Dynamics of human serotonin synthesis differentially link to reward anticipation and feedback.

Serotonin (5-HT) plays an essential role in reward processing, however, the possibilities to investigate 5-HT action in humans during emotional stimulation are particularly limited. Here we demonstrate the feasibility of assessing reward-specific dynamics in 5-HT synthesis using functional PET (fPET), combining its molecular specificity with the high temporal resolution of blood oxygen level dependent (BOLD) fMRI. Sixteen healthy volunteers underwent simultaneous fPET/fMRI with the radioligand [11C]AMT, a substrate for tryptophan hydroxylase. During the scan, participants completed the monetary incentive delay task and arterial blood samples were acquired for quantifying 5-HT synthesis rates. BOLD fMRI was recorded as a proxy of neuronal activation, allowing differentiation of reward anticipation and feedback. Monetary gain and loss resulted in substantial increases in 5-HT synthesis in the ventral striatum (VStr, +21% from baseline) and the anterior insula (+41%). In the VStr, task-specific 5-HT synthesis was further correlated with BOLD signal changes during reward feedback (ρ = -0.65), but not anticipation. Conversely, 5-HT synthesis in the anterior insula correlated with BOLD reward anticipation (ρ = -0.61), but not feedback. In sum, we provide a robust tool to identify task-induced changes in 5-HT action in humans, linking the dynamics of 5-HT synthesis to distinct phases of reward processing in a regionally specific manner. Given the relevance of altered reward processing in psychiatric disorders such as addiction, depression and schizophrenia, our approach offers a tailored assessment of impaired 5-HT signaling during cognitive and emotional processing.

Synaptic signaling modeled by functional connectivity predicts metabolic demands of the human brain.

PURPOSE: The human brain is characterized by interacting large-scale functional networks fueled by glucose metabolism. Since former studies could not sufficiently clarify how these functional connections shape glucose metabolism, we aimed to provide a neurophysiologically-based approach. METHODS: 51 healthy volunteers underwent simultaneous PET/MRI to obtain BOLD functional connectivity and [18F]FDG glucose metabolism. These multimodal imaging proxies of fMRI and PET were combined in a whole-brain extension of metabolic connectivity mapping. Specifically, functional connectivity of all brain regions were used as input to explain glucose metabolism of a given target region. This enabled the modeling of postsynaptic energy demands by incoming signals from distinct brain regions. RESULTS: Functional connectivity input explained a substantial part of metabolic demands but with pronounced regional variations (34 - 76%). During cognitive task performance this multimodal association revealed a shift to higher network integration compared to resting state. In healthy aging, a dedifferentiation (decreased segregated/modular structure of the brain) of brain networks during rest was observed. Furthermore, by including data from mRNA maps, [11C]UCB-J synaptic density and aerobic glycolysis (oxygen-to-glucose index from PET data), we show that whole-brain functional input reflects non-oxidative, on-demand metabolism of synaptic signaling. The metabolically-derived directionality of functional inputs further marked them as top-down predictions. In addition, the approach uncovered formerly hidden networks with superior efficiency through metabolically informed network partitioning. CONCLUSIONS: Applying multimodal imaging, we decipher a crucial part of the metabolic and neurophysiological basis of functional connections in the brain as interregional on-demand synaptic signaling fueled by anaerobic metabolism. The observed task- and age-related effects indicate promising future applications to characterize human brain function and clinical alterations.

Validation of cardiac image-derived input functions for functional PET quantification.

PURPOSE: Functional PET (fPET) is a novel technique for studying dynamic changes in brain metabolism and neurotransmitter signaling. Accurate quantification of fPET relies on measuring the arterial input function (AIF), traditionally achieved through invasive arterial blood sampling. While non-invasive image-derived input functions (IDIF) offer an alternative, they suffer from limited spatial resolution and field of view. To overcome these issues, we developed and validated a scan protocol for brain fPET utilizing cardiac IDIF, aiming to mitigate known IDIF limitations. METHODS: Twenty healthy individuals underwent fPET/MR scans using [18F]FDG or 6-[18F]FDOPA, utilizing bed motion shuttling to capture cardiac IDIF and brain task-induced changes. Arterial and venous blood sampling was used to validate IDIFs. Participants performed a monetary incentive delay task. IDIFs from various blood pools and composites estimated from a linear fit over all IDIF blood pools (3VOI) and further supplemented with venous blood samples (3VOIVB) were compared to the AIF. Quantitative task-specific images from both tracers were compared to assess the performance of each input function to the gold standard. RESULTS: For both radiotracer cohorts, moderate to high agreement (r: 0.60-0.89) between IDIFs and AIF for both radiotracer cohorts was observed, with further improvement (r: 0.87-0.93) for composite IDIFs (3VOI and 3VOIVB). Both methods showed equivalent quantitative values and high agreement (r: 0.975-0.998) with AIF-derived measurements. CONCLUSION: Our proposed protocol enables accurate non-invasive estimation of the input function with full quantification of task-specific changes, addressing the limitations of IDIF for brain imaging by sampling larger blood pools over the thorax. These advancements increase applicability to any PET scanner and clinical research setting by reducing experimental complexity and increasing patient comfort.

Whole-brain deuterium metabolic imaging via concentric ring trajectory readout enables assessment of regional variations in neuronal glucose metabolism.

Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non-invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium-labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase-encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non-Cartesian spatial-spectral sampling schemes for whole-brain 2H FID-MR Spectroscopic Imaging to assess time-resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower-resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6']-2H glucose. Time-resolved whole brain 2H FID-DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density-weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal-to-noise ratios associated with smaller voxels, low-rank denoising of the spatiotemporal data was performed during reconstruction. Sixty-three minutes after oral tracer uptake three-dimensional (3D) CRT-DMI maps featured 19% higher (p = .006) deuterium-labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p = .01) 2H-Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low-resolution PE-DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM- and WM-dominated areas for 2H-Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p = .045), while no regional differences were observed for 2H-Glx concentrations. In this study, we successfully implemented 3D FID-MRSI with fast CRT encoding for dynamic whole-brain DMI at 7 T with 2.5-fold increased spatial resolution compared with conventional whole-brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM- compared with WM-dominated regions, which could not be reproduced using whole-brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non-invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications.

Non-invasive assessment of stimulation-specific changes in cerebral glucose metabolism with functional PET.

PURPOSE: Functional positron emission tomography (fPET) with [18F]FDG allows quantification of stimulation-induced changes in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires invasive arterial blood sampling, limiting its widespread use. Here, we introduce a novel fPET method without the need for an input function. METHODS: We validated the approach using two datasets (DS). For DS1, 52 volunteers (23.2 ± 3.3 years, 24 females) performed Tetris® during a [18F]FDG fPET scan (bolus + constant infusion). For DS2, 18 participants (24.2 ± 4.3 years, 8 females) performed an eyes-open/finger tapping task (constant infusion). Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as reference. We then estimated simplified outcome parameters, including GLM beta values and percent signal change (%SC), and compared them, region and whole-brain-wise. RESULTS: We observed higher agreement with the reference for DS1 than DS2. Both DS resulted in strong correlations between regional task-specific beta estimates and CMRGlu (r = 0.763…0.912). %SC of beta values exhibited strong agreement with %SC of CMRGlu (r = 0.909…0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870…0.979) as well as %SC (Dice = 0.932…0.997), respectively. CONCLUSION: The non-invasive method reliably estimates task-specific changes in glucose metabolism without blood sampling. This streamlines fPET, albeit with the trade-off of being unable to quantify baseline metabolism. The simplification enhances its applicability in research and clinical settings.

Effects of lockdowns on neurobiological and psychometric parameters in unipolar depression during the COVID-19 pandemic.

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

White matter volume and treatment with selective progesterone receptor modulator in patients with premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) is a mood disorder for which selective progesterone receptor modulator (SPRM) treatment has been demonstrated to be beneficial. The neural signatures of this treatment have been so far identified as greater fronto-cingulate reactivity during aggressive response to provocation, but no changes in terms of gray matter structure. White matter has recently been found to differ between patients with PMDD and healthy controls. The present study thus sought to investigate the relationship between white matter volume and SPRM treatment in patients with PMDD. A pharmaco-neuroimaging study was conducted on patients with PMDD participating in a randomized controlled trial. Participants underwent magnetic resonance imaging before and after treatment randomization to ulipristal acetate (an SPRM), or placebo, for three months. The interaction effect of treatment by time on white matter volume (WMV) was assessed. Voxel based morphometry analyses were performed on both a whole brain exploratory level and on regions of interest. No treatment effect was observed on WMV in any region, including the anterior thalamic radiations, cingulum, forceps minor, fornix, inferior fronto-occipital fasciculus, superior cerebellar peduncle, superior longitudinal fasciculus, and uncinate fasciculus. This is the first finding to indicate that no white matter volume alterations follow three-month progesterone antagonism, suggesting that white matter volume does not participate in symptom relief upon SPRM treatment for PMDD.

Gender Dysphoria and Sexual Euphoria: A Bayesian Perspective on the Influence of Gender-Affirming Hormone Therapy on Sexual Arousal.

Self-reported sexual orientation of transgender individuals occasionally changes over transition. Using functional magnetic resonance imaging, we tested the hypothesis that neural and behavioral patterns of sexual arousal in transgender individuals would shift from the assigned to the experienced gender (e.g., trans women's responses becoming more dissimilar to those of cis men and more similar to those of cis women). To this aim, trans women (N = 12) and trans men (N = 20) as well as cisgender women (N = 24) and cisgender men (N = 14) rated visual stimuli showing male-female, female-female or male-male intercourse for sexual arousal before and after four months of gender-affirming hormone therapy. A Bayesian framework allowed us to incorporate previous behavioral findings. The hypothesized changes could indeed be observed in the behavioral responses with the strongest results for trans men and female-female scenes. Activation of the ventral striatum supported our hypothesis only for female-female scenes in trans women. The respective application or depletion of androgens in trans men and trans women might partly explain this observation. The prominent role of female-female stimuli might be based on the differential responses they elicit in cis women and men or, in theory, the controversial concept of autogynephilia. We show that correlates of sexual arousal in transgender individuals might change in the direction of the experienced gender. Future investigations should elucidate the mechanistic role of sex hormones and the cause of the differential neural and behavioral findings.The study was registered at ClinicalTrials.gov (NCT02715232), March 22, 2016.

High-temporal resolution functional PET/MRI reveals coupling between human metabolic and hemodynamic brain response.

PURPOSE: Positron emission tomography (PET) provides precise molecular information on physiological processes, but its low temporal resolution is a major obstacle. Consequently, we characterized the metabolic response of the human brain to working memory performance using an optimized functional PET (fPET) framework at a temporal resolution of 3 s. METHODS: Thirty-five healthy volunteers underwent fPET with [18F]FDG bolus plus constant infusion, 19 of those at a hybrid PET/MRI scanner. During the scan, an n-back working memory paradigm was completed. fPET data were reconstructed to 3 s temporal resolution and processed with a novel sliding window filter to increase signal to noise ratio. BOLD fMRI signals were acquired at 2 s. RESULTS: Consistent with simulated kinetic modeling, we observed a constant increase in the [18F]FDG signal during task execution, followed by a rapid return to baseline after stimulation ceased. These task-specific changes were robustly observed in brain regions involved in working memory processing. The simultaneous acquisition of BOLD fMRI revealed that the temporal coupling between hemodynamic and metabolic signals in the primary motor cortex was related to individual behavioral performance during working memory. Furthermore, task-induced BOLD deactivations in the posteromedial default mode network were accompanied by distinct temporal patterns in glucose metabolism, which were dependent on the metabolic demands of the corresponding task-positive networks. CONCLUSIONS: In sum, the proposed approach enables the advancement from parallel to truly synchronized investigation of metabolic and hemodynamic responses during cognitive processing. This allows to capture unique information in the temporal domain, which is not accessible to conventional PET imaging.

Changes to hypothalamic volume and associated subunits during gender-affirming hormone therapy.

BACKGROUND: Among its pleiotropic properties, gender-affirming hormone therapy (GHT) affects regional brain volumes. The hypothalamus, which regulates neuroendocrine function and associated emotional and cognitive processes, is an intuitive target for probing GHT effects. We sought to assess changes to hypothalamus and hypothalamic subunit volumes after GHT, thereby honouring the region's anatomical and functional heterogeneity. METHODS: Individuals with gender dysphoria and cisgender controls underwent 2 MRI measurements, with a median interval of 145 days (interquartile range [IQR] 128.25-169.75 d, mean 164.94 d) between the first and second MRI. Transgender women (TW) and transgender men (TM) underwent the first MRI before GHT and the second MRI after approximately 4.5 months of GHT, which comprised estrogen and anti-androgen therapy in TW or testosterone therapy in TM. Hypothalamic volumes were segmented using FreeSurfer, and effects of GHT were tested using repeated-measures analysis of covariance. RESULTS: The final sample included 106 participants: 38 TM, 15 TW, 32 cisgender women (CW) and 21 cisgender men (CM). Our analyses revealed group × time interaction effects for total, left and right hypothalamus volume, and for several subunits (left and right inferior tubular, left superior tubular, right anterior inferior, right anterior superior, all p corr < 0.01). In TW, volumes decreased between the first and second MRI in these regions (all p corr ≤ 0.01), and the change from the first to second MRI in TW differed significantly from that in CM and CW in several subunits (p corr < 0.05). LIMITATIONS: We did not address the influence of transition-related psychological and behavioural changes. CONCLUSION: Our results suggest a subunit-specific effect of GHT on hypothalamus volumes in TW. This finding is in accordance with previous reports of positive and negative effects of androgens and estrogens, respectively, on cerebral volumes.

The influence of sex steroid treatment on insular connectivity in gender dysphoria.

BACKGROUND: Sex-specific differences in brain connectivity were found in various neuroimaging studies, though little is known about sex steroid effects on insular functioning. Based on well-characterized sex differences in emotion regulation, interoception and higher-level cognition, gender-dysphoric individuals receiving gender-affirming hormone therapy represent an interesting cohort to investigate how sex hormones might influence insular connectivity and related brain functions. METHODS: To analyze the potential effect of sex steroids on insular connectivity at rest, 11 transgender women, 14 transgender men, 20 cisgender women, and 11 cisgender men were recruited. All participants underwent two magnetic resonance imaging sessions involving resting-state acquisitions separated by a median time period of 4.5 months and also completed the Bermond-Vorst alexithymia questionnaire at the initial and final examination. Between scans, transgender subjects received gender-affirming hormone therapy. RESULTS: A seed based functional connectivity analysis revealed a significant 2-way interaction effect of group-by-time between right insula, cingulum, left middle frontal gyrus and left angular gyrus. Post-hoc tests demonstrated an increase in connectivity for transgender women when compared to cisgender men. Furthermore, spectral dynamic causal modelling showed reduced effective connectivity from the posterior cingulum and left angular gyrus to the left middle frontal gyrus as well as from the right insula to the left middle frontal gyrus. Alexithymia changes were found after gender-affirming hormone therapy for transgender women in both fantasizing and identifying. CONCLUSION: These findings suggest a considerable influence of estrogen administration and androgen suppression on brain networks implicated in interoception, own-body perception and higher-level cognition.

Reproducibility of 3D MRSI for imaging human brain glucose metabolism using direct (2H) and indirect (1H) detection of deuterium labeled compounds at 7T and clinical 3T.

INTRODUCTION: Deuterium 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 using 2H MRSI (DMI) and 1H 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. METHODS: Five volunteers (4 m/1f) were scanned in repeated sessions for 60 min after overnight fasting and 0.8 g/kg oral [6,6'-2H2]-glucose administration using time-resolved 3D 2H FID-MRSI with elliptical phase encoding at 7T and 3D 1H FID-MRSI with a non-Cartesian concentric ring trajectory readout at clinical 3T. RESULTS: One hour after oral tracer administration regionally averaged deuterium labeled Glx4 concentrations and the dynamics were not significantly different over all participants between 7T 2H DMI and 3T 1H 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 Glc6 data 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 individual 2H and 1H data points a weak to moderate negative correlation was observed for Glx4 concentrations in GM (r=-0.52, p<0.001), and WM (r=-0.3, p<0.001) dominated regions, while a strong negative correlation was observed for Glc6 data GM (r=-0.61, p<0.001) and WM (r=-0.70, p<0.001). CONCLUSION: This study demonstrates that indirect detection of deuterium labeled compounds using 1H 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 to 2H 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.

Compromised white matter is related to lower cognitive performance in adults with phenylketonuria.

Despite increasing knowledge about the effects of phenylketonuria on brain structure and function, it is uncertain whether white matter microstructure is affected and if it is linked to patients' metabolic control or cognitive performance. Thus, we quantitatively assessed white matter characteristics in adults with phenylketonuria and assessed their relationship to concurrent brain and blood phenylalanine levels, historical metabolic control and cognitive performance. Diffusion tensor imaging and 1H spectroscopy were performed in 30 adults with early-treated classical phenylketonuria (median age 35.5 years) and 54 healthy controls (median age 29.3 years). Fractional anisotropy and mean, axial and radial diffusivity were investigated using tract-based spatial statistics, and white matter lesion load was evaluated. Brain phenylalanine levels were measured with 1H spectroscopy whereas concurrent plasma phenylalanine levels were assessed after an overnight fast. Retrospective phenylalanine levels were collected to estimate historical metabolic control, and a neuropsychological evaluation assessed the performance in executive functions, attention and processing speed. Widespread reductions in mean diffusivity, axial diffusivity and fractional anisotropy occurred in patients compared to controls. Mean diffusivity and axial diffusivity were decreased in several white matter tracts and were most restricted in the optic radiation (effect size rrb = 0.66 to 0.78, P < 0.001) and posterior corona radiata (rrb = 0.83 to 0.90, P < 0.001). Lower fractional anisotropy was found in the optic radiation and posterior corona radiata (rrb = 0.43 to 0.49, P < 0.001). White matter microstructure in patients was significantly associated with cognition. Specifically, inhibition was related to axial diffusivity in the external capsule (rs = -0.69, P < 0.001) and the superior (rs = -0.58, P < 0.001) and inferior longitudinal fasciculi (rs = -0.60, P < 0.001). Cognitive flexibility was associated with mean diffusivity of the posterior limb of the internal capsule (rs = -0.62, P < 0.001), and divided attention correlated with fractional anisotropy of the external capsule (rs = -0.61, P < 0.001). Neither concurrent nor historical metabolic control was significantly associated with white matter microstructure. White matter lesions were present in 29 out of 30 patients (96.7%), most often in the parietal and occipital lobes. However, total white matter lesion load scores were unrelated to patients' cognitive performance and metabolic control. In conclusion, our findings demonstrate that white matter alterations in early-treated phenylketonuria persist into adulthood, are most prominent in the posterior white matter and are likely to be driven by axonal damage. Furthermore, diffusion tensor imaging metrics in adults with phenylketonuria were related to performance in attention and executive functions.

Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo.

Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.e. monoamine concentrations) were shown to affect MAO-A levels. We assessed the effect of MAOA (rs1137070, rs2064070, rs6323) and TPH2 (rs1386494, rs4570625) variants associated with risk for depression and related clinical phenomena on global MAO-A distribution volume (VT) using [11C]harmine PET in 51 participants (21 individuals with seasonal affective disorder (SAD) and 30 healthy individuals (HI)). Statistical analyses comprised general linear models with global MAO-A VT as dependent variable, genotype as independent variable and age, sex, group (individuals with SAD, HI) and season as covariates. rs1386494 genotype significantly affected global MAO-A VT after correction for age, group and sex (p < 0.05, corr.), with CC homozygotes showing 26% higher MAO-A levels. The role of rs1386494 on TPH2 function or expression is poorly understood. Our results suggest rs1386494 might have an effect on either, assuming that TPH2 and MAO-A levels are linked by their common product/substrate, 5-HT. Alternatively, rs1386494 might influence MAO-A levels via another mechanism, such as co-inheritance of other genetic variants. Our results provide insight into how genetic variants within serotonin turnover translate to the cerebral serotonin system. Clinicaltrials.gov Identifier: NCT02582398. EUDAMED Number: CIV-AT-13-01-009583.

Reproducibility of 3D MRSI for imaging human brain glucose metabolism using direct ( 2 H) and indirect ( 1 H) detection of deuterium labeled compounds at 7T and clinical 3T.

Introduction: Deuterium 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'- 2 H 2 ]-glucose, its uptake and synthesis of downstream metabolites can be mapped via direct or indirect detection of deuterium resonances using 2 H MRSI (DMI) and 1 H 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. Methods: Five volunteers (4m/1f) were scanned in repeated sessions for 60 min after overnight fasting and 0.8g/kg oral [6,6'- 2 H 2 ]-glucose administration using time-resolved 3D 2 H FID-MRSI with elliptical phase encoding at 7T and 3D 1 H FID-MRSI with a non-Cartesian concentric ring trajectory readout at clinical 3T. Results: One hour after oral tracer administration regionally averaged deuterium labeled Glx 4 concentrations and the dynamics were not significantly different over all participants between 7T 2 H DMI and 3T 1 H 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 Glc 6 data 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 individual 2 H and 1 H data points a weak to moderate negative correlation was observed for Glx 4 concentrations in GM (r=-0.52, p<0.001), and WM (r=-0.3, p<0.001) dominated regions, while a strong negative correlation was observed for Glc 6 data GM (r=- 0.61, p<0.001) and WM (r=-0.70, p<0.001). Conclusion: This study demonstrates that indirect detection of deuterium labeled compounds using 1 H 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 to 2 H 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.

Body mass index and clinical outcomes in individuals with major depressive disorder: Findings from the GSRD European Multicenter Database.

BACKGROUND: Individuals with major depressive disorder (MDD) are at higher risk for obesity. In turn, weight gain is a predisposing factor for depression. Although clinical data are sparse, suicide risk also appears to be elevated in obese patients. This study used data from the European Group for the Study of Resistant Depression (GSRD) to investigate clinical outcomes associated with body mass index (BMI) in MDD. METHODS: Data were drawn from 892 participants with MDD over the age of 18 years (580 female, 50.5 ± 13.6 years). Response and resistance to antidepressant medication, depression rating scale scores, and further clinical and sociodemographic variables were compared using multiple logistic and linear regressions controlled for age, sex, and risk of weight gain due to psychopharmacotherapy. RESULTS: Of the 892 participants, 323 were categorized as treatment-responsive and 569 as treatment-resistant. Within this cohort, 278 (31.1 %) were overweight (BMI = 25-29.9 kg/m2) and 151 (16.9 %) were obese (BMI > 30 kg/m2). Elevated BMI was significantly associated with higher suicidality, longer duration of psychiatric hospitalizations over their lifetimes, earlier age of onset of MDD, and comorbidities. There was a trend-wise association of BMI with treatment resistance. LIMITATIONS: Data were analyzed in a retrospective, cross-sectional design. BMI was used as an exclusive measure of overweight and obesity. CONCLUSIONS: Participants with comorbid MDD and overweight/obesity were at risk for worse clinical outcomes, suggesting that weight gain should be closely monitored in individuals with MDD in daily clinical practice. Further studies are needed to explore the neurobiological mechanisms linking elevated BMI to impaired brain health.

Task-evoked metabolic demands of the posteromedial default mode network are shaped by dorsal attention and frontoparietal control networks.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

Comparison of cardiac image-derived input functions for quantitative whole body [18F]FDG imaging with arterial blood sampling.

Introduction: Dynamic positron emission tomography (PET) and the application of kinetic models can provide important quantitative information based on its temporal information. This however requires arterial blood sampling, which can be challenging to acquire. Nowadays, state-of-the-art PET/CT systems offer fully automated, whole-body (WB) kinetic modelling protocols using image-derived input functions (IDIF) to replace arterial blood sampling. Here, we compared the validity of an automatic WB kinetic model protocol to the reference standard arterial input function (AIF) for both clinical and research settings. Methods: Sixteen healthy participants underwent dynamic WB [18F]FDG scans using a continuous bed motion PET/CT system with simultaneous arterial blood sampling. Multiple processing pipelines that included automatic and manually generated IDIFs derived from the aorta and left ventricle, with and without motion correction were compared to the AIF. Subsequently generated quantitative images of glucose metabolism were compared to evaluate performance of the different input functions. Results: We observed moderate to high correlations between IDIFs and the AIF regarding area under the curve (r = 0.49-0.89) as well as for the cerebral metabolic rate of glucose (CMRGlu) (r = 0.68-0.95). Manual placing of IDIFs and motion correction further improved their similarity to the AIF. Discussion: In general, the automatic vendor protocol is a feasible approach for the quantification of CMRGlu for both, clinical and research settings where expertise or time is not available. However, we advise on a rigorous inspection of the placement of the volume of interest, the resulting IDIF, and the quantitative values to ensure valid interpretations. In protocols requiring longer scan times or where cohorts are prone to involuntary movement, manual IDIF definition with additional motion correction is recommended, as this has greater accuracy and reliability.

1H magnetic resonance spectroscopic imaging of deuterated glucose and of neurotransmitter metabolism at 7 T in the human brain.

Impaired glucose metabolism in the brain has been linked to several neurological disorders. Positron emission tomography and carbon-13 magnetic resonance spectroscopic imaging (MRSI) can be used to quantify the metabolism of glucose, but these methods involve exposure to radiation, cannot quantify downstream metabolism, or have poor spatial resolution. Deuterium MRSI (2H-MRSI) is a non-invasive and safe alternative for the quantification of the metabolism of 2H-labelled substrates such as glucose and their downstream metabolic products, yet it can only measure a limited number of deuterated compounds and requires specialized hardware. Here we show that proton MRSI (1H-MRSI) at 7 T has higher sensitivity, chemical specificity and spatiotemporal resolution than 2H-MRSI. We used 1H-MRSI in five volunteers to differentiate glutamate, glutamine, γ-aminobutyric acid and glucose deuterated at specific molecular positions, and to simultaneously map deuterated and non-deuterated metabolites. 1H-MRSI, which is amenable to clinically available magnetic-resonance hardware, may facilitate the study of glucose metabolism in the brain and its potential roles in neurological disorders.