Early Impact of Bariatric Surgery on Brain Functionality

Abstract

Obesity is a chronic inflammatory disease with an alarming number of cases recorded, becoming a global public health problem. Thus, an increasing number of eligible individuals choose to undergo metabolic and bariatric surgery (MBS), known for its effective results in weight reduction and improvement of metabolic conditions. Despite reversing the damage to the central nervous system caused by obesity, these procedures also present neuronal complications. Therefore, in this review, we explore the early impact of MBS on the brain of postoperative patients, with effects observed up to 6 months after surgery, covering hormonal changes, reward mechanisms, as well as influence on mood and mental health. Although improvements in mood and quality of life are reported, the early postoperative phases can be marked by emotional vulnerability, nutritional deficiencies, and psychiatric complications. These findings highlight the benefits and risks associated with MBS, underscoring the need for interventions to maintain quality of life in the postoperative period.

INTRODUCTION

Obesity is a metabolic disorder characterized by the accumulation of fat in the body, and it also poses health risks, as it is associated with the development of other diseases [1,2]. Annually, obesity-related comorbidities account for more than 5 million global deaths [3]. Due to its increasing incidence over the years, obesity has been considered a global epidemic [4]. According to data from the World Health Organization (WHO), in 2022, 2.5 million adults were overweight, of which more than 890 million were obese, indicating that 1 in 8 people in the world lived with obesity. In the same year, 43% of adults aged 18 and over were overweight, and 16% were living with obesity. Furthermore, between 1990 and 2022, the global prevalence of obesity has more than doubled in the number of cases [5]. Furthermore, estimates indicate that by 2030 there will be a 33% increase in the prevalence of this disease [6].

Although there are interventions for controlling obesity, many patients have low adherence to conventional, dietary and pharmacological treatments [7]. Among the alternatives, metabolic and bariatric surgery (MBS) has stood out as an effective option due to its lasting weight loss effects and metabolic benefits superior to conventional treatments [8]. There are different approaches to MBS, however, considering the most common current procedures, the most notable are vertical gastrectomy (VSG), also known as Sleeve, and Roux-en-Y gastric bypass (RYGB) [9]. Interventions differ from each other due to their properties, and can be restrictive, malabsorption, or a combination of both. Restrictive procedures seek to reduce the amount of food to be ingested, while malabsorption procedures reduce the absorption of nutrients from food [10].

In addition to the metabolic benefits, improving cardiovascular conditions, dyslipidemia, type 2 diabetes mellitus (DM2) and systemic arterial hypertension (SAH), MBS has also been shown to reduce the incidence of cancer and overall mortality SAH. At the brain level, other benefits are found, including structural, functional and cognitive benefits, especially recovering the damage caused by obesity [11].

In contrast, individuals who undergo MBS often have nutritional deficiencies in vitamins such as iron, folic acid, calcium and vitamin B12, which can be detrimental to neurological functioning [11]. An example of this is the development of Wernicke-Korsakoff syndrome. This condition is characterized by an acute phase, Wernicke's encephalopathy, where symptoms of mental confusion and impaired motor coordination are common. Subsequent to this, Korsakoff syndrome manifests itself, presenting signs of anterograde amnesia [12]. This neurological disorder is a consequence of thiamine deficiency and usually appears days or weeks after the procedure [12,13]. Additionally, other neurological complications after MBS are also common, some of which include damage to peripheral nerves, ataxia, encephalopathy, myelopathy, neuropathy, myopathy and psychiatric disorders [13].

Despite the complications associated with MBS, it is important to consider the negative impact of obesity on the central nervous system (CNS). It has been reported that individuals with obesity have a high risk of developing neurodegenerative diseases [14], cognitive decline [15], mood disorders, as well as structural brain changes, and impairment of the blood-brain barrier (BBB) favoring a neuroinflammatory state [16]. This, together with the maintenance of metabolic diseases, makes MBS a viable option, however, attention must be paid to the damage it can cause to the brain [13]. Thus, given that obesity causes brain damage, a phenomenon also observed in bariatric patients, and that studies present controversial results, this review seeks to elucidate the effects that MBS can have on the brain of patients after surgery.

OBESITY: THE GROWING GLOBAL PHENOMENON AND ITS HEALTH IMPLICATIONS

Obesity is a multifactorial chronic disease, as it can be influenced by genetic and environmental factors. Specifically, it is triggered by an imbalance between high caloric intake and low energy expenditure [17]. Obesity is defined by the WHO as a state that is harmful to health caused by the accumulation of fat [5]. In this sense, the classification of obesity is commonly based on the body mass index (BMI), where the individual is considered obese when they have a BMI greater than or equal to 30 kg/m². However, this method is not the most appropriate, as it does not take into account the individual's body composition, nor does it differentiate between visceral fat and subcutaneous fat. This distinction is crucial, as excess visceral fat is a significant risk factor for obesity and its comorbidities [5,18,19].

In this context, there are 2 main types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), which perform distinct functions. BAT produces heat through thermogenesis, facilitated by the high concentration of mitochondria, which harbor uncoupling protein-1 [20]. On the other hand, WAT stores energy, since the excess of nutrients ingested generates a positive energy balance, which in turn is stored in adipocytes, in the form of triacylglycerides [21,22]. In addition, WAT is also involved in the secretion of hormones, cytokines and metabolic homeostasis [21,23].

Therefore, when there is an excess of calories ingested, adipose tissue expands due to the accumulation of fat, resulting in an increase in the volume of adipocytes, known as hypertrophy, which in turn favors a pro-inflammatory environment, secretion of cytokines and fibrosis of adipose tissue [24,25]. As a result of excess lipids in adipocytes, there is insulin resistance. In response to this condition, hyperplasia occurs to repair this damage, generating new adipocytes [24]. As a result, blood vessels cannot support tissue expansion, thus blood supply and oxygen supply are affected, leading to hypoxia [26,27].

In this context, hypoxia initiates the activation of hypoxia-inducible factor 1-α. This molecule is upregulated in cases of obesity, consequently stimulating the generation of pro-inflammatory agents. This, consequently, leads to an inflammatory reaction in adipocytes and immune cells, for example, tissue macrophages [28,29]. These can be expressed from the stimulation of interleukin (IL)-4, IL-13, glucocorticosteroids and prostaglandin E2, having anti-inflammatory properties, by secreting IL-10 and transforming growth factor β, playing an important role in homeostasis and tissue repair. On the other hand, there are macrophages with a pro-inflammatory phenotype, which in turn are expressed from the stimulation of interferon-gamma or bacterial products, such as lipopolysaccharides [30,31]. These are the predominant type of macrophage in obesity, increasing in turn cytokines such as tumor necrosis factor (TNF), IL-6 and IL-1β, reactive oxygen species, resulting in the development of insulin resistance and culminating in inflammation of adipose tissue [25,30,31].

In addition, substances secreted by adipocytes, known as adipokines, play a significant role in the regulation of immunity and glucose metabolism. Thus, in obesity, pro-inflammatory adipokines are secreted, such as TNF, IL-6, leptin and adiponectin, for example [32]. The release of these favors an inflammatory state in individuals with this disease [33].

On the other hand, adiponectin is an adipokine with anti-inflammatory, insulin-sensitizing and cardioprotective action. However, in obese individuals, there is a reduction in its levels [32,34]. Contrary to the effect of adiponectin, leptin is a hormone with pro-inflammatory action, and is most expressed in obesity [25,32]. Additionally, leptin plays important roles in regulating food intake, reproduction, angiogenesis, homeostasis, lipolysis, and thermogenesis [34,35].

Given the problem of obesity, the search for effective interventions is constant, aiming to control this disease and its comorbidities. Among the current non-invasive alternatives are calorie restriction diets [36], practice of physical exercise [37], use of probiotics and prebiotics [38] and pharmacological treatment [39]. On the other hand, many patients do not achieve the expected results with these alternatives and turn to MBS, due to its long-lasting results in weight reduction and metabolic advantages [7,39].

BARIATRIC SURGERY: EXPLORING THE PROCEDURES AND IMPACT OF SURGERY FOR OBESITY CONTROL

MBS has been commonly used in the treatment of obesity, often demonstrating better results compared to non-surgical interventions. These improvements are evident in weight reduction and in the control of diseases such as diabetes, myocardial infarction, stroke and cancer [39,40]. However, surgery is recommended for individuals with a BMI equal to or greater than 30 kg/m², classified as grade I obesity and who have comorbidities associated with obesity, or individuals with a BMI equal to or greater than 35 kg/m², even in the absence of comorbidities related to obesity, particularly among individuals aged between 18 and 65 years [40].

From 2003 to 2018, surgical procedures for obesity worldwide increased fivefold, from 140,000 procedures in 2003 to 720,000 in 2018 [41]. According to the American Society for Metabolic and Bariatric Surgery, a total of 279,967 individuals in the United States underwent bariatric surgery in the year 2022, representing an increase of approximately 29.79% compared to 2016 numbers [42]. Worldwide, in 2021, Europe and North America recorded the highest numbers of MBS, with 178,471 and 186,568 surgeries recorded, respectively. In the same year, Latin America also recorded high numbers of MBS, totaling 104,239 surgeries. In contrast, regions such as Asia-Pacific documented approximately 76,000 procedures, while the Middle East and North Africa reported the lowest number, with around 52,918 procedures. Thus, the total number of MBSs conducted globally in 2021 totaled around 599,000 surgeries [43].

Currently, there are a few options available for MBS, including jejunoileal intestinal bypass, adjustable gastric banding, biliopancreatic diversion with duodenal switch, RYGB, and VSG [44]. Of these, VSG is the most commonly performed procedure, being a restrictive technique, generally performed laparoscopically, where approximately 80% of the stomach is resected, reducing its volume capacity, in order to limit the intake of macronutrients [45,46]. This occurs because, in addition to limiting intake, the portion of the stomach that has P/D1 cells is affected. These cells are important for the production of ghrelin, and consequently, the decrease in the levels of this hormone increases the feeling of satiety [46]. Furthermore, this technique is recognized for being minimally invasive, resulting in substantial weight reduction in a short period of time and presenting favorable survival rates [46]. Above all, it is considered a simple surgery, which requires little operating time, and does not require anastomosis [47]. A better quality of life is also reported post-surgery and an improvement in comorbidities associated with obesity [48].

These benefits are observed in studies such as the SLEEVEPASS randomized clinical trial of Salminen et al. [49], this study assessed the equivalence of VSG to RYGB. The results of individuals undergoing VSG demonstrated an estimated average loss of excess weight in 5 years of 49%. In this study, reductions in comorbidities were also observed, such as DM2 in 37% of patients, dyslipidemia in 47% and hypertension in 29%. In the long term, in the follow-up of the SLEEVEPASS study [50], an estimated average weight loss of 43.5% was observed 10 years after VSG, and reductions in comorbidities were also observed, however, in smaller percentages.

On the other hand, weight regain, gastroesophageal reflux, heartburn, nutritional deficiencies and fistula formation are also found in these patients [47,48]. Corroborating with study of Våge et al. [51], which evaluated and monitored 117 patients undergoing VSG for 2 years. An increase of 12.8% in gastroesophageal reflux disease was observed before the procedure, to 27.4% in 2 years. Bleeding requiring transfusion was also reported in 5% of patients, and low ferritin levels were also found post-surgery. Another study demonstrated that there was weight regain in 26.9% of patients after VSG, gastroesophageal reflux disease, and postoperative complications such as fistula and bleeding were also found in 16.9% and 5.4% of patients, respectively [52].

Another frequently used method is RYGB, which involves a combination of a restrictive and malabsorptive approach. This technique not only reduces food intake, but also reduces food absorption [9]. As in VSG, hormones associated with the regulation of satiety are also affected, with a lower production of ghrelin, and greater secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) [53]. These changes are influenced by the method used in this procedure, where a proximal gastric pouch is created, which isolates it from the distal portion of the stomach, a region that is anastomosed with the Roux limb of the jejunum, resulting in a limitation in gastric capacity [40]. Furthermore, RYGB has been associated with improvements in morbidity and mortality levels, weight reduction in a short period of time, improvement in comorbidities, and consequently a better quality of life [53].

Corroborating with study of Level et al. [54], who followed for 5 years and compared results obtained with single anastomosis gastric bypass (SAGB) and RYGB. It was observed that patients undergoing RYGB achieved 100% remission of DM2, insulin resistance, dyslipidemia, gastroesophageal reflux disease and 66.6% of hypertensive conditions, resulting in 89% resolution of comorbidities in the RYGB group, while individuals undergoing SAGB showed a 77% reduction in comorbidities. However, there were no statistical differences when comparing the groups. In the previously cited study by Salminen et al. [49], positive results were also found after RYGB. Individuals undergoing RYGB achieved a 57% weight loss. Regarding comorbidities, 45% achieved diabetes remission, 60% and 51% discontinued medication for dyslipidemia and hypertension, respectively. Results superior to those achieved with VSG.

On the other hand, hernia [55,56], gastroduodenal peptic disease, fistulas and bleeding [57], are observed post-surgery. Furthermore, it is a procedure of great technical difficulty [53,56]. Study of Bossen et al. [58], which aimed to evaluate whether smoking was associated with the development of hernia after RYGB, demonstrated that 5 years after the procedure, 11% of patients presented internal hernia. Furthermore, this study demonstrated that smoking is in fact associated with the risk of developing hernia, as well as excessive weight loss.

Above all, MBS has increasingly emerged as a popular choice among individuals struggling with obesity, mainly due to its improvement in comorbidities, in addition to presenting high safety and low incidence of complications, rates that are comparable to simple surgical interventions, such as cholecystectomy and appendectomy [59]. However, some negative effects are also common, such as nutritional and vitamin deficiencies [60], weight recovery [61], development of cholelithiasis [62], in addition to increased rates of suicide, substance use disorders and other mental health-related problems [63]. Furthermore, changes at the brain level are also observed post MBS [64].

INFLUENCE OF MBS ON INTESTINAL HORMONES AND THE SATIETY CENTER

Some substances influence brain activity, including intestinal hormones and adipokines, such as leptin, GLP-1 and PYY. These hormones play a role in regulating appetite and undergo changes postoperatively, causing a decrease in calorie consumption. This in turn affects brain regions and contributes to sustained weight loss [65]. These substances are affected after MBS, their changes are illustrated in Fig. 1.

Fig. 1. Altered mechanisms after MBS. MBS results in a decrease in ghrelin levels in the stomach. In the intestine, an increase in GLP-1, PYY and SCFA levels is observed, which contributes to reduced inflammation. This information is transmitted to the brain via afferent fibers of the vagus nerve, projecting to the NTS and distributing to the hypothalamus. In the ARC, POMC/CART stimulation and NPY/AgRP inhibition occur. POMC projections to the PVN nucleus act as agonists of MC4R receptors, sending anorectic signals to the periphery, which decreases food intake. The hypothalamus also influences the brain's reward system. There is controversy regarding the impact of MBS on the levels of dopamine D1 and D2 receptors, CB1, and 5-HT in brain reward regions. An increase in the levels of MOR receptors in the brain has also been reported.

PVN = paraventricular nucleus, MC4R = melanocortin receptor 4, ARC = arcuate nucleus, POMC = proopiomelanocortin, CART = cocaine- and amphetamine-regulated transcript, NPY = neuropeptide Y, AgRP = agouti-related protein, NTS = nucleus tractus solitarius, NAcc = nucleus accumbens, MOR = μ-opioid receptors, D1 = dopamine receptor 1, D2 = dopamine receptor 2, CB1 = cannabinoid receptor type 1, VTA = ventral tegmental area, R5-HT = serotonin receptor, CNS = central nervous system, GLP-1 = glucagon-like peptide 1, PYY = peptide YY, SCFA = short-chain fatty acids, MBS = metabolic and bariatric surgery.

In this sense, together with the decrease in adipose tissue after MBS, it is proposed that there is a reduction in leptin levels, to counteract the leptin resistance developed during obesity [66]. However, this decrease in levels can result in weight regain. This can be explained by the fact that, once obesity sets in, the regulation of energy balance regulates metabolism to ensure that consistent fat levels are maintained even after MBS, which combined with the decrease in leptin levels, can lead to an increase in food intake and a decrease in energy expenditure [67]. It is worth noting that GLP-1 and PYY are hormones secreted by intestinal cells. These tend to increase their levels after surgery, thus collectively increasing satiety signaling. The mechanisms of GLP-1 include improving glucose metabolism, slowing the rate of gastric emptying, and facilitating weight loss. On the other hand, PYY influences glucose homeostasis after surgery [68].

Furthermore, MBS induces substantial changes in the composition of the intestinal microbiota, resulting in a beneficial profile of short-chain fatty acids (SCFA) and reducing inflammation. Changes are also observed at the brain level, given the impact of surgery on neuronal activity, increasing satiety signals transmitted by GLP-1 and PYY. This phenomenon occurs because intestinal microorganisms convert dietary nutrients into metabolites, such as SCFA, leading enteroendocrine cells to secrete intestinal peptides associated with satiety, such as GLP-1 and PYY. In this way, signaling from the intestine to the brain is facilitated by afferent fibers of the vagus nerve, which transmit sensory information to the nodose ganglion, which in turn projects information from the intestine to the nucleus of the solitary tract, and is consequently distributed to the hypothalamus. This is involved in the regulation of energy balance, appetite, and food intake, especially in the neurons of the arcuate nucleus of the hypothalamus (ARC) [68,69].

The ARC is one of the nuclei of the hypothalamus that plays a key role in energy balance. It comprises groups of neurons located in the mediobasal hypothalamus. Its location, unlike other nuclei of the hypothalamus, is partially outside the BBB, strategically positioned to intercept signals from circulating hormones and nutrients [70]. Thus, hormones such as ghrelin, leptin, PYY and GLP-1 activate their respective receptors located in ARC neurons, stimulating the release of anorexigenic neuropeptides, such as pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART), or orexigenic neuropeptides, such as neuropeptide Y (NPY) and agouti-related peptide (AgRP) [71]. While leptin stimulates the activity of POMC/CART neurons and inhibits NPY/AgRP, ghrelin in turn stimulates NPY/AgRP [68]. Thus, POMC, the precursor of α-melanocyte-stimulating hormone, projects to the paraventricular nucleus, which contains high levels of melanocortin 3 receptor and melanocortin 4 receptor (MC4R) [71]. Above all, MC4R is the receptor that plays a crucial role in energy balance, thus, POMC acts as an agonist of this receptor, while AgRP, as its antagonist [70]. When MC4R is activated, anorectic signals are sent to the periphery, leading to decreased food intake. Because of this effect, changes in this receptor are often associated with obesity [68,70]. After MBS, there appears to be increased activation of POMC/CART, and reduced activation of NPY/AgRP [68]. In contrast to other interventions, such as the calorie restriction diet, which has been shown to increase NPY/AgRP expression, indicating reduced satiety [72].

Due to these changes observed post-surgery, there is also a decrease in hedonic food responses and in the reward system, impacting the food preferences of these individuals, who begin to opt more frequently for low-energy foods. Together, these hormonal, brain and behavioral changes contribute to the success of MBS in promoting weight loss and improving metabolic health [73]. Given the importance of these modifications, a more in-depth view of the MBS mechanisms involved in the reward and neurotransmission system is essential.

IMPACT OF MBS ON THE REWARD SYSTEM, NEUROTRANSMISSION AND MENTAL HEALTH

It is well established that there is an interconnection between homeostatic and reward circuits, mediated by the hypothalamus (Fig. 1) [74]. In addition to playing a crucial role in homeostatic control, peripheral anorexigenic and orexigenic signals exert influence beyond the hypothalamus, but also on other brain structures involved in the reward system [75]. This has been associated as an important factor in the neuropathology of obesity and represents the neural reaction to internal or external stimuli, promoting behaviors related to eating, which, in turn, are based on pleasure, desire and learning [76,77,78].

Thus, the reward system consists mainly of the mesolimbic dopaminergic pathway, which drives food-seeking behavior, especially in the presence of hyperpalatable foods, such as ultra-processed, fatty and sugar-rich foods [76,77]. After exposure to these foods, dopaminergic neurons are transported from the ventral tegmental area (VTA) to specific brain regions, especially the nucleus accumbens (NAcc) [68]. Other regions are also involved, including subcortical structures (ventral pallidum and amygdala), striatum (NAcc, caudate nucleus, and putamen), prefrontal cortex (orbitofrontal cortex, insula, and anterior cingulate cortex), and brainstem (VTA and substantia nigra) [76].

It is widely recognized that dopamine plays a key role in the food reward effect, especially in relation to eating behavior, desire and learning components [77]. Among the most described dopaminergic receptors are dopamine 1 (D1) and dopamine 2 (D2) receptors. These are distributed in the mesolimbic system, in regions such as the NAcc, substantia nigra, VTA and amygdala [79]. In obesity, it has been reported that there is a decrease in D1 and D2 receptors, and an increase in dopamine transporter [80]. This may be attributed to individuals' intermittent search for palatable foods to sustain the reward symptom, leading to a vicious cycle that contributes to obesity. Consequently, habituation to these stimuli is triggered, which leads to a reduction in dopaminergic activation, presumably resulting from a lower availability of D2 receptors [80,81,82]. Thus, it has been suggested that MBS may lead to changes in the availability of dopamine receptors, specifically D1 and D2 receptors, located in the striatum. While rats exposed to a high-fat diet show reduced binding to these receptors, RYGB may lead to the normalization of these levels [83]. However, these results diverge in some studies, indicating a reduction in D2 availability [84], or even that it remains unchanged after the procedure [85,86].

The opioidergic system, which comprises μ, κ, δ receptors, is another neurotransmission system that plays a significant role in the regulation of food intake [87]. Activation of these receptors occurs through endogenous peptides, such as endorphins, enkephalins and dynorphins, in response to natural reward signals [87,88]. The distribution of these peptides and receptors includes the NAcc, VTA, and the hypothalamus [88,89]. Opioid infusion into the NAcc leads to increased consumption of alcohol, sugary and high-fat foods, indicating a relationship with the hedonic aspects of the reward system [90]. Individuals with obesity have been shown to have reduced availability of μ-opioid receptors (MORs) in reward-related brain regions, potentially leading to increased hedonic eating and contributing to dysfunctional eating behaviors [86,91]. This phenomenon was observed in a preliminary study using positron emission tomography (PET) involving obese individuals undergoing a dietary intervention, where changes in the availability of cerebral MOR were observed [92]. Furthermore, Karlsson et al. [86], also conducted a PET study indicating that 6 months after MBS, cerebral MOR availability in reward-related areas such as striatum, insula, amygdala, thalamus, orbitofrontal cortex, and anterior cingulate cortex was restored.

The endocannabinoid system, like the opioid system, plays a role in controlling food intake. In this system, the cannabinoid receptor type 1 (CB1) and the cannabinoid receptor type 2 are G-protein coupled receptors, acting mainly in the hypothalamus and the mesolimbic system [91]. In this system, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol are found. These compounds increase the consumption of tasty foods by acting on CB1 receptors, also present in the parabrachial nucleus, responsible for taste signaling [93]. In the hypothalamus, endocannabinoid levels increase during fasting and decrease during periods of satiety [91]. Hormones such as leptin normally regulate these levels by suppressing the expression of CB1 receptors, however, leptin resistance commonly seen in obesity can disrupt this regulation, leading to increased eating behaviors [94]. In the NAcc and VTA regions, endocannabinoids influence the release of dopamine in response to palatable foods, promoting greater demand for these foods, due to the associated sensation of pleasure [91]. After RYGB surgery, in turn, there is a reduction in CB1 expression in the small intestine, and it has been shown that the administration of AEA impaired the surgical outcome, considerably decreasing weight loss after RYGB. It is proposed that, after RYGB, CB1 expression decreases at the intestinal level, but remains unchanged in the hypothalamus [95].

Serotonin is another neurotransmitter involved in regulating food intake and controlling body weight, as obesity is often associated with changes in serotonin signaling [96,97]. The distribution of serotonin 5-HT2C receptors in several regions of the CNS, particularly those involved in the control of eating behavior, such as the hippocampus, amygdala and limbic regions, highlights their importance in this process. Thus, 5-HT2C receptor agonists decrease food intake, while antagonists increase appetite and body weight. It is known that the activation of this receptor plays an inhibitory role in the regulation of reward-related behavior, together with its activation in the VTA, contributing to the reduction of homeostatic and hedonic feeding [97]. In obesity, it is assumed that there is a reduction in serotonergic signaling, which consequently results in greater food consumption [96]. Although it is suggested that MBS may lead to normalization of 5-HT function, in a study of Ratner et al. [98] it was observed that there were no major changes in serotonergic markers, indicating that weight loss alone is not enough to lead to significant changes in this system. Furthermore, another study demonstrated that treatment with a 5-HT2C agonist was able to reduce food intake by 43% and increase weight loss in animals subjected to RYGB [99].

In addition to changes in neurotransmission, MBS has been shown to be able to restore some obesity-induced changes in brain reward areas [100]. A pilot study demonstrated reductions in the postprandial fractional amplitude of low-frequency fluctuations (fALFFs) in brain regions associated with food reward, including the postcentral gyrus, precentral gyrus, and right superior frontal gyrus, in individuals undergoing RYGB. This suggests an alteration in the neural response to food-related cues postoperatively [78].

Furthermore, in a longitudinal study that followed individuals undergoing VSG for 12 months, an improvement in adaptive eating behaviors was observed. There was also a reduction in activity in areas such as the NAcc, other regions of the striatum and the amygdala, associated with an increase in the desire for palatable foods, suggesting that after VSG there was a normalization of both eating behaviors and the regulation of the reward system [101]. These changes are important, since hedonic eating can be a contributing factor to weight regain after MBS [102]. These findings are essential and may predict long-term success after MBS. However, it is also important to consider the impact of surgery on patients’ emotional state.

In addition to the aforementioned changes, MBS also has a considerable impact on the mood of patients postoperatively. It is crucial to note that a significant percentage, ranging from 22.4% to 45%, of individuals seeking MBS treatment experience some form of mood disorder [103]. Some studies show that MBS tends to reduce disorders such as depression, anxiety, and improve quality of life and body image [103,104,105,106]. On the other hand, research indicates a correlation between MBS and a heightened susceptibility to suicide, self-harm, depression and substance use disorders [107,108].

A study that evaluated the results 10 to 18 years after MBS reported a significant reduction in the rate of depression, from 27.1% in the pre-surgical period to 4.2% in the post-surgical reassessment. Regarding anxiety, a decrease was also observed, from 7.3% to 2.1% [109]. Study of Smith et al. [110], which assessed the trajectory of depressive symptoms from the pre-surgical period to 7 years after surgery, demonstrated a decrease in the severity of depression levels in the long term. At the seventh year after the procedure, 74.8% of the individuals had minimal symptoms, compared to 58% of the individuals in the pre-surgical period. Furthermore, the percentage of individuals with mild and moderate levels of depression was lower after 7 years than 6 months after MBS. Severe symptoms were observed in only 1.9% of patients 7 years after MBS.

One of the factors associated with these conditions is significant weight regain after surgery [111]. This correlation is demonstrated through a study based on post-MBS assessments, where weight regain increased to 48%, depressive symptoms to 46%, and anxiety symptoms to 63%, a higher frequency than that observed preoperatively [105].

In addition, there is a change in lifestyle, as surgical options restrict both dietary volume and absorption. Restrictive procedures such as VSG mainly affect the absorption of iron, selenium and vitamin B12, while malabsorptive procedures such as RYGB affect the absorption of vitamins, minerals and micronutrients that are crucial for cellular enzymatic reactions and biochemical pathways [112]. Among them, thiamine or vitamin B1 deficiency is one of the common CNS complications, affecting up to 49% of individuals undergoing the procedure. This deficiency can result in the development of Wernicke-Korsakoff syndrome, leading to neurological dysfunctions, including altered cognitive function, confusion and impaired motor skills [13,113].

In a 12-year cohort study, it was observed that individuals who underwent malabsorptive procedures were more likely to develop depression compared to those who underwent restrictive procedures. This suggests that nutrient malabsorption plays a more significant role in the development of depression, going beyond simply reducing food intake [114]. Corroborating additional studies, which highlight a connection between vitamin B deficiency and an increased risk of depression, anxiety and CNS disorders such as dementia and Alzheimer's disease [115,116]. Similarly, vitamin C deficiency can also lead to depression [112]. Despite the numerous long-term benefits and implications, considering brain changes that occur in the short term, that is, up to 6 months after surgery, is essential, as they are still little explored.

CEREBRAL INFLUENCE OF MBS DURING THE FIRST 6 MONTHS POST-SURGERY

One of the main factors associated with the success of MBS is weight loss, which can be attributed to changes in eating habits and a preference for low-energy foods [117]. In fact, study of Baboumian et al. [118] reported that 4 months after MBS, there was an increase in dorsolateral prefrontal cortex activation and a decrease in parahippocampal and fusiform gyrus activation in response to visual and auditory stimuli, to high-energy-density foods vs. low-energy-density foods. These changes in brain activation in limbic regions suggest a decrease in the reward and attention effects related to hypercaloric foods.

Reinforcing existing literature, a study by Zeighami et al. [119] evaluated the brain activity of individuals undergoing different MBS methods, where an increase in fALFF was observed, especially in cortical and subcortical regions, such as the dorsolateral prefrontal cortex, precuneus, inferior temporal gyrus and visual cortex. This effect was observed especially in the period of 4 months after surgery. However, morphological changes observed through modifications in gray matter density were only observed twelve months after the procedure. Furthermore, in this study, some individuals were lost to follow-up between twelve and 24 months, making it impossible to analyze whether this effect of fALFF was in fact more pronounced in the short term.

Another study evaluating fALFF in individuals after CBM demonstrated that one month after the procedure, there was an increase in fALFF in the caudate and hypothalamus, and a decrease in the orbitofrontal cortex. Reduced connectivity of the orbitofrontal cortex with mesolimbic regions, such as the amygdala, thalamus and hippocampus, was also observed, suggesting that surgery normalizes brain activity in areas involved in food motivation, sensory processing, emotion and reward [120].

On the other hand, especially in these early stages post-MBS, there may be an increase in responsiveness to the reward system, triggered by the period of food restriction and changes in the gastrointestinal tract [121]. This abrupt change in habits can impact bariatric patients with no previous history of depression, making them symptomatic, given the significant influence of diet on the mood of these individuals and the impossibility of overeating as a way of coping with daily emotions [121,122].

In contrast to some positive results, Järvholm et al. [123] found in their study that 11% of adolescents who underwent MBS reported a significant increase in symptoms of anxiety and depression 4 months after the procedure, compared to their pre-surgical levels. Furthermore, in a cross-sectional study, it was observed that twelve months after the procedure, anxiety and stress levels worsened, while depression levels reduced, suggesting that quality of life may remain compromised for twelve months after the procedure [124]. Corroborating additional studies, which demonstrate that between 6 and 12 months post-surgery, a reduction in depressive symptoms is observed [125,126].

On the other hand, this reduction in depressive symptoms may be confounded by preexisting depression, Yuan et al. [127] demonstrated that MBS in individuals without a previous diagnosis of depression was significantly associated with the development of postsurgical depression. In agreement with this, a prospective study using the Hamilton Depression Rating Scale demonstrated higher scores indicative of depressive symptoms in the preoperative period and 6 months after surgery, compared to healthy controls. However, after twelve months, no statistically significant differences were found between the groups [128]. These findings, together with the brain and behavioral changes previously described in this article following MBS, are summarized in Table 1.

Table 1. Brain and behavioral changes after MBS.

Post-MBS time	Main findings	Evaluation method	References
6 months	↓ fALFF postprandial in reward-related regions (postcentral gyrus, precentral gyrus, and superior frontal gyrus)	fALFF	Agarwal et al. [78]
1.5 months (7 weeks)	↓ Dopamine D2 receptor availability	PET	Dunn et al. [84]
1.5 months (6 weeks)	Unchanged D2 receptor	Single photon emission computed tomography	De Weijer et al. [85]
6 months	Unchanged D2 receptor; ↑ brain μ-opioid receptors in areas related to the reward system	PET	Karlsson et al. [86]
12 months	↓ Activity of the nucleus accumbens, striatum, and amygdala	fMRI	Holsen et al. [101]
6 weeks, 3 and 6 months	↓ Depression and anxiety	Patient-Reported Outcomes Measurement Information System	Aylward et al. [104]
7 to 14 years	↑ Depression and anxiety	BDI/State-Trait Anxiety Inventory (IDATE)	Freire et al. [105]
10 to 18 years	↓ Depression and anxiety	Medical records	de la Cruz-Muñoz et al. [109]
7 years	↓ Depression	BDI	Smith et al. [110]
4 months	↑ Activation of the dorsolateral prefrontal cortex; ↓ parahippocampal and fusiform gyrus activation	fMRI, in response to food cues	Baboumian et al. [118]
4 and 12 months	↑ fALFF cortical and subcortical regions; ↑ gray matter density	fALFF	Zeighami et al. [119]
1 month	↑ ALFF in the caudate and hypothalamus; ↓ connectivity of the orbitofrontal cortex with the amygdala, thalamus, and hippocampus	fMRI/Amplitude of low-frequency fluctuation ALFF	Duan et al. [120]
4 months	51% of patients presented unchanged anxiety and depression; 11% ↑ depression/anxiety	Beck Youth Inventories/BDI-II	Järvholm et al. [123]
12 months	↑ Anxiety and stress; ↓ depression	Depression Anxiety Stress Scale	ElBarazi [124]
6 months	↓ Symptoms of depression	BDI-II	Efferdinger et al. [125]
6 and 12 months	↓ Depression	BDI-II/BDI	Kotackova et al. [126], White et al. [103]
Long-term follow-up	Bariatric surgery had a hazard ratio of 1.31 and 1.50 for subsequent depression/development of depression	Cox regression	Yuan et al. [127], Arhi et al. [121]
6 months	Higher scores indicative of depressive symptoms preoperatively and six months postoperatively compared with healthy controls	Hamilton Depression Rating Scale	Çalışır et al. [128]

MBS = metabolic and bariatric surgery, fALFF = fractional amplitude of low-frequency fluctuation, D2 = dopamine 2, PET = positron emission tomography, fMRI = Functional magnetic resonance imaging, BDI = beck depression inventory, IDATE = inventário de ansiedade traço-estado, ALFF = amplitude of low-frequency fluctuation.

Therefore, it is clear that in addition to the metabolic and bodily influence of MBS, it also plays a crucial role in the mental and emotional health of individuals. Thus, the real impact that occurs in the short term, up to 6 months after surgery, remains uncertain, making further studies necessary in this initial post-surgical period to clarify these issues. Furthermore, it is crucial to develop interventions that preserve brain functionality and quality of life in the early postoperative period in order to optimize MBS outcomes.

CONCLUSION

Given the high prevalence of obesity worldwide and the increasing numbers of individuals undergoing MBS, clarifying the brain mechanisms involved may provide insight into how this procedure can impact not only the body, but also the mind. By exploring the effects of the procedure on satiety, the reward system, neurotransmitters and mood, a complex connection between the body’s physiology and mental processes is revealed. Although MBS brings benefits such as sustained weight loss, resolution of comorbidities, and improvement in quality of life, it is crucial to be aware of the possible risks of the procedure, including nutritional deficiencies and psychological effects. These findings highlight the importance of a multidisciplinary approach in the treatment of obesity, since it is of utmost importance to change habits after surgery for better results, but mainly, they highlight the need for more research to fully understand the effects of MBS on the CNS.