Disruption of Accumbens and Thalamic White Matter Connectivity Revealed by Diffusion Tensor Tractography in Young Men with Genetic Risk for Obesity

Abstract

Background: Neurovascular coupling is associated with white matter (WM) structural integrity, and it is regulated by specific subtypes of dopaminergic receptors. An altered activity of such receptors, highly expressed in reward-related regions, has been reported in carriers of obesity-risk alleles of the fat mass and obesity associated (FTO) gene. Among the reward-related regions, the thalamus and the nucleus accumbens are particularly vulnerable to blood pressure dysregulation due to their peculiar anatomo-vascular characteristics, and have been consistently reported to be altered in early-stage obesity. We have thus hypothesized that a disruption in thalamus and nucleus accumbens WM microstructure, possibly on neurovascular basis, could potentially be a predisposing factor underlying the enhanced risk for obesity in the risk-allele carriers.Methods: We have tested WM integrity in 21 male participants genotyped on the FTO risk single nucleotide polymorphisms (SNP) rs9939609, through a deterministic tractography analysis. Only homozygous participants (9 AA, 12 TT) were included. 11 tracts were selected and categorized as following according to our hypothesis: “risk tracts”, “obesity-associated tracts”, and a control tract (forcpes major). We investigated whether an association existed between genotype, body mass index (BMI) and WM microstructural integrity in the “risk-tracts” (anterior thalamic radiation and accumbofrontal fasciculus) compared to other tracts. Moreover, we explored whether WM diffusivity could be related to specific personality traits in terms of punishment and reward sensitivity, as measure by the BIS/BAS questionnaire.Results: An effect of the genotype and an interaction effect of genotype and BMI were detected on the fractional anisotropy (FA) of the “risk tracts”. Correlations between WM diffusivity parameters and measures of punishment and reward sensitivity were also detected in many WM tracts of both networks.Conclusions: A disruption of the structural connectivity from the nucleus accumbens and the thalamus might occur early in carriers of the FTO AA risk-allele, and possibly act as a predisposing factor to the development of obesity.

Differences in brain structure and function in children with the FTO obesity‐risk allele

“…Further, Wiemerslage's sample shows significant BMI differences and includes overweight participants, whereas Melhorn uses a matched sample of participants with average BMI. Thus, although the present findings are consistent with some of the existing literature, the use of mixed methodologies and exclusion of the cerebellum from analyses in nearly half of the existing literature 7,11,12 precludes studies from ascertaining what role, if any, the cerebellum plays in FTO‐ related risk for obesity. Of note, the four aforementioned studies documenting FTO differences all examined different FTO SNPs (rs1421085, rs17817449, and rs9939609).…”

“…Overall lower brain volumes, 5 as well as specific volumetric reductions in the nucleus accumbens, 6 have been documented in FTO risk allele carriers relative to noncarriers. Further, white matter (WM) microstructure abnormalities have been detected in risk allele carriers in the anterior thalamic radiations and the accumbofrontal fasciculus 7 . However, one study failed to document differences in WM integrity across genotypes 8 .…”

Neuroimaging in the Kleine-Levin Syndrome

“…Still, a wide range of behavioural symptoms, as those reported in KLS, seem to depend on the dopaminergic portion of the reward network. The ventral/limbic part of the network, including the anterior thalamic radiation, nucleus accumbens, caudate nucleus and the putamen, has been reported in connection with obesity, hypersexuality, aggressive behaviour and gambling [ 26 – 30 ]. In addition, the accumbo-frontal fasciculus and the anterior thalamic radiation are part of a cortico-striato-thalamo-cortical loop [ 29 ] which contain structures that also are targets for deep brain stimulation (DBS) in obsessive-compulsive and other psychiatric disorders [ 31 , 32 ].…”

Call to action regarding the vascular‐bipolar link: A report from the Vascular Task Force of the International Society for Bipolar Disorders

“…However, the observational nature of the study precludes definitive conclusions regarding the direction of the observed associations. Moreover, “third variable” causes such as genes that impact both BMI and limbic brain structure/function cannot be excluded 189‐191 …”