalopram and learning as the relearning task) might have been chosen insufficiently to induce detectable alterations. Previous studies examining the effects of SSRIs on white matter tracts in humans are underrepresented, but do mainly yield towards non-significant findings. The results implicate that escitalopram does not impact white matter microstructures in healthy subjects.

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, serotonergic agents were shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in human patients. To investigate this assumption, 99 healthy subjects underwent six weeks of emotional or non-emotional learning and subsequent relearning. Resting-state functional magnetic resonance imaging was performed before and after the learning phases to investigate changes in FC. During relearning, subjects received either a daily dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo. Escitalopram intake modulated FC changes in a network comprising Broca’s area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus. More specifically, escitalopram increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and additionally the connectivity from medial prefrontal cortex to Broca’s area for emotional relearning. The context-dependence of these effects supports the assumption that SSRIs in clinical practice might improve neuroplasticity rather than psychiatric symptoms per se. Correlations with learning behavior further point towards a relationship with extinction processes in relearning. These results demonstrate that escitalopram intake during relearning results in content-dependent network adaptations and support the conclusion that enhanced neuroplasticity might be the major underlying mechanism also in humans. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on serotonin-facilitated neuroplasticity of the human brain.

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 abstract is available here: https://uscholar.univie.ac.at/o:1227600

Increased cerebral monoamine oxidase A (MAO-A) levels have been shown in non-seasonal depression using positron emission tomography (PET). Seasonal affective disorder (SAD) is a sub-form of major depressive disorder and is typically treated with bright light therapy (BLT). The serotonergic system is affected by season and light. Hence, this study aims to assess the relevance of brain MAO-A levels to the pathophysiology and treatment of SAD. Changes to cerebral MAO-A distribution (1) in SAD in comparison to healthy controls (HC), (2) after treatment with BLT and (3) between the seasons, were investigated in 24 patients with SAD and 27 HC using [11C]harmine PET. PET scans were performed in fall/winter before and after 3 weeks of placebo-controlled BLT, as well as in spring/summer. Cerebral MAO-A distribution volume (VT, an index of MAO-A density) did not differ between patients and HC at any of the three time-points. However, MAO-A VT decreased from fall/winter to spring/summer in the HC group (F 1, 187.84 = 4.79, p

Previous evidence indicates that transcranial direct stimulation (tDCS) is a neuromodulatory brain stimulation technique. Easy applicability, low side-effects and negligible costs facilitated its wide–spread application in efforts to modulate brain function, however neuronal mechanisms of tDCS are insufficiently understood. Hence, we investigated the immediate impact of tDCS on the brain’s glucose consumption in a continuous infusion protocol with the radioligand 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET). This novel functional PET (fPET) method is capable to reliably detect area-specific and dynamic absolute glucose demand related to neuronal activity in a single molecular imaging session. Fifteen healthy subjects underwent tDCS at 0.5, 1 and 2 mA (mA) at the bilateral dorsolateral prefrontal cortex (dlPFC, cathodal right) for 10 min during functional [18F]FDG-PET lasting 70 min. Active stimulation compared to sham did not yield significant changes in glucose consumption at any tested stimulation intensity in this paradigm. Exploratory investigation of aftereffects provided hints for increased glucose consumption with a delay of 5 min at 1 mA in the right posterior temporal cortex. This is the first study investigating changes of glucose consumption in the brain during tDCS. The lack of immediately increased glucose consumption indicates that energy demanding processes in the brain such as glutamatergic signaling might not be immediately increased by tDCS. However, our results implicate the need of fPET investigations for medium-term and long-term effects.

Impaired cognitive flexibility represents a widespread symptom in psychiatric disorders, including major depressive disorder (MDD), a disease, characterized by an imbalance of neurotransmitter concentrations. While memory formation is mostly associated with glutamate, also gamma-Aminobutyric acid (GABA) and serotonin show attributions in a complex interplay between neurotransmitter systems. Treatment with selective serotonin reuptake inhibitors (SSRIs) does not solely affect the serotonergic system but shows downstream effects on GABA- and glutamatergic neurotransmission, potentially helping to restore cognitive function via neuroplastic effects. Hence, this study aims to elaborate the effects of associative relearning and SSRI treatment on GABAergic and glutamatergic function within and between five brain regions using magnetic resonance spectroscopy imaging (MRSI). In this study, healthy subjects were randomized into four groups which underwent three weeks of an associative relearning paradigm, with or without emotional connotation, under SSRI (10mg escitalopram) or placebo administration. MRSI measurements, using a spiral-encoded, 3D-GABA-edited MEGA-LASER sequence at 3T, were performed on the first and last day of relearning. Mean GABA+/tCr (GABA+ = GABA + macromolecules; tCr = total creatine) and Glx/tCr (Glx = glutamate + glutamine) ratios were quantified in a ROI-based approach for the hippocampus, insula, putamen, pallidum and thalamus, using LCModel. A total of 66 subjects ((37 female, mean age ± SD = 25.4±4.7) for Glx/tCr and 58 subjects (32 female, mean age ± SD = 25.1±4.7) for GABA+/tCr were included in the final analysis. A significant measurement by region and treatment (SSRI vs placebo) interaction on Glx/tCr ratios was found (pcor=0.017), with post hoc tests confirming differential effects on hippocampus and thalamus (pcor=0.046). Moreover, treatment by time comparison, for each ROI independently, showed a reduction of hippocampal Glx/tCr ratios after SSRI treatment (puncor=0.033). No significant treatment effects on GABA+/tCr ratios or effects of relearning condition on any neurotransmitter ratio could be found. Here, we showed a significant SSRI- and relearning-driven interaction effect of hippocampal and thalamic Glx/tCr levels, suggesting differential behavior based on different serotonin transporter and receptor densities. Moreover, an indication for Glx/tCr adaptions in the hippocampus after three weeks of SSRI treatment could be revealed. Our findings are in line with animal studies reporting glutamate adaptions in the hippocampus following chronic SSRI intake. Due to the complex interplay of serotonin and hippocampal function, involving multiple serotonin receptor subtypes on glutamatergic cells and GABAergic interneurons, the interpretation of underlying neurobiological actions remains challenging.

Electroconvulsive therapy (ECT) is the treatment of choice for severe mental illness including treatment-resistant depression (TRD). Increases in volume of the hippocampus and amygdala following ECT have consistently been reported.AimsTo investigate neuroplastic changes after ECT in specific hippocampal subfields and amygdala nuclei using high-resolution structural magnetic resonance imaging (MRI) (trial registration: clinicaltrials.gov - NCT02379767).MRI scans were carried out in 14 patients (11 women, 46.9 years (s.d. = 8.1)) with unipolar TRD twice before and once after a series of right unilateral ECT in a pre-post study design. Volumes of subcortical structures, including subfields of the hippocampus and amygdala, and cortical thickness were extracted using FreeSurfer. The effect of ECT was tested using repeated-measures ANOVA. Correlations of imaging and clinical parameters were explored.Increases in volume of the right hippocampus by 139.4 mm3 (s.d. = 34.9), right amygdala by 82.3 mm3 (s.d. = 43.9) and right putamen by 73.9 mm3 (s.d. = 77.0) were observed. These changes were localised in the basal and lateral nuclei, and the corticoamygdaloid transition area of the amygdala, the hippocampal-amygdaloid transition area and the granule cell and molecular layer of the dentate gyrus. Cortical thickness increased in the temporal, parietal and insular cortices of the right hemisphere.Following ECT structural changes were observed in hippocampal subfields and amygdala nuclei that are specifically implicated in the pathophysiology of depression and stress-related disorders and retain a high potential for neuroplasticity in adulthood.Declaration of interestS.K. has received grants/research support, consulting fees and/or honoraria within the past 3 years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe and Servier. R.L. received travel grants and/or conference speaker honoraria from Shire, AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, and Roche Austria GmbH.

Neural plasticity is a complex process dependent on neurochemical underpinnings. Next to the glutamatergic system which contributes to memory formation via long-term potentiation (LTP) and long-term depression (LTD), the main inhibitory neurotransmitter, GABA is crucially involved in neuroplastic processes. Hence, we investigated changes in glutamate and GABA levels in the brain in healthy participants performing an associative learning paradigm. Twenty healthy participants (10 female, 25 ± 5 years) underwent paired multi-voxel magnetic resonance spectroscopy imaging before and after completing 21 days of a facial associative learning paradigm in a longitudinal study design. Changes of GABA and glutamate were compared to retrieval success in the hippocampus, insula and thalamus. No changes in GABA and glutamate concentration were found after 21 days of associative learning. However, baseline hippocampal GABA levels were significantly correlated with initial retrieval success (pcor = 0.013, r = 0.690). In contrast to the thalamus and insula (pcor>0.1), higher baseline GABA levels in the hippocampus were associated with better retrieval performance in an associative learning paradigm. Therefore, our findings support the importance of hippocampal GABA levels in memory formation in the human brain in vivo.