Search

Mapping the neuronal response during cognitive processing is of crucial importance to gain new insights into human brain function. BOLD imaging and ASL are established MRI methods in this endeavor. Recently, the novel approach of functional PET (fPET) was introduced, enabling absolute quantification of glucose metabolism at rest and during task execution in a single measurement. Here, we report test-retest reliability of fPET in direct comparison to BOLD imaging and ASL. Twenty healthy subjects underwent two PET/MRI measurements, providing estimates of glucose metabolism, cerebral blood flow (CBF) and blood oxygenation. A cognitive task was employed with different levels of difficulty requiring visual-motor coordination. Task-specific neuronal activation was robustly detected with all three imaging approaches. The highest reliability was obtained for glucose metabolism at rest. Although this dropped during task performance it was still comparable to that of CBF. In contrast, BOLD imaging yielded high performance only for qualitative spatial overlap of task effects but not for quantitative comparison. Hence, the combined assessment of fPET and ASL offers reliable and simultaneous absolute quantification of glucose metabolism and CBF at rest and task.

PurposeIn the human brain endogenous dopamine release is commonly assessed by the PET competition model. Although thoroughly validated, cognitive processing yields low signal changes and the assessment of several task conditions requires repeated scanning. Using the framework of functional PET imaging we introduce a novel approach which leverages the incorporation of the radioligand 6-[18F]FDOPA into the dynamic fast-acting regulation of the corresponding enzyme activities by neuronal firing and neurotransmitter release. We demonstrate the feasibility of the approach by the assessment of widely described sex differences in dopamine neurotransmission.MethodsReward and punishment processing was behaviorally investigated in 36 healthy participants, where 16 underwent fPET and fMRI while performing the monetary incentive delay task. 6-[18F]FDOPA was applied as bolus+infusion during a single 50 min PET acquisition. Task-specific changes in dopamine synthesis were identified with the general linear model and quantified with the Gjedde-Patlak plot.ResultsMonetary gain induced 78% increase in nucleus accumbens dopamine synthesis vs. 49% for loss in men. Interestingly, the opposite was discovered in women (gain: 51%, loss: 78%). Behavioral modeling revealed direct associations of task-specific dopamine synthesis with reward sensitivity in men (rho = −0.7) and with punishment sensitivity in women (rho = 0.89). As expected, fMRI showed robust task-specific neuronal activation but no sex difference.ConclusionsOur findings provide a dopaminergic basis for well-known behavioral differences in reward and punishment processing between women and men. This has important implications in psychiatric conditions showing sex-specific prevalence rates, altered reward processing and dopamine signaling. The high temporal resolution and pronounced magnitude of task-specific changes make fPET a promising tool to investigate functional neurotransmitter dynamics during cognitive or emotional processing in various brain disorders.

Die Wernicke-Encephalopathie (WE) ist eine neurologische Komplikation eines klinisch manifesten Thiaminmangels. Thiaminmangelerscheinungen stellen eine relevante Ursache für akutes und subakutes Delir dar und haben verheerende Langzeitfolgen. In der vorliegenden Kasuistik berichten wir über Thiaminsubstitution im Falle eines 49-jährigen Patienten, welcher im Rahmen einer Alkoholabhängigkeitserkrankung zum körperlichen Entzug und psychischer Stabilisierung am Universitätsklinikum Tulln stationär aufgenommen wurde. Weiters besprochen werden Standards in der Wernicke-Prophylaxe, Diskrepanzen in Guidelines und Tipps für die Praxis.

Changes in distribution of associated molecular targets have been reported across several neuropsychiatric disorders. However, the high-resolution topology of most proteins is unknown and simultaneous in vivo measurement in multi-receptor systems is complicated. To account for the missing proteomic information, mRNA transcripts are typically used as a surrogate. Nonetheless, post-transcriptional and post-translational processes might cause the discrepancy between the final distribution of proteins and gene expression patterns. Therefore, this study aims to investigate ex vivo links between mRNA expression and corresponding receptor density in the human cerebral cortex.To this end, autoradiography data on the density of 15 different receptors in 38 brain regions were correlated with the expression patterns of 50 associated genes derived from microarray data (mA), RNA sequencing data (RNA-Seq) provided by the Allen Human Brain Atlas and predicted mRNA expression patterns (pred-mRNA). Spearman’s rank correlation was used to evaluate the possible links between proteomic data and mRNA expression patterns.Correlations between mRNA and protein density varied greatly between targets: Positive associations were found for e.g. the serotonin 1A (pred-mRNA: rs = 0.708; mA: rs = 0.601) or kainate receptor (pred-mRNA: rs = 0.655; mA: rs = 0.601; RNA-Seq: rs = 0.575), while most of the investigated target receptors showed low or negative correlations.The high variability in the correspondence of mRNA expression and receptor warrants caution when inferring the topology of molecular targets in the brain from transcriptome data. This highlights the longstanding value of molecular imaging data and the need for comprehensive proteomic data.

Pharmacological imaging of the effects of selective serotonin reuptake inhibitors (SSRI) may aid the clarification of their mechanism of action and influence treatment of highly prevalent neuropsychiatric conditions if the detected effects could be related to patient outcomes. In a randomized double-blind design, 38 healthy participants received a constant infusion of 8 mg citalopram or saline during either their first or second of two PET/MR scans. Resting-state functional MRI (fMRI) was acquired simultaneously with PET data on the binding of serotonin transporters (5-HTT) using [11C]DASB. Three different approaches for modeling of pharmacological fMRI response were tested separately. These relied on the use of regressors corresponding to (1) the drug infusion paradigm, (2) time courses of citalopram plasma concentrations and (3) changes in 5-HTT binding measured in each individual, respectively. Furthermore, the replication of results of a widely used model-free analysis method was attempted which assesses the deviation of signal in discrete time bins of fMRI data acquired after start of drug infusion. Following drug challenge, average 5-HTT occupancy was 69±7% and peak citalopram plasma levels were 111.8 ± 21.1 ng/ml. None of the applied methods could detect significant differences in the pharmacological response between SSRI and placebo scans. The failed replication of SSRI effects reported in the literature despite a threefold larger sample size highlights the importance of appropriate correction for family-wise error in order to avoid spurious results in pharmacological imaging. This calls for the development of analysis methods which take regional specialization and the dynamics of brain activity into account.

Background Parcellation of the cerebral cortex serves the investigation of the emergence of uniquely human brain functions and disorders. Transcriptome data enable the characterization of the molecular properties of cortical areas in unprecedented detail. Previously, we predicted the expression of 18,686 genes in the entire human brain based on microarray data. Here, we employed these data to parcellate the cortex and study the regional enrichment of disease-associated genes. Methods We performed agglomerative hierarchical clustering based on normalized transcriptome data to delineate areas with distinct gene expression profiles. Subsequently, we tested these profiles for the enrichment of gene sets associated with brain disorders by genome-wide association studies and expert-curated databases using gene set enrichment analysis. Results Transcriptome-based parcellation identified borders in line with major anatomical landmarks and the functional differentiation of primary motor, somatosensory, visual, and auditory areas. Gene set enrichment analysis based on curated databases suggested new roles of specific areas in psychiatric and neurological disorders while reproducing well-established links for movement and neurodegenerative disorders, for example, amyotrophic lateral sclerosis (motor cortex) and Alzheimer’s disease (entorhinal cortex). Meanwhile, gene sets derived from genome-wide association studies on psychiatric disorders exhibited similar enrichment patterns driven by pleiotropic genes expressed in the posterior fusiform gyrus and inferior parietal lobule. Conclusions The identified enrichment patterns suggest the vulnerability of specific cortical areas to various influences that might alter the risk of developing one or several brain disorders. For several diseases, specific genes were highlighted, which could lead to the discovery of novel disease mechanisms and urgently needed treatments.

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 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 ability to solve cognitive tasks depends upon adaptive changes in the organization of whole-brain functional networks. However, the link between task-induced network reconfigurations and their underlying energy demands is poorly understood. We address this by multimodal network analyses integrating functional and molecular neuroimaging acquired concurrently during a complex cognitive task. Task engagement elicited a marked increase in the association between glucose consumption and functional brain network reorganization. This convergence between metabolic and neural processes was specific to feedforward connections linking the visual and dorsal attention networks, in accordance with task requirements of visuo-spatial reasoning. Further increases in cognitive load above initial task engagement did not affect the relationship between metabolism and network reorganization but only modulated existing interactions. Our findings show how the upregulation of key computational mechanisms to support cognitive performance unveils the complex, interdependent changes in neural metabolism and neuro-vascular responses.

The quantification of big pools of diverse molecules provides important insights on brain function, but is often restricted to a limited number of observations, which impairs integration with other modalities. To resolve this issue, a method allowing for the prediction of mRNA expression in the entire brain based on microarray data provided in the Allen Human Brain Atlas was developed. Microarray data of 3702 samples from 6 brain donors was registered to MNI and cortical surface space using FreeSurfer. For each of 18,686 genes, spatial dependence of transcription was assessed using variogram modelling. Variogram models were employed in Gaussian process regression to calculate best linear unbiased predictions for gene expression at all locations represented in well-established imaging atlases for cortex, subcortical structures and cerebellum. For validation, predicted whole-brain transcription of the HTR1A gene was correlated with [carbonyl-11C]WAY-100635 positron emission tomography data collected from 30 healthy subjects. Prediction results showed minimal bias ranging within ±0.016 (cortical surface), ±0.12 (subcortical regions) and ±0.14 (cerebellum) in units of log2 expression intensity for all genes. Across genes, the correlation of predicted and observed mRNA expression in leave-one-out cross-validation correlated with the strength of spatial dependence (cortical surface: r = 0.91, subcortical regions: r = 0.85, cerebellum: r = 0.84). 816 out of 18,686 genes exhibited a high spatial dependence accounting for more than 50% of variance in the difference of gene expression on the cortical surface. In subcortical regions and cerebellum, different sets of genes were implicated by high spatially structured variability. For the serotonin 1A receptor, correlation between PET binding potentials and predicted comprehensive mRNA expression was markedly higher (Spearman ρ = 0.72 for cortical surface, ρ = 0.84 for subcortical regions) than correlation of PET and discrete samples only (ρ = 0.55 and ρ = 0.63, respectively). Prediction of mRNA expression in the entire human brain allows for intuitive visualization of gene transcription and seamless integration in multimodal analysis without bias arising from non-uniform distribution of available samples. Extension of this methodology promises to facilitate translation of omics research and enable investigation of human brain function at a systems level.

Positron emission tomography enables to quantify protein expression and to visualize physiological processes in vivo based on the measurement of highly specific radioligands bound to the target molecule of interest. While medications targeting the serotonergic neurotransmitter system are widely used in the treatment of psychiatric disorders, imaging of molecular changes using PET allowed for the elucidation of the contribution of this neurotransmitter system to the pathophysiology of these diseases. Here, we provide an overview of the basic measurement principles and available radioligands and demonstrate applications in basic and clinical research.

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.

Pleasure and motivation are important factors for goal-directed behavior and well-being in both animals and humans. Intact hedonic capacity requires an undisturbed interplay between a number of different brain regions and transmitter systems. Concordantly, dysfunction of networks encoding for reward have been shown in depression and other psychiatric disorders. The development of technological possibilities to investigate connectivity on a functional level in humans and to directly influence networks in animals using optogenetics among other techniques has provided new important insights in this field of research. In this review, we aim to provide an overview on the neurobiological substrates of anhedonia on a network level. For this purpose, definition of anhedonia and the involved reward components are described first, then current data on reward networks in healthy individuals and in depressed patients are summarized, and the roles of different neurotransmitter systems involved in reward processing are specified. Based on this information, the impact of different therapeutic approaches on reward processing is described with a particular focus on deep brain stimulation (DBS) as a possibility for a direct modulation of human brain structures in vivo. Overall, results of current studies emphasize the importance of anhedonia in psychiatric disorders and the relevance of targeting this phenotype for a successful psychiatric treatment. However, more data incorporating these results for the refinement of methodological approaches are needed to be able to develop individually tailored therapeutic concepts based on both clinical and neurobiological profiles of patients.

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.