Self-reported intake of high-fat and high-sugar diet is not associated with cognitive stability and flexibility in healthy men

Animal studies indicate that a high-fat/high-sugar diet (HFS) can change dopamine signal transmission in the brain, which could promote maladaptive behavior and decision-making. Such diet-induced changes may also explain observed alterations in the dopamine system in human obesity. Genetic variants that modulate dopamine transmission have been proposed to render some individuals more prone to potential effects of HFS. The objective of this study was to investigate the association of HFS with dopamine-dependent cognition in humans and how genetic variations might modulate this potential association. Using a questionnaire assessing the self -reported consumption of high-fat/high-sugar foods, we investigated the association with diet by recruiting healthy young men that fall into the lower or upper end of that questionnaire (low fat/sugar group: LFS, n = 45; high fat/sugar group: HFS, n = 41) and explored the interaction of fat and sugar consumption with COMT Va1158Met and Taq1A genotype. During functional magnetic resonance imaging (fMRI) scanning, male partici-pants performed a working memory (WM) task that probes distractor-resistance and updating of WM repre-sentations. Logistic and linear regression models revealed no significant difference in WM performance between the two diet groups, nor an interaction with COMT Va1t58Met or Tag1A genotype. Neural activation in task -related brain areas also did not differ between diet groups. Independent of diet group, higher BMI was associ-ated with lower overall accuracy on the WM task. This cross-sectional study does not provide evidence for diet -related differences in WM stability and flexibility in men, nor for a predisposition of COMT Va1158Met or Tag1A genotype to the hypothesized detrimental effects of an HFS diet. Previously reported associations of BMI with WM seem to be independent of HFS intake in our male study sample.Peer reviewe

Dopaminergic basis for signalling belief updates, but not surprise, and the link to paranoia

Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine’s role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based functional magnetic resonance imaging (fMRI) task designed to separate the neural processing of meaningful and meaningless sensory information. We modelled participant behaviour using a normative Bayesian observer model, and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired positron emission tomography (PET) imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioural sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans, and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted

The relation among aging, dopamine-regulating genes, and neurocognition

When people are getting old, they often feel increasingly harder to concentrate, and become slower and more inflexible during tasks that involve focused attention, information maintenance in the face of distractions, and when fast switching according to changing goals is required. These cognitive functions are collectively referred to as working memory (WM). Both cross-sectional and longitudinal studies have reported WM impairment in aging. Moreover, aging is accompanied by alterations in brain structure, brain function, and dopaminergic neurotransmission. This thesis sought to link WM to brain structure, brain function, and dopamine (DA)-related genes in large samples of younger and older adults. The chief aims were to provide neural and genetic evidence to increase our understanding of the mechanisms of age-related deficits in WM. The DRD2/ANKK1-Taq1A polymorphism has been associated with DA D2 receptor densities in caudate. In study I, we investigated the effects of this polymorphism on grey-matter (GM) volume in striatum in older adults, and examined whether the genetic effect interacts with age. Results showed that the A allele of the DRD2/ANKK1-Taq1A polymorphism was associated with smaller GM volume in caudate and this effect was only observed in older adults (>72 years). The DRD2-C957T polymorphism has been linked to DA D2 receptor densities in both striatum and extrastriatal areas, such as in prefrontal cortex (PFC). In study II, we investigated the genetic effects of two DRD2 polymorphisms on WM functioning and examined how these effects may interact with adult age. In comparing younger and older adults, we found that the old had lower caudate activity in a highly demanding WM task. In addition, there were single and joint genetic effects of the two DRD2 polymorphisms on WM performance and frontostriatal brain activity. The genetic effects on brain function were observed in older, but not in younger adults, suggesting magnified genetic effects in aging. In study III, we related white-matter integrity with WM performance in a large sample across a wide age range. Results demonstrated that WM was associated with white-matter integrity in multiple tracts, indicating that WM functioning relies on global structural connections among multiple brain regions. Moreover, white-matter integrity could partially account for the age-related difference in WM. The COMT-Val158Met polymorphism has been associated with PFC DA levels. In this study, we found genetic effects of COMT on white-matter microstructure, suggesting a relation between dopaminergic function and white-matter integrity. In study IV, we investigated changes of white-matter integrity and WM performance using longitudinal data. We found that white-matter integrity declined across 10 years in the whole sample (25-80 years) and the decline was greater for older than for younger adults, reflecting a non-linear relation between age and white matter. More importantly, we found change – change associations of white-matter integrity and WM performance in several tracts including genu and body of corpus callosum and superior longitudinal fasciculus, suggesting that impaired WM performance in aging might reflect age-related decrease of white-matter integrity in these tracts. Collectively, these studies demonstrate age-related differences and changes in brain structure and brain function associated with impaired WM performance in aging. The findings support and extend previous work on the roles of DA in WM functioning and brain integrity in aging, and contribute to our understanding of neural and genetic correlates of WM, and how these are affected in aging

The selective updating of working memory: a predictive coding account

Goal-relevant information maintained in working memory is remarkably robust and resistant to distractions. However, our nervous system is endowed with exceptional flexibility; therefore such information can be updated almost effortlessly. A scenario – not uncommon in our daily life – is that selective maintaining and updating information can be achieved concurrently. This is an intriguing example of how our brain balances stability and flexibility, when organising its knowledge. A possibility – one may draw upon to understand this capacity – is that working memory is represented as beliefs, or its probability densities, which are updated in a context-sensitive manner. This means one could treat working memory in the same way as perception – i.e., memories are based on inferring the cause of sensations, except that the time scale ranges from an instant to prolonged anticipation. In this setting, working memory is susceptible to prior information encoded in the brain’s model of its world. This thesis aimed to establish an interpretation of working memory processing that rests on the (generalised) predictive coding framework, or hierarchical inference in the brain. Specifically, the main question it asked was how anticipation modulates working memory updating (or maintenance). A novel working memory updating task was designed in this regard. Blood-oxygen-level dependent (BOLD) imaging, machine learning, and dynamic causal modelling (DCM) were applied to identify the neural correlates of anticipation and the violation of anticipation, as well as the causal structure generating these neural correlates. Anticipation induced neural activity in the dopaminergic midbrain and the striatum. Whereas, the fronto-parietal and cingulo-operculum network were implicated when an anticipated update was omitted, and the midbrain, occipital cortices, and cerebellum when an update was unexpected. DCM revealed that anticipation is a modulation of backward connections, whilst the associated surprise is mediated by forward and local recurrent modulations. Two mutually antagonistic pathways were differentially modulated under anticipatory flexibility and stability, respectively. The overall results indicate that working memory may as well follow the cortical message-passing scheme that enables hierarchical inference

Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods: Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results: Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [ 123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions: Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic- cortical pathwa

Age-differential relationships among dopamine D1 binding potential, fusiform BOLD signal, and face-recognition performance

Facial recognition ability declines in adult aging, but the neural basis for this decline remains unknown. Cortical areas involved in face recognition exhibit lower dopamine (DA) receptor availability and lower blood-oxygen-level-dependent (BOLD) signal during task performance with advancing adult age. We hypothesized that changes in the relationship between these two neural systems are related to age differences in face-recognition ability. To test this hypothesis, we leveraged positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to measure D1 receptor binding potential (BPND) and BOLD signal during facerecognition performance. Twenty younger and 20 older participants performed a face-recognition task during fMRI scanning. Face recognition accuracy was lower in older than in younger adults, as were D1 BPND and BOLD signal across the brain. Using linear regression, significant relationships between DA and BOLD were found in both age-groups in face-processing regions. Interestingly, although the relationship was positive in younger adults, it was negative in older adults (i.e., as D1 BPND decreased, BOLD signal increased). Ratios of BOLD:D1 BPND were calculated and relationships to face-recognition performance were tested. Multiple linear regression revealed a significant Group BOLD:D1 BPND Ratio interaction. These results suggest that, in the healthy system, synchrony between neurotransmitter (DA) and hemodynamic (BOLD) systems optimizes the level of BOLD activation evoked for a given DA input (i.e., the gain parameter of the DA input-neural activation function), facilitating task performance. In the aged system, however, desynchronization between these brain systems would reduce the gain parameter of this function, adversely impacting task performance and contributing to reduced face recognition in older adults

Human aging, dopamine, and cognition : molecular and functional imaging of executive functions and implicit learning

Age-related deficits are legion in task switching, updating of information in working memory (WM) and inhibiting irrelevant information, collectively referred to as executive functions. Executive functions are tightly coupled to the dopaminergic system, and marked dopamine (DA) losses are observed across adulthood and aging. Several human molecular imaging studies have sought confirmation for the hypothesis that age-related DA losses are associated with deficits in executive functions in older adults. Study I extends this line of research by investigating the association between caudate DA D1 receptor density and functional network connectivity in younger (20-30 years) and older adults (65-75 years) using positron emission tomography and functional magnetic resonance imaging (fMRI). In line with the notion that striatal DA is a critical modulator in cortico-striato-cortical pathways, caudate D1 receptor density was significantly associated with fronto-parietal connectivity in functional brain networks related to executive functioning, and there were marked age-related reductions in DA D1 binding potential. These results show that age-related losses of caudate D1 receptors may contribute to reduced functional-network integrity in older adults. Study II examined age differences in D1 receptor density in several striatal and cortical regions of interest. On average, D1 receptor densities were reduced by around 20 % for older compared to younger adults. Most interestingly, correlations between striatal and cortical receptor densities were reduced in older compared to younger adults, suggesting that dopaminergic losses in striatum and cortex occur relatively independently. Moreover, reduced correlations between striatal and cortical receptor densities were related to slower cognitive interference resolution in older adults. This pattern suggests that an imbalance in dopaminergic regulation between striatum and cortex may contribute to older adults’ deficits in executive functions. Implicit learning remains relatively spared in older adults despite strong associations to striatal functions and DA. This fact presents a paradox for the hypothesis that age- related DA losses mediate cognitive decline in aging. Study III and IV explore possible compensatory mechanisms, which may contribute to preserved implicit learning among older adults. Study III showed that increases in striatal fMRI activations during implicit sequence learning were accompanied by decreasing activation of the right medial temporal lobe (MTL) in younger adults. Older adults, however, relied on both striatum and right MTL during task performance. This pattern suggests that the MTL is not necessary for implicit learning in younger adults, but serves compensatory purposes in old age. Study IV used a dual-task design during fMRI acquisition in which a secondary task, designed to tax the MTL, was performed concurrent with an implicit sequence-learning task comparable to that used in Study III. Consistent with the interpretation of the data from Study III, the secondary task disrupted learning in older, but not younger adults. Moreover, differential effects of the secondary task on learning in younger and older adults were observed in activation patterns for right MTL. Collectively, the four studies provide novel insights into the mechanisms by which dopaminergic losses in aging contribute to deficits in executive functions, and suggest compensatory processes, which may account for the relative sparing of implicit learning in old age