Assessment of α4β2 nicotinic acetylcholine receptor (nAChR) availability and neuronal response to rewarding food-cues in human obesity using simultaneous PET-MRI

Introduction: Cholinergic modulation of brain reward circuits appears to play a crucial role in information processing about salience as a key biological mechanism in obesity (OB). Changes in acetylcholine (ACh) transmission, however, that lead to abnormal eating behavior have not been demonstrated in vivo in human OB so far. We investigated the α4β2 nAChRs availability and neuronal network activity applying simultaneous PET-MRI and the α4β2 nAChR ligand (-)-[¹⁸F]flubatine in individuals with OB with high or low disinhibited eating behavior and normal-weight controls (NW) at resting-state (rest) and after food cue stimulation (stim). We assumed that 1) α4β2 nAChR of the mesolimbic system is altered in OB compared with NW, and 2) attentional bias towards salient food cues in high-disinhibited eaters is related to changes in thalamic α4β2*-nAChR availability and large-scale networks as markers for differences in eating traits.

Methods: Twenty-six healthy individuals with OB (n=11; 7♀; age 42±15 yrs; BMI 37±3 kg/m²) and NW (n=15; 12♀; age 28±7 yrs; BMI 22±2 kg/m²) underwent PET-MRI (Siemens Biograph) twice on separate days at rest and under stim. (-)-[¹⁸F]flubatine was applied using a bolus-infusion protocol (201±6 MBq) over 165 min with list mode acquisition (0-60 min and 120-165 min p.i.) paralleled by T1 MPRAGE for anatomical co-registration and functional EPI sequences during rest or stim. Total distribution volumes V_T (mL/cm³) were estimated as the ratio between mean (−)-[¹⁸F]flubatine radioactivity in tissue between 120 and 165 min and free parent (−)-[¹⁸F]flubatine in the plasma obtained from venous blood. During second scan (stim), pictures representing food-associated cues of different salient information (high and low caloric) were shown 120-135 min p.i. as part of an fMRI task. fMRI data were analyzed through eigenvector centrality mapping (ECM) and functional connectivity (FC) analyses.

Results: 1) Under rest, V_T of the ventral tegmental area/substantia nigra (VTA/SN) tend lower in OB (16.1±2.1) as compared with NW (17.5±2.2; p=0.1) while ECM showed significantly higher centrality of the nucleus accumbens in NW (T=3.43; p_uncorr<0.001). V_T did not differ in other brain regions (e.g., the thalamus: 26.3±3.4 and 26.2±2.5, respectively, p=0.9) between OB and NW. During stim V_T tend higher versus rest in OB (VTA/SN: 17.0±1.7, p=0.3; thalamus: 28.3±3.5, p=0.2) but not in NW (VTA/SN: 17.7±2.6, p=0.9; thalamus: 25.9±3.2, p=0.8). Applying V_T of the VTA/SN as a covariate in FC analyses using VTA as a seed markedly weakened the strong FC (p_uncorr<0.001) between VTA and the orbito-frontal cortex (OFC) to nearly non-significant level. 2) Furthermore, ECM revealed high centrality (p_uncorr<0.001) of the insula as a core node of the salience network in NW but not in OB at rest while stim studies showed high centrality in fronto-parietal attentional/executive control networks in both (NW>OB).

Conclusions: These first in-human data provide an insight into α4β2 nAChR-mediated mesolimbic-cholinergic mechanism that is altered in individuals with obesity. Specifically, the number of available α4β2 nAChR binding sites in the VTA-mesolimbic system has an impact on the function of the OFC which is the most important brain region for providing a global value judgement of food. Currently, we investigate whether thalamic α4β2 nAChR values in OB represents an altered cholinergic control over attention to high-incentive, salient cues. Acknowledgements: The work was supported by the Federal Ministry of Education and Research, Germany, FKZ: 01E01001.