Investigation into the neurocognitive mechanisms underlying self-regulatory processes in eating behaviours

Prior research has demonstrated that the integrity of the executive control system is correlated with obesogenic behaviour tendencies in a theoretically meaningful way. However, due to the paucity of experimental evidence demonstrating directionality and causality of this relation, there is a need for research investigating the nature via which prefrontal-mediated executive control abilities influence vulnerability to obesity-conducive eating habits (i.e., the overconsumption of calorie dense snack foods). As such, current body of research employed experimental methodologies to assess the causal relation between the functionality of the prefrontal cortex (PFC) and dietary self-restraint as mediated via executive control. A secondary objective was to determine the capacity via which aerobic exercise and continuous theta burst (cTBS) methodologies can be used to both attenuate and optimize executive control within an experimental context. Study 1 used meta-analytic methods to determine the reliability of validity of both up-regulatory (intermittent theta burst stimulation; iTBS) and down-regulatory (cTBS) theta burst stimulation (TBS) methodologies targeting the PFC on executive function (EF) task performance. Findings suggest that TBS protocols appear to be valid and effective means of modulating EF task performance within experimental contexts. However, the attenuating effects of cTBS may be more reliable than the excitatory effects of iTBS. Study 2 utilized cTBS and EEG methodologies to assess the extent in which changes in attentional engagement to high caloric food images and cognitive control influence consumptive patterns. Findings indicated that the attenuation of activity in the left dorsolateral prefrontal cortex (dlPFC) via cTBS significantly impaired executive control abilities. Further, a significant increase in the cravings for and consumption of appetitive high caloric foods was apparent following active relative to sham cTBS, an effect that was mediated by a significant increase in the attentional engagement to high caloric food images. Most importantly, this effect was specific to high-caloric foods and did not translate to changes in cravings or consumption of low calorie foods. Study 3 sought to determine whether aerobic exercise methodologies can be used to enhance EF following temporary perturbations in dlPFC functionality. Findings indicated that an acute bout of moderate intensity exercise mitigated the cTBS-induced decrements in EF more quickly than the very light intensity control condition. Study 4 used the same aerobic exercise methodologies as Study 3 to determine if exercise-induced enhancements in executive control results in the subsequent transfer to self-control in the dietary domain. Findings revealed that a bout of moderate aerobic exercise can both enhance inhibitory control and improve dietary choices, providing the first evidence of a direct cross-domain transfer effect of exercise-induced cognitive enhancement to an unrelated domain. Together, these findings demonstrate that the attenuation and optimization of EFs results in subsequent changes in dietary self-restraint in the theorized directions

Contextual cues as modifiers of cTBS effects on indulgent eating

Background: Prior studies have found that continuous theta burst stimulation (cTBS) targeting the left dlPFC results in reliable increases in consumption of calorie-dense food items. However, it is not known to what extent such effects are modified by cues in the immediate eating environment. Tempting environments (i.e., those saturated with appetitive eating cues) may lead to more reliance on cognitive control networks involving the dlPFC, thereby enhancing cTBS effects on indulgent eating. Objective/Hypothesis: The objective was to examine the extent to which cTBS effects on indulgent eating would be modified by contextual cues. It was hypothesized that cTBS effects would be stronger in the presence of facilitating cues. Methods: Using a single-blinded between-subjects factorial design, 107 TMS-naïve adults were randomly assigned to one of four conditions: 1) active cTBS + facilitating cues, 2) sham cTBS + facilitating cues, 3) active cTBS + inhibiting cues, 4) sham cTBS + inhibiting cues. Following stimulation participants completed a flanker paradigm and a taste test during which quantity consumed was assessed surreptitiously. Results: Findings revealed a significant interaction between stimulation and cue type (F(1,102)=6.235, p=.014), such that cTBS resulted in increased food consumption (compared to sham) in the presence of the facilitating cue but not in the presence of the inhibiting cue. Moderated mediational analyses showed selective mediation of cTBS effects on consumption through cTBS attenuation of flanker interference scores. Conclusions: The effects of cTBS on indulgent eating are strengthened in the presence of facilitating cues. Methodologically speaking, facilitating cues may be a functional prerequisite for exploring cTBS effects on eating in the laboratory. Substantively, the findings also suggest that facilitating cues in the eating environment may amplify counter-intentional food indulgence in everyday life via cognitive control failure

Invasive and Non-invasive Stimulation of the Obese Human Brain

Accumulating evidence suggests that non-invasive and invasive brain stimulation may reduce food craving and calorie consumption rendering these techniques potential treatment options for obesity. Non-invasive transcranial direct current stimulation (tDCS) or repetitive transcranial magnet stimulation (rTMS) are used to modulate activity in superficially located executive control regions, such as the dorsolateral prefrontal cortex (DLPFC). Modulation of the DLPFC’s activity may alter executive functioning and food reward processing in interconnected dopamine-rich regions such as the striatum or orbitofrontal cortex. Modulation of reward processing can also be achieved by invasive deep brain stimulation (DBS) targeting the nucleus accumbens. Another target for DBS is the lateral hypothalamic area potentially leading to improved energy expenditure. To date, available evidence is, however, restricted to few exceptional cases of morbid obesity. The vagal nerve plays a crucial role in signaling the homeostatic demand to the brain. Invasive or non-invasive vagal nerve stimulation (VNS) is thus assumed to reduce appetite, rendering VNS another possible treatment option for obesity. Based on currently available evidence, the U.S. Food and Drug Administration recently approved VNS for the treatment of obesity. This review summarizes scientific evidence regarding these techniques’ efficacy in modulating food craving and calorie intake. It is time for large controlled clinical trials that are necessary to translate currently available research discoveries into patient care

The effects of continuous theta burst stimulation (cTBS) to the left dorsolateral prefrontal cortex on executive control resources, subjective food cravings, and the consumption of appetitive snack foods.

Prior research has demonstrated that stronger executive control resources (ECR) are positively associated with healthy dietary habits. Given that ECRs are understood to involve the operation of the prefrontal cortex, specifically the dorsolateral prefrontal cortex (DLPFC), the differential operation of the DLPFC may explain individual differences in dietary self-control. The present study was designed to examine the causal status of the relationship between DLPFC function and two parameters of dietary self-control: subjective food cravings and the consumption of appetitive snack foods. Using a within subjects design, 21 female participants received both active and sham continuous theta burst stimulation (cTBS) to the left dorsolateral prefrontal cortex. Subjective food cravings were assessed before and after each stimulation session, and the amount of food consumed during a bogus taste test was objectively measured following each stimulation session. In addition, following each stimulation session participants completed three standardized ECR measures. Results indicated that participants consumed significantly more snack foods following active as compared to sham stimulation, but this finding was specific to the consumption of appetitive foods (i.e., milk chocolate and potato chips). In addition, as compared with sham stimulation, performance on the Stroop task was significantly impaired following active stimulation. Finally, stronger food cravings were reported following active relative to sham stimulation, but these were highly selective the reinforcement-anticipation aspect of cravings. Together, these results support the contention that the ECRs, as modulated through DLPFC activity, regulates food cravings and the consumption of palatable energy dense foods

Testing the relative contributions of the dlPFC and mPFC to decision-making about eating and finances across the adult lifespan

Background: Prior neuroimaging and neuromodulation studies have shown that the dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC) are important nodes for self-control and decision-making, but through separable processes. However, very little is known about the relative contribution of both these regions in two important domains of decision making for older adults: 1) financial judgement and 2) consumption of appetitive high-caloric snacks foods. Objective and Hypothesis: The objective of the study was to examine the effects of excitatory brain stimulation (iTBS) on financial decision making and eating, as mediated through cognitive performance. Given that the PFC and its subregions are differentially sensitive to the effects of aging, it was hypothesized that age (older versus younger) might moderate the effects of stimulation. It was further hypothesized that excitatory stimulation would lead to a decrease in consumption of appetitive snack foods and improvement in financial decision making (i.e., reduced discounting of delayed rewards; delay discounting). Methods: Using a single-blinded, between-subjects experimental design, a sample of 22 younger adults and 21 older adults (N = 43) were randomly assigned to receive iTBS in one of the three conditions: 1) active iTBS to the left dlPFC; involved in the modulation of pre-potent responses; 2) active iTBS to bilateral dmPFC; which is involved in subjective valuation processing, or 3) sham iTBS; the control/placebo condition. After the stimulation session, participants completed two cognitive tasks (delay discounting and flanker), and a bogus taste test. Functional-near infrared spectroscopy (fNIRS) was used to validate iTBS effects on cognitive task performance via changes in blood oxygen saturation levels. Results: Results indicated null effects of iTBS on food consumption, flanker performance and delay discounting, with no moderation by age category. However, a significant moderating effect of gender emerged, such that a significant increase in calorie dense food consumption was evident among those in the dmPFC stimulation condition. This effect was mainly driven by the consumption of sweet foods. Finally, fNIRS data suggested a strong left lateralized activation on the incongruent versus congruent flanker task, with overall lower oxygen demand in the active stimulation than the sham stimulation. In contrast, medial channels were activated for the delay discounting task, with a significant increase in oxygen demand for the dmPFC condition compared to the sham condition

Neurobiological mechanisms of control in alcohol use disorder – Moving towards mechanism-based non-invasive brain stimulation treatments

Alcohol use disorder (AUD) is characterized by excessive habitual drinking and loss of control over alcohol intake despite negative consequences. Both of these aspects foster uncontrolled drinking and high relapse rates in AUD patients. Yet, common interventions mostly focus on the phenomenological level, and prioritize the reduction of craving and withdrawal symptoms. Our review provides a mechanistic understanding of AUD and suggests alternative therapeutic approaches targeting the mechanisms underlying dysfunctional alcohol-related behaviours. Specifically, we explain how repeated drinking fosters the development of rigid drinking habits and is associated with diminished cognitive control. These behavioural and cognitive effects are then functionally related to the neurobiochemical effects of alcohol abuse. We further explain how alterations in fronto-striatal network activity may constitute the neurobiological correlates of these alcohol-related dysfunctions. Finally, we discuss limitations in current pharmacological AUD therapies and suggest non-invasive brain stimulation (like TMS and tDCS interventions) as a potential addition/alternative for modulating the activation of both cortical and subcortical areas to help re-establish the functional balance between controlled and automatic behaviour

Repetitive Transcranial Magnetic Stimulation by Theta Burst

Transcranial magnetic stimulation (TMS) is a non-invasive diagnostic and therapeutic technique used to stimulate the brain in several neurological and psychiatric diseases, even though the main bases underlying its action are not fully understood. Theta Burst Stimulation (TBS), a patterned form of repetitive TMS, has been assuming particular importance due to its faster application. Research of TBS effects on some higher cortical functions such as cognition after stimulation of the prefrontal cortex (PFC), or its possible influence in some less studied cortical regions (as the temporal cortex) has been limited and revealed inconsistent results. One of the problems assessing the cognitive TBS after-effects relates to the use of multiple evaluation methods, with different sensitivities. In this matter, the use of neurophysiology studies such as the auditory P300, a cognitive evoked potential, may be of particular importance. To date, studies addressing the association between auditory P300 and TBS are scarce, and some contradictory results were found. The study of other higher cognitive domains such as creativity is even rarer, but it may be relevant given that part of the neural networks involved in creative processing are associated with the PFC. The effect of TMS over the PFC, studying the modulation of functions mediated by the autonomic nervous system has also been reported, but there is still a significant disagreement between the rare studies performed. So far, the extent of the modulatory effects associated with TBS at the sensory level is still poorly known, and research with TBS over the auditory cortex, despite showing some positive results, remains inconclusive, with some reports of sound hypersensitivity after sessions with higher intensity stimulation. It should also be noted that a significant part of the knowledge about the effects of TBS derives from studies in patients, with dysfunctional neuronal networks or hemispheric lesions, which add challenges to the search for scientific evidence in healthy individuals. Given the uncertainties that remain regarding the extent of the neuromodulatory effects of TBS, the primary objective of this thesis focused on increasing the scientific knowledge related to the use of TBS in the healthy brain. Therefore, we intended to study the neurophysiological responses (such as auditory P300), the functional responses (such as auditory thresholds), and the physiological responses (such as cerebral oximetry and blood pressure) associated with the application of TBS in the prefrontal and temporal cortices. All studies used a target population of healthy young adults, with an average age of approximately 23 years, and similar education. TBS was performed accordingly to the 600-pulse paradigm described by Huang et al. (continuous and intermittent). Sham-controlled, double-blind intervention protocols were used, with random distribution by the respective groups. The main objective of the study in chapter III was to evaluate the effect of TBS on the dorsolateral prefrontal cortex (DLPFC) of both cerebral hemispheres in cognitive processing. The objective was to assess if the auditory P300 would be influenced by the stimulation type. Results revealed that the mean P300 peak latency after TBS decreased only after leftward iTBS. A significant delay in P300 latency was originated from both right and left cTBS. Amplitude response did not change significantly. The results covered in chapter IV derived from the use of TBS on the left DLPFC, studying the possibility of a relationship between the post-TBS auditory P300 and the post-TBS neuropsychological tests: Trail Making Test (TMT) and the Stroop Test of Words and Colours. Results revealed that cTBS led to a delay of the P300, also significantly influencing the expected performance on Stroop C and Stroop Interference when compared to the groups submitted to iTBS and sham stimulation. No significant results were found in the TMT tests for any type of TBS stimulation. In Chapter V, we studied the cerebral oximetry using Near Infra-Red Spectroscopy, blood pressure, and heart rate, after applying TBS to the right and left DLPFC. We found a significant reduction in oximetry in the left frontal region after ipsilateral cTBS and a significant decrease in systolic blood pressure after cTBS to the right DLPFC. Chapter VI covered the evaluation of the effects of TBS over the left temporal cortex, specifically studying the auditory thresholds in the ear closest to the coil. Results showed no major side effects after iTBS, cTBS, or sham stimulation. It was also found that iTBS led to lower hearing thresholds, especially when comparing the iTBS and sham groups at 500Hz and between the iTBS and cTBS groups at 4000Hz. Chapter VII addresses a patent concerning the technique and possible use of iTBS as a method to influence creative processing. After iTBS over the right DLPFC, results of an adapted selection of the Torrance Tests of Creative Thinking suggest that divergent thinking, originality and fluency improved significantly compared to the sham group. An integrative analysis of the results shows that TBS seems to effectively influence the underlying cortical neurons and cortico-subcortical networks. The findings thus support the existence of a trans-synaptic effect advocated initially for the classic repetitive TMS, which after the publication of our research can continue to be extended with greater confidence to TBS protocols. Our results also support the most consensual theory about the modulatory effects of the two main forms of TBS – intermittent (excitatory) and continuous (inhibitory) – particularly on the prefrontal and temporal cortices. The effects of TBS seem to be intrinsically correlated with the hemispheric lateralization and this may be related to the specific functions or dominance of each hemisphere and the specific stimulated cortical regions. The combined results of this investigation also seem to suggest that the inhibition induced by cTBS seems more effective when compared to the excitatory effect of iTBS, which seemed stronger in the left hemisphere. After all our research with TBS in more than one cortical region, we can infer that this is a safe technique, with rare and incipient side effects. The encouraging results after using iTBS in the auditory cortex opens new perspectives regarding future implementations of the technique and should be replicated in patients, particularly with mild sensorineural hearing loss, in order to assess whether this stimulation protocol can be a valid therapeutic technique in these cases. We also conclude that the techniques used to study TBS-related effects, as the P300 or the NIRS, can be very useful in the future, as an attempt to identify the effectiveness of the therapeutic use of TBS protocols, possibly allowing to adapt and modify the idealized interventions, leading to a personalized patient intervention. Our findings provide relevant information, necessary to increase the technical and scientific credibility required for achieving a more comprehensive and reliable clinical use of TBS. This is crucial at a time when transcranial magnetic stimulation use as an off-label therapy for numerous neurological and psychiatric diseases grows unregulated, and the patient best interests must be defended.A estimulação magnética transcraniana (EMT) é uma técnica de diagnóstico e terapêutica não invasiva, que tem vindo a evoluir nos últimos 35 anos. A aplicação terapêutica da forma repetitiva da EMT (EMTr), tem vindo a demonstrar a sua utilidade científica e clínica, com aplicação em várias doenças neurológicas e psiquiátricas como a depressão major, a perturbação obsessivo-compulsiva, dor e reabilitação em doentes com acidentes vasculares cerebrais, ainda que as principais bases subjacentes à sua acção não sejam totalmente compreendidas. A EMT baseia-se no princípio da indução magnética e na sua capacidade de induzir correntes elétricas no tecido cortical. Esses campos magnéticos (pulsos) originados por uma bobina adjacente ao couro cabeludo originam um fluxo iónico intracraniano que irá provocar a despolarização da membrana neuronal, desencadeando assim um potencial de ação. Embora a EMT exerça os seus efeitos predominantemente na área cortical adjacente à bobina, os potenciais de ação induzidos espalham-se trans-sinapticamente, originando a propagação da ativação para regiões corticais e subcorticais vizinhas pertencentes à rede neuronal em questão. Parece ocorrer ainda a aparente capacidade de influenciar a função do hemisfério contralateral à estimulação possivelmente por mediação calossal. Os efeitos da EMTr ao nível da modulação da excitabilidade neuronal estão intrinsecamente dependentes das características da estimulação, nomeadamente ao nível da frequência e padronização dos estímulos. A aplicação de frequências inferiores ou iguais a 1 Hz (EMTr de baixa frequência) são associadas à indução de um efeito inibitório neuronal, enquanto que a aplicação de frequências acima de 1 Hz, normalmente acima dos 5 Hz (EMTr de alta frequência), podem induzir um efeito excitatório. Em 2005 surgiu uma forma padronizada de aplicação dos pulsos magnéticos, denominada Theta Burst Stimulation (TBS), na qual grupos de 3 pulsos com alta frequência (bursts de 50Hz) são enviados a cada 200 milissegundos (5 Hz – frequência teta), implicando normalmente a aplicação de 600 pulsos por cada sessão de estimulação. Este é um protocolo que assume particular importância pela sua rápida aplicação, levando menos de 3 minutos a executar, sendo significativamente mais célere do que os protocolos clássicos de EMTr (que podem exceder 30 minutos). Efeitos neuromodulatórios opostos podem ser igualmente induzidos com TBS, sendo que a aplicação ininterrupta da estimulação durante 40 segundos – TBS contínua (cTBS) – parece originar uma diminuição na excitabilidade cortical com uma duração de até 50 minutos pós-estimulação, enquanto que a aplicação de apenas 2 segundos de TBS intervalada por 8 segundos de pausa – TBS intermitente (iTBS) – durante 190 segundos, terá a capacidade de induzir aumento na excitabilidade cortical até cerca de 60 minutos pós-estimulação. Apesar do volume significativo de investigação acumulada na estimulação com EMTr e TBS, demonstrando a sua capacidade modulatória e a sua aplicabilidade na prática clínica, a investigação dos seus efeitos sobre algumas funções corticais superiores como a cognição ou os efeitos da aplicação em algumas regiões corticais menos estudadas como a região temporal tem sido mais limitada (principalmente com a TBS) e apresentado alguns resultados contraditórios. O córtex pré-frontal assume particular importância associado à aplicação da EMTr/TBS dada a extensa rede de conexões com outras regiões corticais (como o córtex motor, o córtex sensitivo, a amígdala, o tálamo e o hipocampo), importantes em doenças como a depressão (desequilíbrio inter-hemisférico pré-frontal verificado por neuroimagem), e ainda pela sua aparente capacidade de influenciar funções autonómicas e cardiovasculares. Meta-análises como a de Lowe et al. 2018, avaliando os efeitos da TBS sobre o córtex pré-frontal, revelam que parece existir um efeito negativo no desempenho das tarefas de função executiva após estimulação com cTBS e um efeito positivo mas em menor grau após estimulação com iTBS. No entanto, o efeito mais definido da estimulação sobre as várias dimensões cognitivas permanece envolto em alguma dúvida, dado que por um lado têm surgido alguns resultados negativos e por outro lado a maioria dos estudos tem usado populações relativamente pequenas, com infrequente recurso a grupos sham. Um dos principais problemas na avaliação dos possíveis efeitos da estimulação magnética repetitiva prende-se com o uso de diversos métodos de avaliação, com diferentes sensibilidades para o estudo das várias dimensões cognitivas, ou ainda com técnicas com menor resolução temporal (como os estudos de imagem cerebral funcional) comparativamente a técnicas neurofisiológicas. Neste ponto, a utilização de estudos no âmbito da neurofisiologia, como os potenciais de longa latência, pode assumir particular importância. O P300 auditivo, é um potencial evocado cognitivo, dependente da atenção e capacidade de discriminação do sujeito, traduzindo estadios mais superiores ou avançados de processamento associado a uma tarefa. As origens neuronais do P300 são múltiplas e bi-hemisféricas, associando-se a regiões como o hipocampo, o córtex pré-frontal ventrolateral e o córtex cingulado posterior. Até à data, são raros os estudos que abordaram a associação entre o P300 auditivo e a EMTr e ainda mais raros combinando a estimulação com TBS e o P300. A avaliação dos resultados prévios sugere que a estimulação magnética pode ser capaz de influenciar o processamento cognitivo e que as alterações podem ser monitorizadas pelo P300, mas são encontrados alguns resultados contraditórios, existindo significativas discrepâncias na metodologia usada. […

Manipulating neuronal communication by using low-intensity repetitive transcranial magnetic stimulation combined with electroencephalogram

Repetitive transcranial magnetic stimulation (rTMS) modulates ongoing brain rhythms by activating neuronal structures and evolving different neuronal mechanisms. In the current work, the role of stimulation strength and frequency for brain rhythms was studied. We hypothesized that a weak oscillating electric field induced by low-intensity rTMS could induce entrainment effects in the brain. To test the hypothesis, we conducted three separate experiments, in which we stimulated healthy human participants with rTMS. We individualized stimulation parameters using computational modeling of induced electric fields in the targets and individual frequency estimated by electroencephalography (EEG). We demonstrated the immediately induced entrainment of occipito-parietal and sensorimotor mu-alpha rhythm by low-intensity rTMS that resulted in phase and amplitude changes measured by EEG. Additionally, we found long-lasting corticospinal excitability changes in the motor cortex measured by motor evoked potentials from the corresponding musle.2021-11-2

Examining the bidirectional associations between adiposity and cognitive function using population-level data

Background: The association between adiposity and cognitive function has been extensively explored in previous literature, and numerous cross-sectional and longitudinal analyses suggest a reliable association. However, most previous studies on this topic were predominantly executed with a narrow, unidirectional assumption that baseline adiposity predicts future cognitive function (i.e., the “brain-as-outcome” perspective). Literature within neuropsychology, the cognitive neurosciences and cognitive epidemiology suggests that baseline cognitive function may also predict the development of adiposity (i.e., the “brain-as-predictor” perspective), although this reverse directionality has not been extensively explored to date using population-level datasets. Instead, relatively small-scale experimental studies have shown that temporary attenuation of some facets of cognitive function, particularly the executive control domain, could result in disinhibited eating. Therefore, it is plausible that impaired cognitive function affects the implementation of behaviors that confer downstream risk for adiposity. Taken together, these findings suggest that the association between adiposity and cognitive function could be reciprocal, but bidirectional effects have not been explored systematically in previous literature. This dissertation aimed to examine the hypothesized bidirectional associations between adiposity and cognitive function and their possible mediation paths using population-level datasets in three age groups: older adults, middle-aged adults, and adolescents. Methods: Studies 1 and 2 were conducted using the Canadian Longitudinal Study on Aging (CLSA) datasets. Study 1 was a cross-sectional analysis of the baseline CLSA comprehensive cohort (N = 30,097), whereas Study 2 was a prospective analysis of the baseline and first follow-up datasets. The bidirectionality hypotheses were examined using three indicators of cognitive function (animal fluency, Stroop interference, and mean reaction time) and four indicators of adiposity (body mass index [BMI], total fat mass, waist circumference [WC] and waist-hip ratio [WHR]). Hierarchical multivariable regression, multivariate multivariable regression and cross-lagged panel model with latent variable modeling (CLPM-L) were employed to test the study hypotheses. Mediation analyses were conducted for lifestyle (e.g., diet, physical activity) and physical health status (e.g., hypertension, blood pressure and diabetes) variables. Study 3 was a prospective analysis of the Adolescent Brain Cognitive Development (ABCD) dataset (N = 11,878). The above-mentioned bidirectional hypotheses were examined using two indicators of adiposity (e.g., BMI z score [zBMI] and WC) and five indicators of cognitive function included in the NIH Toolbox Cognitive Battery (e.g., Flanker, pattern recognition, picture sequence, picture vocabulary and oral reading tasks). Multivariate multivariable regression and CLPM-L were employed to test the study hypotheses. Mediation analyses were conducted for lifestyle (e.g., diet, physical activity) variables, physical health status (e.g., blood pressure) variables, and lateral prefrontal cortex (PFC) morphology features (volume and thickness). Results: Study 1 showed that measures of cognitive functions were significantly associated with adiposity after controlling for confounders in cross-sectional analysis of the CLSA baseline datasets. In general, superior performance on animal fluency, Stroop, and reaction time tasks was associated with lower adiposity by most metrics. These associations were more substantial for moderate- and high-income sub-populations and mediated through lifestyle behavior (e.g., diet and physical activity) and physical health conditions (e.g., diabetes and diet). Study 2 suggested that higher baseline adiposity was associated with higher Stroop interference at follow-up for both middle-aged and older adults. Similarly, higher baseline Stroop interference was associated with higher follow-up adiposity, but only in middle-aged adults. Effects involving semantic fluency and processing speed were less consistent. The above effects persisted following covariate adjustments and when used latent variable modeling of the adiposity variable. Significant mediation effects were observed for blood pressure, diabetes, and diet. Study 3 revealed that higher baseline zBMI and WC were associated with worse follow-up picture sequence and better picture vocabulary task performance, respectively. Likewise, superior baseline performance on Flanker and picture sequence tasks was associated with better follow-up adiposity status. A bidirectional association was observed between episodic memory and zBMI. Latent adiposity modeling showed a bidirectional association with executive function (measured by Flanker task) but not with other cognitive domains. Significant mediation effects were observed for blood pressure, physical activity, and lateral PFC volume/thickness. Conclusion: This dissertation examined the possibility of bidirectional associations between adiposity and cognitive function among older adults, middle-aged adults, and adolescents. Findings suggested that bidirectional associations between adiposity and cognitive function exist among adolescents and middle-aged individuals. In contrast, findings involving older adult population supported primarily a “brain-as-outcome” perspective on the association between adiposity and cognitive function