An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning.

Variations in the fat mass and obesity-associated (FTO) gene are linked to obesity. However, the underlying neurobiological mechanisms by which these genetic variants influence obesity, behavior, and brain are unknown. Given that Fto regulates D2/3R signaling in mice, we tested in humans whether variants in FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling and is also associated with obesity. In a behavioral and fMRI study, we demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans. Furthermore, dynamic causal modeling confirmed that FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic predisposition alters reward processing not only in obesity, but also in other disorders with altered D2R-dependent impulse control, such as addiction. Significance statement: Variations in the fat mass and obesity-associated (FTO) gene are associated with obesity. Here we demonstrate that variants of FTO affect dopamine-dependent midbrain brain responses and learning from negative outcomes in humans during a reward learning task. Furthermore, FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic vulnerability in reward processing can increase predisposition to obesity.

FTO gene variant modulates the neural correlates of visual food perception.

Variations in the fat mass and obesity associated (FTO) gene are currently the strongest known genetic factor predisposing humans to non-monogenic obesity. Recent experiments have linked these variants to a broad spectrum of behavioural alterations, including food choice and substance abuse. Yet, the underlying neurobiological mechanisms by which these genetic variations influence body weight remain elusive. Here, we explore the brain structural substrate of the obesity-predisposing rs9939609 T/A variant of the FTO gene in non-obese subjects by means of multivariate classification and use fMRI to investigate genotype-specific differences in neural food-cue reactivity by analysing correlates of a visual food perception task. Our findings demonstrate that MRI-derived measures of morphology along middle and posterior fusiform gyrus (FFG) are highly predictive for FTO at-risk allele carriers, who also show enhanced neural responses elicited by food cues in the same posterior FFG area. In brief, these findings provide first-time evidence for FTO-specific differences in both brain structure and function already in non-obese individuals, thereby contributing to a mechanistic understanding of why FTO is a predisposing factor for obesity.

Temporally remote destabilization of prediction after rare breaches of expectancy.

While neural signatures of breaches of expectancy and their immediate effects have been investigated, thus far, temporally more remote effects have been neglected. The present fMRI study explored neural correlates of temporally remote destabilization of prediction following rare breaches of expectancy with a mean delay of 14 s. We hypothesized temporally remote destabilization to be reflected either in an attenuation of areas related to long-term memory or in an increase of lateral fronto-parietal loops related to the encoding of new stimuli. Monitoring a deterministic 24-digit sequence, subjects were asked to indicate occasional sequential omissions by key press. Temporally remote destabilization of prediction was expected to be revealed by contrasting sequential events whose equivalent was omitted in the preceding sequential run n-1 (destabilized events) with sequential events without such history (nondestabilized events). Temporally remote destabilization of prediction was reflected in an attenuation of activity in the dorsal frontomedian cortex (Brodmann Area (BA) 9) bilaterally. Moreover, activation of the left medial BA 9 was enhanced by contrasting nondestabilized events with breaches. The decrease of dorsal frontomedian activation in the case of destabilized events might be interpreted as a top-down modulation on perception causing a less expectation-restricted encoding of the current stimulus and hence enabling the adaptation of expectation and prediction in the long run.

Objects Mediate Goal Integration in Ventrolateral Prefrontal Cortex during Action Observation.

Actions performed by others are mostly not observed in isolation, but embedded in sequences of actions tied together by an overarching goal. Therefore, preceding actions can modulate the observer's expectations in relation to the currently perceived action. Ventrolateral prefrontal cortex (vlPFC), and inferior frontal gyrus (IFG) in particular, is suggested to subserve the integration of episodic as well as semantic information and memory, including action scripts. The present fMRI study investigated if activation in IFG varies with the effort to integrate expected and observed action, even when not required by the task. During an fMRI session, participants were instructed to attend to short videos of single actions and to deliver a judgment about the actor's current goal. We manipulated the strength of goal expectation induced by the preceding action, implementing the parameter "goal-relatedness" between the preceding and the currently observed action. Moreover, since objects point to the probability of certain actions, we also manipulated whether the current and the preceding action shared at least one object or not. We found an interaction between the two factors goal-relatedness and shared object: IFG activation increased the weaker the goal-relatedness between the preceding and the current action was, but only when they shared at least one object. Here, integration of successive action steps was triggered by the re-appearing (shared) object but hampered by a weak goal-relatedness between the actually observed manipulation. These findings foster the recently emerging view that IFG is enhanced by goal-related conflicts during action observation.

Correction: Objects Mediate Goal Integration in Ventrolateral Prefrontal Cortex during Action Observation.

[This corrects the article DOI: 10.1371/journal.pone.0134316.].

Joint principles of motor and cognitive dysfunction in Parkinson's disease.

Traditionally, the lateral premotor cortex (PM) is assigned a role in stimulus-driven rather than memory-driven motor control, whereas the opposite holds for the mesial premotor cortex (supplementary motor area, SMA). Consistently, patients with Parkinson's Disease (PD), in which a specific functional degradation of the mesial loop (i.e., SMA-Striatum) occurs, show impaired memory-driven but relatively preserved stimulus-driven motor control. However, both parts of the premotor cortex are involved in perceptual prediction tasks as well. Here we tested whether the functional bias described on the motor level (i.e., memory-driven/mesial versus stimulus-driven/lateral) can also be detected in perceptual prediction tasks thereby suggesting that PD patients exhibit the same pattern of impaired memory-driven and preserved stimulus-driven control in the cognitive domain. To this end, we investigated 20 male PD-patients "on" and "off" dopaminergic medication while performing a serial prediction task (SPT). A specific modification was implemented to the classical SPT (SPT0) that caused shifts from stimulus- to memory-based prediction (SPT+). As a result, PD patients showed a significantly impaired performance "off" compared to "on" medication for SPT+, whereas no significant "on"/"off"-effects were found for SPT0. Descriptively, the "off"-performance decreased gradually with increasing demands on memory-based prediction. Furthermore, the severity of motor deficits according to the UPDRS III correlated significantly with impaired performance in SPT0 "on" medication. Importantly, an even stronger dependency was found for UPDRS III and SPT+. These findings point to a role of the SMA-striatal loop in memory-driven serial prediction beyond the motor domain.