Multisensory control of ingestive movements and the myth of food addiction in obesity. Comment on Nazim Keven and Kathleen Akins, Neonatal imitation in context: sensory-motor development in the perinatal period

Some individuals have a neurogenetic vulnerability to developing strong facilitation of ingestive movements by learned configurations of biosocial stimuli. Condemning food as addictive is mere polemic, ignoring the contextualised sensory control of the mastication of each mouthful. To beat obesity, the least fattening of widely recognised eating patterns need to be measured and supported

Nucleus accumbens volume is related to obesity measures in an age‐dependent fashion

Motivation theories of obesity suggest that one of the brain mechanisms underlying pathological eating and weight gain is the dysregulation of dopaminergic circuits. While these dysregulations occur likely at the microscopic level, studies on gray matter volume reported macroscopic differences associated with obesity. One region suggested to play a key role in the pathophysiology of obesity is the nucleus accumbens (NAcc). We performed a meta‐analysis of findings regarding NAcc volume and overweight/obesity. We additionally examined whether gray matter volume in the NAcc and other mesolimbic areas depends on the longitudinal trajectory of obesity, using the UK Biobank dataset. To this end, we analysed the data using a latent growth model, which identifies whether certain variables of interest (e.g. NAcc volume) is related to another variable's (BMI) initial values or longitudinal trajectories. Our meta‐analysis showed that, overall, NAcc volume is positively related to BMI. However, further analyses revealed that the relationship between NAcc volume and BMI is dependent on age. For younger individuals such relationship is positive, while for older adults it is negative. This was corroborated by our analysis in the UK Biobank dataset, which includes older adults, where we found that higher BMI was associated with lower NAcc and thalamus volume. Overall, our study suggests that increased NAcc volume in young age might be a vulnerability factor for obesity, while in the older age decreased NAcc volume with increased BMI might be an effect of prolonged influences of neuroinflammation on the brain

a systematic review and meta-analysis

OKThere is significant evidence linking a 'reward deficiency syndrome' (RDS), comprising decreased availability of striatal dopamine D2-like receptors (DD2lR) and addiction-like behaviors underlying substance use disorders and obesity. Regarding obesity, a systematic review of the literature with a meta-analysis of such data is lacking. Following a systematic review of the literature, we performed random-effects meta-analyses to determine group differences in case-control studies comparing DD2lR between individuals with obesity and non-obese controls and prospective studies of pre- to post-bariatric surgery DD2lR changes. Cohen's d was used to measure effect size. Additionally, we explored factors potentially associated with group differences in DD2lR availability, such as obesity severity, using univariate meta-regression. In a meta-analysis including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies, striatal DD2lR availability did not significantly differ between obesity and controls. However, in studies comprising patients with class III obesity or higher, group differences were significant, favoring lower DD2lR availability in the obesity group. This effect of obesity severity was corroborated by meta-regressions showing inverse associations between the body mass index (BMI) of the obesity group and DD2lR availability. Post-bariatric changes in DD2lR availability were not found, although a limited number of studies were included in this meta-analysis. These results support lower DD2lR in higher classes of obesity which is a more targeted population to explore unanswered questions regarding the RDS.publishersversionpublishe

Sex differences in the influence of body mass index on anatomical architecture of brain networks.

Background/objectivesThe brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters.Subjects/methodsStructural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age.ResultsIn both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions.ConclusionsIn individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology

Food addiction: a valid concept?

Can food be addictive? What does it mean to be a food addict? Do common underlying neurobiological mechanisms contribute to drug and food addiction? These vexing questions have been the subject of considerable interest and debate in recent years, driven in large part by the major health concerns associated with dramatically increasing body weights and rates of obesity in the United States, Europe, and other regions with developed economies. No clear consensus has yet emerged on the validity of the concept of food addiction and whether some individuals who struggle to control their food intake can be considered food addicts. Some, including Fletcher, have argued that the concept of food addiction is unsupported, as many of the defining features of drug addiction are not seen in the context of feeding behaviors. Others, Kenny included, have argued that food and drug addiction share similar features that may reflect common underlying neural mechanisms. Here, Fletcher and Kenny argue the merits of these opposing positions on the concept of food addiction.Wellcome Trust Bernard Wolfe Health Neurosciencce Fund National Institutes of Health, US

Nucleus accumbens volume is related to obesity measures in an age‐dependent fashion

Motivation theories of obesity suggest that one of the brain mechanisms underlying pathological eating and weight gain is the dysregulation of dopaminergic circuits. While these dysregulations occur likely at the microscopic level, studies on gray matter volume reported macroscopic differences associated with obesity. One region suggested to play a key role in the pathophysiology of obesity is the nucleus accumbens (NAcc). We performed a meta‐analysis of findings regarding NAcc volume and overweight/obesity. We additionally examined whether gray matter volume in the NAcc and other mesolimbic areas depends on the longitudinal trajectory of obesity, using the UK Biobank dataset. To this end, we analysed the data using a latent growth model, which identifies whether certain variables of interest (e.g. NAcc volume) is related to another variable's (BMI) initial values or longitudinal trajectories. Our meta‐analysis showed that, overall, NAcc volume is positively related to BMI. However, further analyses revealed that the relationship between NAcc volume and BMI is dependent on age. For younger individuals such relationship is positive, while for older adults it is negative. This was corroborated by our analysis in the UK Biobank dataset, which includes older adults, where we found that higher BMI was associated with lower NAcc and thalamus volume. Overall, our study suggests that increased NAcc volume in young age might be a vulnerability factor for obesity, while in the older age decreased NAcc volume with increased BMI might be an effect of prolonged influences of neuroinflammation on the brain

Atlas of type 2 dopamine receptors in the human brain: Age and sex dependent variability in a large PET cohort

BackgroundThe dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved.MethodsIn this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (D2R) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018.ResultsStriatal D2R availability decreased through age for both sexes (2-5 % in striatal ROIs per 10 years) and was higher in females versus males throughout age (7-8% in putamen). BMI and striatal D2R availability were weakly associated. There was no consistent lateralization of striatal D2R. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135).ConclusionsD2R availability is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering D2R expression.​​​​​​​</ul

Deep Brain Stimulation for Obesity: A Review and Future Directions

The global prevalence of obesity has been steadily increasing. Although pharmacotherapy and bariatric surgeries can be useful adjuvants in the treatment of morbid obesity, they may lose long-term effectiveness. Obesity result largely from unbalanced energy homeostasis. Palatable and densely caloric foods may affect the brain overlapped circuits involved with homeostatic hypothalamus and hedonic feeding. Deep brain stimulation (DBS) consists of delivering electrical impulses to specific brain targets to modulate a disturbed neuronal network. In selected patients, DBS has been shown to be safe and effective for movement disorders. We review all the cases reports and series of patients treated with DBS for obesity using a PubMed search and will address the following obesity-related issues: (i) the hypothalamic regulation of homeostatic feeding; (ii) the reward mesolimbic circuit and hedonic feeding; (iii) basic concepts of DBS as well as the rationale for obesity treatment; (iv) perspectives and challenges in obesity DBS. The small number of cases provides preliminary evidence for the safety and the tolerability of a potential DBS approach. The ventromedial (n = 2) and lateral (n = 8) hypothalamic nuclei targets have shown mixed and disappointing outcomes. Although nucleus accumbens (n = 7) targets were more encouraging for the outcomes of body weight reduction and behavioral control for eating, there was one suicide reported after 27 months of follow-up. The authors did not attribute the suicide to DBS therapy. The identification of optimal brain targets, appropriate programming strategies and the development of novel technologies will be important as next steps to move DBS closer to a clinical application. The identification of electrical control signals may provide an opportunity for closed-loop adaptive DBS systems to address obesity. Metabolic and hormonal sensors such as glycemic levels, leptin, and ghrelin levels are candidate control signals for DBS. Focused excitation or alternatively inhibition of regions of the hypothalamus may provide better outcomes compared to non-selective DBS. Utilization of the NA delta oscillation or other physiological markers from one or multiple regions in obesity-related brain network is a promising approach. Experienced multidisciplinary team will be critical to improve the risk-benefit ratio for this approach

Impulsividade, plasticidade sináptica e caracterização da transmissão dopaminérgica no córtex pré-frontal medial e no córtex orbitofrontal de ratas expostas à restrição de crescimento intrauterino

Indivíduos com restrição de crescimento intrauterino (RCIU) demonstram um risco aumentado de apresentar desfechos metabólicos adversos ao longo da vida. Estudos mais recentes têm sugerido que a RCIU também possa alterar de forma persistente as preferências alimentares nestes indivíduos. Uma vez que alterações nos hábitos alimentares podem estar na origem do desenvolvimento de várias das doenças associadas à RCIU, torna-se importante identificar variações no comportamento desses indivíduos que favoreçam o consumo alimentar inadequado e investigar os mecanismos neuroquímicos potencialmente associados a essas alterações. Uma maior compreensão destes mecanismos poderia auxiliar tanto na prevenção quanto no manejo mais eficiente destes desfechos adversos. Neste contexto, o objetivo deste trabalho foi avaliar o comportamento impulsivo, a plasticidade sináptica e a sinalização dopaminérgica no córtex pré-frontal medial (mPFC) e no córtex orbitofrontal (OFC) de ratas expostas a um protocolo de RCIU. Os resultados obtidos demonstram que a RCIU está associada a uma maior impulsividade em uma tarefa que avalia a tolerância dos animais ao atraso no recebimento de recompensas. Ao analisarmos os níveis de receptores D1, D2 e transportador DAT em diferentes fases da vida dos animais (dias 1, 21, 80 e 160 pós natal), foram observadas diferenças apenas na idade adulta, onde os animais RCIU apresentaram níveis reduzidos de receptores D1 no OFC e níveis elevados de receptores D2 no mPFC.Obesity is a multifactorial disorder in which increased prevalence is related to changes in lifestyle, and both stress and consumption of high-fat diets are largely involved. Exposure to environmental factors at early stages of development may cause persistent changes in the central nervous system and endocrine-metabolic system, which may result in the development of the obesity phenotype. The pre-pubertal period is a sensitive phase of development, characterized by the maturation of systems involved in energy homeostasis and stress responses. Interventions during this period may influence the susceptibility to disease or resilience in adulthood. Social isolation is considered a potent stressor for rodents and humans and exposure to this factor during the pre-pubertal period may have long-term emotional, behavioral, and metabolic effects. The stress exposure during early stages of development can cause changes in eating behavior and induce the preference for “comfort foods”, rich in sugars and fats. Both, stress and high-fat diets intake can program the metabolism in a sex-different manner through modulation of hormones signaling involved in regulation of energy homeostasis. In addition, these environmental factors may lead to an imbalance between the production of reactive oxygen species and antioxidant defenses favoring oxidative stress, which can induce the oxidation of biomolecules and lead to mitochondrial dysfunctions. Based on the above ideas, the aim of this thesis was to investigate the long-term effects of social isolation during the pre-pubertal period (postnatal day 21-28), associated with chronic high-fat diet on metabolic, oxidative and mitochondrial parameters in the total hypothalamus, comparing males and females. Individuals born with intrauterine growth restriction (IUGR) show an increased risk for adverse outcomes throughout their lives. Recent studies have suggested that IUGR could permanently change the food preferences in these individuals. Since changes in feeding habits may be at the origin of the development of many of the IUGR associated diseases, it becomes important to identify behavioral deviations in these individuals that favor an inappropriate food intake and to identify the neurochemical mechanisms potentially related to these alterations. A better comprehension of these mechanisms could help in the prevention and a more efficient management of these outcomes. In this context, the aim of this study was to evaluate impulsive behavior, synaptic plasticity and dopaminergic signaling at the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC) from female rats exposed to an IUGR protocol. Our results showed that the IUGR is associated with an increased impulsiveness in a task that evaluates the animal's tolerance to a delayed reward. When we look at the levels of D1 and D2 dopamine receptors and DAT transporter at different life phases (PND 1, 21, 80 and 160), we found differences only at the adult life, where the IUGR animals showed decreased levels of D1 receptors at the OFC and increased levels of D2 receptors at the mPFC. Additionally, we found altered levels of tyrosine hydroxylase at the PFC of IUGR animals already on the first day of life. Regarding synaptic plasticity, we observed an altered pattern of synaptophysin at the OFC in the period comprehended between prepubertal age and the early adult life. Through electrochemical recordings of dopamine levels, we found a blunted release in the mPFC of IUGR animals in response to the exposure and the intake of palatable foods. Once more in the mPFC, we found an altered pattern of dopamine release in the IUGR animals during the occurrence of a tune that predicted the receipt of different food reward magnitudes. The results we obtained suggest that IUGR can induce behaviors associated with an increased food intake, program mesolimbic dopaminergic system in order to favor a hypofunctionality in response to palatable foods and favor the attention toward food cues. Early changes in dopamine synthesis, associated with changes in the pattern of synaptic development may be underlying the dopaminergic dysfunctions we observed in different regions of the PFC in adult animals. With this work, we advanced in the investigation regarding the biochemical and behavioral mechanisms that link the IUGR to an increased risk of metabolic diseases and obesity throughout life