ORCID Profile
0000-0002-9739-0724
Current Organisation
Medizinische Universität Wien
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Publisher: Springer Science and Business Media LLC
Date: 09-05-2022
DOI: 10.1038/S42003-022-03362-4
Abstract: The neurobiological basis of learning is reflected in adaptations of brain structure, network organization and energy metabolism. However, it is still unknown how different neuroplastic mechanisms act together and if cognitive advancements relate to general or task-specific changes. Therefore, we tested how hierarchical network interactions contribute to improvements in the performance of a visuo-spatial processing task by employing simultaneous PET/MR neuroimaging before and after a 4-week learning period. We combined functional PET and metabolic connectivity mapping (MCM) to infer directional interactions across brain regions. Learning altered the top-down regulation of the salience network onto the occipital cortex, with increases in MCM at resting-state and decreases during task execution. Accordingly, a higher ergence between resting-state and task-specific effects was associated with better cognitive performance, indicating that these adaptations are complementary and both required for successful visuo-spatial skill learning. Simulations further showed that changes at resting-state were dependent on glucose metabolism, whereas those during task performance were driven by functional connectivity between salience and visual networks. Referring to previous work, we suggest that learning establishes a metabolically expensive skill engram at rest, whose retrieval serves for efficient task execution by minimizing prediction errors between neuronal representations of brain regions on different hierarchical levels.
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2021
DOI: 10.1101/2021.11.12.468351
Abstract: The neurobiological basis of learning is reflected in adaptations of brain structure, network organization and energy metabolism. However, it is still unknown how different neuroplastic mechanisms act together and if cognitive advancements relate to general or task-specific changes. To address these questions, we tested how hierarchical network interactions contribute to improvements in the performance of a visuo-spatial processing task by employing simultaneous PET/MR neuroimaging before and after a 4-week learning period. We combined functional PET with metabolic connectivity mapping (MCM) to infer directional interactions across brain regions and subsequently performed simulations to disentangle the role of functional network dynamics and glucose metabolism. As a result, learning altered the top-down regulation of the salience network onto the occipital cortex, with increases in MCM at resting-state and decreases during task execution. Accordingly, a higher ergence between resting-state and task-specific effects was associated with better cognitive performance, indicating that these adaptations are complementary and both required for successful skill learning. Simulations further showed that changes at resting-state were dependent on glucose metabolism, whereas those during task performance were driven by functional connectivity between salience and visual networks. Referring to previous work, we suggest that learning establishes a metabolically expensive skill engram at rest, whose retrieval serves for efficient task execution by minimizing prediction errors between neuronal representations of brain regions on different hierarchical levels.
Publisher: Cold Spring Harbor Laboratory
Date: 21-02-2022
DOI: 10.1101/2022.02.16.22271078
Abstract: Previous studies suggest that transcranial magnetic stimulation exerts antidepressant effects by altering functional connectivity (FC). However, knowledge about this mechanism is still limited. Here, we aimed to investigate the effect of bilateral sequential theta-burst stimulation (TBS) on FC in treatment-resistant depression (TRD) in a sham-controlled longitudinal study. TRD patients (n = 20) underwent a three-week treatment of intermittent TBS of the left and continuous TBS of the right dorsolateral prefrontal cortex (DLPFC). Upon this trial’s premature termination, 15 patients had received active TBS and five patients sham stimulation. Resting-state functional magnetic resonance imaging was performed at baseline and after treatment. FC (left and right DLPFC) was estimated for each participant, followed by group statistics (T-tests). Furthermore, depression scores were analyzed (linear mixed models analysis) and tested for correlation with FC. Both groups exhibited reductions of depression scores, however, there was no significant main effect of group, or group and time. Anticorrelations between DLPFC and the subgenual cingulate cortex (sgACC) were observed for baseline FC, corresponding to changes in depression severity. Treatment did not significantly change DLPFC-sgACC connectivity, but significantly reduced FC between the left stimulation target and bilateral anterior insula. Our data is compatible with previous reports on the relevance of anticorrelation between DLPFC and sgACC for treatment success. Furthermore, FC changes between left DLPFC and bilateral anterior insula highlight the effect of TBS on the salience network. Due to the limited s le size, results should be interpreted with caution and are of exploratory nature.
Publisher: Cold Spring Harbor Laboratory
Date: 21-02-2022
DOI: 10.1101/2022.02.17.22271118
Abstract: Theta burst stimulation (TBS) belongs to one of the biological antidepressant treatment options. When applied bilaterally, excitatory intermittent TBS (iTBS) is commonly targeted to the left and inhibitory continuous TBS (cTBS) to the right dorsolateral prefrontal cortex. TBS was shown to influence neurotransmitter systems, while iTBS is thought to interfere with glutamatergic circuits and cTBS to mediate GABAergic neurotransmission. We aimed to expand insights in the therapeutic effects of TBS on the GABAergic and glutamatergic system utilizing 3D-multivxovel magnetic resonance spectroscopy imaging (MRSI) in combination with a novel surface-based MRSI analysis approach to investigate changes of cortical neurotransmitter levels in patients with treatment resistant depression (TRD). Twelve TRD patients (5 female, mean age±SD=35±11 years) completed paired MRSI measurements, using a GABA-edited 3D-multivoxel MEGA-LASER sequence, before and after three weeks of bilateral TBS treatment. Changes in cortical distributions of GABA+/tNAA (GABA+macromolecules relative to total N-acetylaspartate) and Glx/tNAA (Glx=mixed signal of glutamate and glutamine), were investigated in a surface-based region-of-interest (ROI) analysis approach. ANCOVAs revealed a significant increase in Glx/tNAA ratios in the left caudal middle frontal area (p corr .=0.046, F=13.292), an area targeted by iTBS treatment. Whereas, contralateral treatment with cTBS evoked no alterations in glutamate or GABA concentrations. This study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS, using a novel surface-based analysis of 3D-MRSI data. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.
Publisher: Springer Science and Business Media LLC
Date: 02-2023
DOI: 10.1038/S41398-023-02319-3
Abstract: Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT 1A ) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [ carbonyl - 11 C]WAY-100635 including arterial blood s ling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation ( n = 8 and n = 3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted of excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere, time, and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group, time, and HAMD on specific distribution volume (V S ) of 5-HT 1A receptor. While post-hoc comparisons showed no significant changes of 5-HT 1A receptor V S in either group, higher 5-HT 1A receptor V S after treatment correlated with greater difference in HAMD (r = −0.62). The results of this proof-of-concept trial hint towards potential effects of TBS on the distribution of the 5-HT 1A receptor. Due to the small s le size, all results must, however, be regarded with caution.
Publisher: SAGE Publications
Date: 30-05-2021
DOI: 10.1177/0271678X211019827
Abstract: The assessment of dopamine release with the PET competition model is thoroughly validated but entails disadvantages for the investigation of cognitive processes. We introduce a novel approach incorporating 6-[ 18 F]FDOPA uptake as index of the dynamic regulation of dopamine synthesis enzymes by neuronal firing. The feasibility of this approach is demonstrated by assessing widely described sex differences in dopamine neurotransmission. Reward processing was behaviorally investigated in 36 healthy participants, of whom 16 completed fPET and fMRI during the monetary incentive delay task. A single 50 min fPET acquisition with 6-[ 18 F]FDOPA served to quantify task-specific changes in dopamine synthesis. In men monetary gain induced stronger increases in ventral striatum dopamine synthesis than loss. Interestingly, the opposite effect was discovered in women. These changes were further associated with reward (men) and punishment sensitivity (women). As expected, fMRI showed robust task-specific neuronal activation but no sex difference. Our findings provide a neurobiological basis for known behavioral sex differences in reward and punishment processing, with important implications in psychiatric disorders showing sex-specific prevalence, altered reward processing and dopamine signaling. The high temporal resolution and magnitude of task-specific changes make fPET a promising tool to investigate functional neurotransmitter dynamics during cognitive processing and in brain disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 30-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 02-10-2023
Publisher: eLife Sciences Publications, Ltd
Date: 24-04-2023
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2023
DOI: 10.1101/2023.08.02.551631
Abstract: 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 framework at a temporal resolution of 3 seconds. Consistent with simulated kinetic modeling, we observed a constant increase in the [ 18 F]FDG signal during task execution, followed by a rapid return to baseline after stimulation ceased. The simultaneous acquisition of BOLD fMRI revealed that the temporal coupling between hemodynamic and metabolic signals in the primary motor cortex was related to in idual 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 depended on the task-positive network metabolic demands. In sum, the proposed approach enables the advancement from parallel to truly synchronized investigation of metabolic and hemodynamic responses during cognitive processing.
Publisher: eLife Sciences Publications, Ltd
Date: 25-05-2023
DOI: 10.7554/ELIFE.84683
Abstract: 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 ergence 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.
Publisher: Cold Spring Harbor Laboratory
Date: 12-08-2022
DOI: 10.1101/2022.08.12.503715
Abstract: Although BOLD signal decreases in the default mode network (DMN) are commonly observed during attention-demanding tasks, their neurobiological underpinnings are not fully understood. Previous work has shown decreases but also increases in glucose metabolism that match with or dissociate from these BOLD signal decreases, respectively. To resolve this discrepancy, we analyzed functional PET/MRI data from 50 healthy subjects during the performance of the visuo-spatial processing game Tetris® and combined this with previously published data sets of working memory as well as visual and motor stimulation. Our findings show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive brain networks. Specifically, the dorsal attention (involved in Tetris®) and frontoparietal networks (engaged during working memory) shape the glucose metabolism of the posteromedial DMN in opposing directions. External attention-demanding tasks lead to a downregulation of the posteromedial DMN with consistent decreases in the BOLD signal and glucose metabolism, whereas working memory is subject to metabolically expensive mechanisms of BOLD signal suppression. We suggest that the former finding is mediated by decreased glutamate signaling, while the latter results from active GABAergic inhibition, regulating the competition between self-generated and task-driven internal demands. 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.
Publisher: Cold Spring Harbor Laboratory
Date: 22-02-2022
DOI: 10.1101/2022.02.18.22271165
Abstract: Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT 1A ) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [ carbonyl - 11 C]WAY-100635 including arterial blood s ling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n=8 and n=3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted in excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere time and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group time and HAMD on 5-HT 1A receptor specific binding V S . While post-hoc comparisons showed no significant changes of 5-HT 1A V S in either group, higher 5-HT 1A V S after treatment correlated with greater difference in HAMD (r=-0.62), indicative of potential effects of TBS on the 5-HT 1A receptor. Due to the small s le size, all results, however, must be regarded with caution.
Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2021
DOI: 10.1101/2021.01.15.426779
Abstract: 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.
Publisher: Cold Spring Harbor Laboratory
Date: 22-09-2023
Publisher: SAGE Publications
Date: 02-06-2021
DOI: 10.1177/0271678X211020589
Abstract: 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.
Publisher: Cold Spring Harbor Laboratory
Date: 23-12-2019
DOI: 10.1101/2019.12.23.886812
Abstract: In 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-[ 18 F]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. Reward and punishment processing was behaviorally investigated in 36 healthy participants, where 16 underwent fPET and fMRI while performing the monetary incentive delay task. 6-[ 18 F]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. Monetary 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. Our 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.
Publisher: eLife Sciences Publications, Ltd
Date: 21-04-2020
DOI: 10.7554/ELIFE.52443
Abstract: 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.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 07-09-2022
DOI: 10.1038/S41380-022-01733-1
Abstract: Strategies to personalize psychopharmacological treatment promise to improve efficacy and tolerability. We measured serotonin transporter occupancy immediately after infusion of the widely prescribed P-glycoprotein substrate citalopram and assessed to what extent variants of the ABCB1 gene affect drug target engagement in the brain in vivo. A total of 79 participants (39 female) including 31 patients with major depression and 48 healthy volunteers underwent two PET/MRI scans with the tracer [ 11 C]DASB and placebo-controlled infusion of citalopram (8 mg) in a cross-over design. We tested the effect of six ABCB1 single nucleotide polymorphisms and found lower SERT occupancy in ABCB1 rs2235015 minor allele carriers ( n = 26, MAF = 0.18) compared to major allele homozygotes ( t 73 = 2.73, p FWE 0.05) as well as in men compared to women ( t 73 = 3.33, p FWE 0.05). These effects were robust to correction for citalopram plasma concentration, age and diagnosis. From occupancy we derived the ratio of occupied to unoccupied SERT, because in theory this measure is equal to the product of drug affinity and concentration at target sites. A model combining genotype with basic clinical variables, predicted that, at the same dosage, occupied to unoccupied SERT ratio was −14.48 ± 5.38% lower in rs2235015 minor allele carriers, +19.10 ± 6.95% higher in women, −4.83 ± 2.70% lower per 10 kg bodyweight, and −2.68 ± 3.07% lower per 10 years of age. Our results support the exploration of clinical algorithms with adjustment of initial citalopram dosing and highlight the potential of imaging-genetics for precision pharmacotherapy in psychiatry.
Publisher: Elsevier BV
Date: 08-2021
No related grants have been discovered for Godber Mathis Godbersen.