Dataset Information

External awareness and GABA--a multimodal imaging study combining fMRI and [18F]flumazenil-PET.

ABSTRACT: Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [(18)F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders.

SUBMITTER: Wiebking C

PROVIDER: S-EPMC6869063 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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External awareness and GABA--a multimodal imaging study combining fMRI and [18F]flumazenil-PET.

Wiebking Christine C Duncan Niall W NW Qin Pengmin P Hayes Dave J DJ Lyttelton Oliver O Gravel Paul P Verhaeghe Jeroen J Kostikov Alexey P AP Schirrmacher Ralf R Reader Andrew J AJ Bajbouj Malek M Northoff Georg G

Human brain mapping 20120921 1

Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI ...[more]

PMID: 22996793

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Project description:Soluble epoxide hydrolase (sEH) is a bifunctional enzyme located within cytosol and peroxisomes that converts epoxides to the corresponding diols and hydrolyzes phosphate monoesters. It serves to inactivate epoxyeicosatrienoic acids (EETs), which are generated in the brain to couple neuronal activity and cerebral blood flow in normal and pathologic states. Altered regulation of sEH was observed previously in various neuropathologic disorders including vascular dementia and stroke. Inhibitors of sEH are pursued as agents to mitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)-6-18F-fluoronicotinamide (18F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. METHODS:18F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18F-FNDP was measured using an sEH inhibitor screening assay kit. Biodistribution was undertaken in CD-1 mice. Binding specificity was assayed in CD-1 and sEH knock-out mice and Papio anubis (baboon) through pretreatment with an sEH inhibitor to block sEH binding. Dynamic PET imaging with arterial blood sampling was performed in 3 baboons, with regional tracer binding quantified using distribution volume. The metabolism of 18F-FNDP in baboons was assessed using high-performance liquid chromatography. RESULTS:18F-FNDP (inhibition binding affinity constant, 1.73 nM) was prepared in 1 step in a radiochemical yield of 14% ± 7%, specific radioactivity in the range of 888-3,774 GBq/?mol, and a radiochemical purity greater than 99% using an automatic radiosynthesis module. The time of preparation was about 75 min. In CD-1 mice, regional uptake followed the pattern of striatum > cortex > hippocampus > cerebellum, consistent with the known brain distribution of sEH, with 5.2% injected dose per gram of tissue at peak uptake. Blockade of 80%-90% was demonstrated in all brain regions. Minimal radiotracer uptake was present in sEH knock-out mice. PET baboon brain distribution paralleled that seen in mouse, with a marked blockade (95%) noted in all regions indicating sEH-mediated uptake of 18F-FNDP. Two hydrophilic metabolites were identified, with 20% parent compound present at 90 min after injection in baboon plasma. CONCLUSION:18F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18F-FNDP targeted sEH in murine and nonhuman primate brain specifically. 18F-FNDP is a promising PET radiotracer likely to be useful for understanding the role of sEH in a variety of conditions affecting the central nervous system.

Dataset Information

External awareness and GABA--a multimodal imaging study combining fMRI and [18F]flumazenil-PET.

Publications

External awareness and GABA--a multimodal imaging study combining fMRI and [18F]flumazenil-PET.

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