LKB1 suppresses KSHV reactivation and promotes primary effusion lymphoma progression.

Viruses normally reprogram the host cell metabolic pathways as well as metabolic sensors to facilitate their persistence. The serine-threonine liver kinase B1 (LKB1) is a master upstream kinase of 5'-AMP-activated protein kinase (AMPK) that senses the energy status and therefore regulates the intracellular metabolic homeostasis. Previous studies showed that AMPK restricts Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in endothelial cells during primary infection and promotes primary effusion lymphoma (PEL) cell survival. However, the role of LKB1 in KSHV lytic reactivation and KSHV-associated malignancies is unclear. In this study, we found that LKB1 is phosphorylated or activated in KSHV-positive PEL cells. Mechanistically, KSHV-encoded vCyclin mediated LKB1 activation in PEL cells, as vCyclin knockout ablated, while vCyclin overexpression enhanced LKB1 activation. Furthermore, knockdown of LKB1 inactivated AMPK and induced KSHV reactivation, as indicated by the increased expression of viral lytic genes and the increased virions in supernatants. Accordingly, AMPK inhibition by functional knockdown or a pharmacologic inhibitor, Compound C, promoted KSHV reactivation in PEL cells. Furthermore, inhibition of either LKB1 or AMPKα1 efficiently induced cell death by apoptosis of PEL cells both in vitro and in vivo. Together, these results identify LKB1 as a vulnerable target for PEL, which could be potentially exploited for treating other virus-associated diseases.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with several human cancers, such as primary effusion lymphoma (PEL). Here, we showed that serine-threonine liver kinase B1 (LKB1), upstream of 5' AMP-activated protein kinase (AMPK), is activated by KSHV-encoded vCyclin and maintains KSHV latency in PEL cells. Inhibition of either LKB1 or AMPK enhances KSHV lytic replication from latency, which at least partially accounts for PEL cell death by apoptosis. Compound C, a potent AMPK inhibitor, induced KSHV reactivation and efficiently inhibited PEL progression in vivo. Thus, our work revealed that LKB1 is a potential therapeutic target for KSHV-associated cancers.

Functional near-infrared spectroscopy-based neurofeedback training regulates time-on-task effects and enhances sustained cognitive performance.

Time-on-task effect is a common consequence of long-term cognitive demand work, which reflects reduced behavioral performance and increases the risk of accidents. Neurofeedback is a neuromodulation method that can guide individuals to regulate their brain activity and manifest as changes in related symptoms and cognitive behaviors. This study aimed to examine the effects of functional near-infrared spectroscopy-based neurofeedback training on time-on-task effects and sustained cognitive performance. A randomized, single-blind, sham-controlled study was performed: 17 participants received feedback signals of their own dorsolateral prefrontal cortex activity (neurofeedback group), and 16 participants received feedback signals of dorsolateral prefrontal cortex activity from the neurofeedback group (sham-neurofeedback group). All participants received 5 neurofeedback training sessions and completed 2 sustained cognitive tasks, including a 2-back task and a psychomotor vigilance task, to evaluate behavioral performance changes following neurofeedback training. Results showed that neurofeedback relative to the sham-neurofeedback group exhibited increased dorsolateral prefrontal cortex activation, increased accuracy in the 2-back task, and decreased mean response time in the psychomotor vigilance task after neurofeedback training. In addition, the neurofeedback group showed slower decline performance during the sustained 2-back task after neurofeedback training compared with sham-neurofeedback group. These findings demonstrate that neurofeedback training could regulate time-on-task effects on difficult task and enhance performance on sustained cognitive tasks by increasing dorsolateral prefrontal cortex activity.

Obesity is associated with alterations in anatomical connectivity of frontal-corpus callosum.

Obesity has been linked to abnormal frontal function, including the white matter fibers of anterior portion of the corpus callosum, which is crucial for information exchange within frontal cortex. However, alterations in white matter anatomical connectivity between corpus callosum and cortical regions in patients with obesity have not yet been investigated. Thus, we enrolled 72 obese and 60 age-/gender-matched normal weight participants who underwent clinical measurements and diffusion tensor imaging. Probabilistic tractography with connectivity-based classification was performed to segment the corpus callosum and quantify white matter anatomical connectivity between subregions of corpus callosum and cortical regions, and associations between corpus callosum-cortex white matter anatomical connectivity and clinical behaviors were also assessed. Relative to normal weight individuals, individuals with obesity exhibited significantly greater white matter anatomical connectivity of corpus callosum-orbitofrontal cortex, which was positively correlated with body mass index and self-reported disinhibition of eating behavior, and lower white matter anatomical connectivity of corpus callosum-prefrontal cortex, which was significantly negatively correlated with craving for high-calorie food cues. The findings show that alterations in white matter anatomical connectivity between corpus callosum and frontal regions involved in reward and executive control are associated with abnormal eating behaviors.

Preterm birth associated alterations in brain structure, cognitive functioning and behavior in children from the ABCD dataset.

BACKGROUND: Preterm birth is a global health problem and associated with increased risk of long-term developmental impairments, but findings on the adverse outcomes of prematurity have been inconsistent. METHODS: Data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development (ABCD) Study. We identified 1706 preterm children and 1865 matched individuals as Control group and compared brain structure (MRI data), cognitive function and mental health symptoms. RESULTS: Results showed that preterm children had higher psychopathological risk and lower cognitive function scores compared to controls. Structural MRI analysis indicated that preterm children had higher cortical thickness in the medial orbitofrontal cortex, parahippocampal gyrus, temporal and occipital gyrus; smaller volumes in the temporal and parietal gyrus, cerebellum, insula and thalamus; and smaller fiber tract volumes in the fornix and parahippocampal-cingulum bundle. Partial correlation analyses showed that gestational age and birth weight were associated with ADHD symptoms, picvocab, flanker, reading, fluid cognition composite, crystallized cognition composite and total cognition composite scores, and measures of brain structure in regions involved with emotional regulation, attention and cognition. CONCLUSIONS: These findings suggest a complex interplay between psychopathological risk and cognitive deficits in preterm children that is associated with changes in regional brain volumes, cortical thickness, and structural connectivity among cortical and limbic brain regions critical for cognition and emotional well-being.

Brain functional and structural magnetic resonance imaging of obesity and weight loss interventions.

Obesity has tripled over the past 40 years to become a major public health issue, as it is linked with increased mortality and elevated risk for various physical and neuropsychiatric illnesses. Accumulating evidence from neuroimaging studies suggests that obesity negatively affects brain function and structure, especially within fronto-mesolimbic circuitry. Obese individuals show abnormal neural responses to food cues, taste and smell, resting-state activity and functional connectivity, and cognitive tasks including decision-making, inhibitory-control, learning/memory, and attention. In addition, obesity is associated with altered cortical morphometry, a lowered gray/white matter volume, and impaired white matter integrity. Various interventions and treatments including bariatric surgery, the most effective treatment for obesity in clinical practice, as well as dietary, exercise, pharmacological, and neuromodulation interventions such as transcranial direct current stimulation, transcranial magnetic stimulation and neurofeedback have been employed and achieved promising outcomes. These interventions and treatments appear to normalize hyper- and hypoactivations of brain regions involved with reward processing, food-intake control, and cognitive function, and also promote recovery of brain structural abnormalities. This paper provides a comprehensive literature review of the recent neuroimaging advances on the underlying neural mechanisms of both obesity and interventions, in the hope of guiding development of novel and effective treatments.

Associations among body mass index, working memory performance, gray matter volume, and brain activation in healthy children.

To investigate the neural mechanisms underlying the association between poorer working memory performance and higher body mass index (BMI) in children. We employed structural-(sMRI) and functional magnetic resonance imaging (fMRI) with a 2-back working memory task to examine brain abnormalities and their associations with BMI and working memory performance in 232 children with overweight/obesity (OW/OB) and 244 normal weight children (NW) from the Adolescent Brain Cognitive Development dataset. OW/OB had lower working memory accuracy, which was associated with higher BMI. They showed smaller gray matter (GM) volumes in the left superior frontal gyrus (SFG_L), dorsal anterior cingulate cortex, medial orbital frontal cortex, and medial superior frontal gyrus, which were associated with lower working memory accuracy. During the working memory task, OW/OB relative to NW showed weaker activation in the left superior temporal pole, amygdala, insula, and bilateral caudate. In addition, caudate activation mediated the relationship between higher BMI and lower working memory accuracy. Higher BMI is associated with smaller GM volumes and weaker brain activation in regions involved with working memory. Task-related caudate dysfunction may account for lower working memory accuracy in children with higher BMI.

Obesity is associated with decreased gray matter volume in children: a longitudinal study.

Childhood obesity has become a global health problem. Previous studies showed that childhood obesity is associated with brain structural differences relative to controls. However, few studies have been performed with longitudinal evaluations of brain structural developmental trajectories in childhood obesity. We employed voxel-based morphometry (VBM) analysis to assess gray matter (GM) volume at baseline and 2-year follow-up in 258 obese children (OB) and 265 normal weight children (NW), recruited as part of the National Institutes of Health Adolescent Brain and Cognitive Development study. Significant group × time effects on GM volume were observed in the prefrontal lobe, thalamus, right precentral gyrus, caudate, and parahippocampal gyrus/amygdala. OB compared with NW had greater reductions in GM volume in these regions over the 2-year period. Body mass index (BMI) was negatively correlated with GM volume in prefrontal lobe and with matrix reasoning ability at baseline and 2-year follow-up. In OB, Picture Test was positively correlated with GM volume in the left orbital region of the inferior frontal gyrus (OFCinf_L) at baseline and was negatively correlated with reductions in OFCinf_L volume (2-year follow-up vs. baseline). These findings indicate that childhood obesity is associated with GM volume reduction in regions involved with reward evaluation, executive function, and cognitive performance.

Associations between body mass index, sleep-disordered breathing, brain structure, and behavior in healthy children.

Pediatric overweight/obesity can lead to sleep-disordered breathing (SDB), abnormal neurological and cognitive development, and psychiatric problems, but the associations and interactions between these factors have not been fully explored. Therefore, we investigated the associations between body mass index (BMI), SDB, psychiatric and cognitive measures, and brain morphometry in 8484 children 9-11 years old using the Adolescent Brain Cognitive Development dataset. BMI was positively associated with SDB, and both were negatively correlated with cortical thickness in lingual gyrus and lateral orbitofrontal cortex, and cortical volumes in postcentral gyrus, precentral gyrus, precuneus, superior parietal lobule, and insula. Mediation analysis showed that SDB partially mediated the effect of overweight/obesity on these brain regions. Dimensional psychopathology (including aggressive behavior and externalizing problem) and cognitive function were correlated with BMI and SDB. SDB and cortical volumes in precentral gyrus and insula mediated the correlations between BMI and externalizing problem and matrix reasoning ability. Comparisons by sex showed that obesity and SDB had a greater impact on brain measures, cognitive function, and mental health in girls than in boys. These findings suggest that preventing childhood obesity will help decrease SDB symptom burden, abnormal neurological and cognitive development, and psychiatric problems.

Habenular connectivity predict weight loss and negative emotional-related eating behavior after laparoscopic sleeve gastrectomy.

Habenular (Hb) processes negative emotions that may drive compulsive food-intake. Its functional changes were reported following laparoscopic-sleeve-gastrectomy (LSG). However, structural connectivity (SC) of Hb-homeostatic/hedonic circuits after LSG remains unclear. We selected regions implicated in homeostatic/hedonic regulation that have anatomical connections with Hb as regions-of-interest (ROIs), and used diffusion-tensor-imaging with probabilistic tractography to calculate SC between Hb and these ROIs in 30 obese participants before LSG (PreLSG) and at 12-month post-LSG (PostLSG12) and 30 normal-weight controls. Three-factor-eating-questionnaire (TFEQ) and Dutch-eating-behavior-questionnaire (DEBQ) were used to assess eating behaviors. LSG significantly decreased weight, negative emotion, and improved self-reported eating behavior. LSG increased SC between the Hb and homeostatic/hedonic regions including hypothalamus (Hy), bilateral superior frontal gyri (SFG), left amygdala (AMY), and orbitofrontal cortex (OFC). TFEQ-hunger negatively correlated with SC of Hb-Hy at PostLSG12; and increased SC of Hb-Hy correlated with reduced depression and DEBQ-external eating. TFEQ-disinhibition negatively correlated with SC of Hb-bilateral SFG at PreLSG. Increased SC of Hb-left AMY correlated with reduced DEBQ-emotional eating. Higher percentage of total weight-loss negatively correlated with SC of Hb-left OFC at PreLSG. Enhanced SC of Hb-homeostatic/hedonic regulatory regions post-LSG may contribute to its beneficial effects in improving eating behaviors including negative emotional eating, and long-term weight-loss.

Functional Abnormality of the Executive Control Network in Individuals With Obesity During Delay Discounting.

Individuals with obesity (OB) prefer immediate rewards of food intake over the delayed reward of healthy well-being achieved through diet management and physical activity, compared with normal-weight controls (NW). This may reflect heightened impulsivity, an important factor contributing to the development and maintenance of obesity. However, the neural mechanisms underlying the greater impulsivity in OB remain unclear. Therefore, the current study employed functional magnetic resonance imaging with a delay discounting (DD) task to examine the association between impulsive choice and altered neural mechanisms in OB. During decision-making in the DD task, OB compared with NW had greater activation in the dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex, which was associated with greater discounting rate and weaker cognitive control as measured with the Three-Factor Eating Questionnaire (TFEQ). In addition, the association between DLPFC activation and cognitive control (TFEQ) was mediated by discounting rate. Psychophysiological interaction analysis showed decreased connectivity of DLPFC-inferior parietal cortex (within executive control network [ECN]) and angular gyrus-caudate (ECN-reward) in OB relative to NW. These findings reveal that the aberrant function and connectivity in core regions of ECN and striatal brain reward regions underpin the greater impulsivity in OB and contribute to abnormal eating behaviors.

Alterations in Functional and Structural Connectivity of Basal Ganglia Network in Patients with Obesity.

Obesity is related to overconsumption of high-calorie (HiCal) food, which is modulated by brain reward and inhibitory control circuitries. The basal ganglia (BG) are a key set of nuclei within the reward circuitry, but obesity-associated functional and structural abnormalities of BG have not been well studied. Resting-state functional MRI with independent component analysis (ICA) and probabilistic tractography were employed to investigate differences in BG-related functional-(FC) and structural connectivity (SC) between 32 patients with obesity (OB) and 35 normal-weight (NW) participants. Compared to NW, OB showed significantly lower FC strength in the caudate nucleus within the BG network, and seed-based FC analysis showed lower FC between caudate and dorsolateral prefrontal cortex (DLPFC), which was negatively correlated with craving for HiCal food cues. Further SC analysis revealed that OB showed lower SC than NW between left caudate and left DLPFC as measured with fractional anisotropy (FA). Alterations in FC and SC between caudate and DLPFC in obese patients, which highlights the role of BG network in modulating the balance between reward and inhibitory-control.

Brain Connectivity, and Hormonal and Behavioral Correlates of Sustained Weight Loss in Obese Patients after Laparoscopic Sleeve Gastrectomy.

The biological mediators that support cognitive-control and long-term weight-loss after laparoscopic sleeve gastrectomy (LSG) remain unclear. We measured peripheral appetitive hormones and brain functional-connectivity (FC) using magnetic-resonance-imaging with food cue-reactivity task in 25 obese participants at pre, 1 month, and 6 month after LSG, and compared with 30 normal weight controls. We also used diffusion-tensor-imaging to explore whether LSG increases brain structural-connectivity (SC) of regions involved in food cue-reactivity. LSG significantly decreased BMI, craving for high-calorie food cues, ghrelin, insulin, and leptin levels, and increased self-reported cognitive-control of eating behavior. LSG increased FC between the right dorsolateral prefrontal cortex (DLPFC) and the pregenual anterior cingulate cortex (pgACC) and increased SC between DLPFC and ACC at 1 month and 6 month after LSG. Reduction in BMI correlated negatively with increased FC of right DLPFC-pgACC at 1 month and with increased SC of DLPFC-ACC at 1 month and 6 month after LSG. Reduction in craving for high-calorie food cues correlated negatively with increased FC of DLPFC-pgACC at 6 month after LSG. Additionally, SC of DLPFC-ACC mediated the relationship between lower ghrelin levels and greater cognitive control. These findings provide evidence that LSG improved functional and structural connectivity in prefrontal regions, which contribute to enhanced cognitive-control and sustained weight-loss following surgery.

Obese Individuals Show Disrupted Dynamic Functional Connectivity between Basal Ganglia and Salience Networks.

Previous functional magnetic resonance imaging (fMRI) studies have showed obesity (OB)-related alterations in intrinsic functional connectivity (FC) within and between different resting-state networks (RSNs). However, few studies have examined dynamic functional connectivity (DFC). Thus, we employed resting-state fMRI with independent component analysis (ICA) and DFC analysis to investigate the alterations in FC within and between RSNs in 56 individuals with OB and 46 normal-weight (NW) controls. ICA identified six RSNs, including basal ganglia (BG), salience network (SN), right executive control network/left executive control network, and anterior default-mode network (aDMN)/posterior default-mode network. The DFC analysis identified four FC states. OB compared with NW had more occurrences and a longer mean dwell time (MDT) in state 2 (positive connectivity of BG with other RSN) and also had higher FC of BG-SN in other states. Body mass index was positively correlated with MDT and FCs of BG-aDMN (state 2) and BG-SN (state 4). DFC analysis within more refined nodes of RSNs showed that OB had more occurrences and a longer MDT in state 1 in which caudate had positive connections with the other network nodes. The findings suggest an association between caudate-related and BG-related positive FC in OB, which was not revealed by traditional FC analysis, highlighting the utility of adding DFC to the more conventional methods.

Connectome-Based Prediction of Optimal Weight Loss Six Months After Bariatric Surgery.

Despite bariatric surgery being the most effective treatment for obesity, a proportion of subjects have suboptimal weight loss post-surgery. Therefore, it is necessary to understand the mechanisms behind the variance in weight loss and identify specific baseline biomarkers to predict optimal weight loss. Here, we employed functional magnetic resonance imaging (fMRI) with baseline whole-brain resting-state functional connectivity (RSFC) and a multivariate prediction framework integrating feature selection, feature transformation, and classification to prospectively identify obese patients that exhibited optimal weight loss at 6 months post-surgery. Siamese network, which is a multivariate machine learning method suitable for small sample analysis, and K-nearest neighbor (KNN) were cascaded as the classifier (Siamese-KNN). In the leave-one-out cross-validation, the Siamese-KNN achieved an accuracy of 83.78%, which was substantially higher than results from traditional classifiers. RSFC patterns contributing to the prediction consisted of brain networks related to salience, reward, self-referential, and cognitive processing. Further RSFC feature analysis indicated that the connection strength between frontal and parietal cortices was stronger in the optimal versus the suboptimal weight loss group. These findings show that specific RSFC patterns could be used as neuroimaging biomarkers to predict individual weight loss post-surgery and assist in personalized diagnosis for treatment of obesity.

Long-term changes in insula-mesolimbic structural and functional connectivity in obese patients after laparoscopic sleeve gastrectomy.

OBJECTIVE: Brain imaging studies have shown insula-related functional and structural abnormalities in patients with obesity. Laparoscopic sleeve gastrectomy is currently an effective procedure for treating obesity, which promotes acute recovery of brain functional and structural abnormalities in obese patients. The aim of this study was to investigate the long-term impact of laparoscopic sleeve gastrectomy on insula-related structural and functional connectivity. METHODS: Diffusion tensor imaging and resting-state functional magnetic resonance imaging were employed to investigate laparoscopic sleeve gastrectomy-induced changes in insula-related structural connectivity and corresponding resting-state functional connectivity in 25 obese patients prior to (PreLSG) and 12 months post-surgery (PostLSG12). RESULTS: Results showed significant increases in fractional anisotropy and axial diffusivity between the right insula and anterior cingulate cortex, and higher fractional anisotropy of left insula-putamen, left insula-caudate and anterior cingulate cortex-right posterior cingulate cortex/precuneus at PostLSG12 compared with PreLSG. There were significant negative correlations between axial diffusivity of right insula-anterior cingulate cortex and body mass index, and fractional anisotropy of right insula-anterior cingulate cortex with scores on external eating at PostLSG12. Anxiety and depressive status ratings were negatively correlated with fractional anisotropy of left insula-putamen at PostLSG12. In addition, there was a significant decrease in resting-state functional connectivity between left insula and left caudate. CONCLUSIONS: These findings demonstrate long-term changes in insula-related structural and functional connectivity abnormalities promoted by laparoscopic sleeve gastrectomy, which highlight its strong association with long-term weight loss and improvement in eating behaviors.

Alterations in functional connectivity and interactions in resting-state networks in female patients with functional constipation.

BACKGROUND : Patients with functional constipation (FCon) have been reported with brain functional and structural abnormalities. However, no studies have been performed to investigate the differences in resting-state networks (RSNs) and changes in functional connectivity (FC) between RSNs in patients with FCon. Thus, the current study aimed to identify abnormal FC within and interaction between RSNs in patients with FCon to reveal the underlying neural mechanism. METHODS: Functional MRI with independent component analysis was applied to investigate alterations in FC within and functional network connectivity (FNC) between RSNs including default mode- (DMN), basal ganglia- (BGN), salience- (SN), and left and right control executive-networks (LCEN/RCEN) in 39 female patients with FCon and 36 female healthy controls (HC). Patient Assessment of Constipation Quality of Life Scale (PAC-QOL) and Patient Assessment of Constipation Symptom Scale (PAC-SYM) were used to assess the constipation symptoms. RESULTS: FCon patients had changed regional FC between different networks contributing to the abnormal FNC among RSNs compared with HC. Patients with greater stool syndromes had increased FNC of BGN-SN and DMN-LCEN, and patients with greater worries/concerns and PAC-QOL total score had reduced FNC of SN-RCEN. The greater strength changes in FC in prefrontal and parietal cortices were associated with higher negative emotion scores and greater rectal symptoms, respectively. CONCLUSION: The findings suggested that FCon patients had altered FC within and interactions between RSNs and the brain FC changes were associated with constipation symptoms and altered emotions.

Distinct Basal Brain Functional Activity and Connectivity in the Emotional-Arousal Network and Thalamus in Patients With Functional Constipation Associated With Anxiety and/or Depressive Disorders.

OBJECTIVE: Functional constipation (FC) is a common gastrointestinal disorder. Anxiety and/or depressive disorders are common in patients with FC (FCAD). Brain dysfunction may play a role in FC, but the contribution of comorbid anxiety and/or depression in patients with FC is poorly understood. METHODS: Sixty-five FC patients and 42 healthy controls (HCs) were recruited, and a hierarchical clustering algorithm was used to classify FC patients into FCAD and patients without anxiety/depressive status (FCNAD) based on neuropsychological assessment. Resting-state functional magnetic resonance imaging measures including fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity were used to investigate brain functional differences. RESULTS: Thirty-seven patients were classified as FCAD, and 28 patients were classified as FCNAD; as compared with HC, both groups showed decreased activity (fALFF) in the perigenual anterior cingulate cortex (pACC), dorsomedial prefrontal cortex (DMPFC), and precuneus; enhanced precentral gyrus-thalamus connectivity and attenuated precuneus-thalamus connectivity in FCAD/FCNAD highlighted the thalamus as a critical connectivity node in the brain network (pFWE < .05). In comparison with FCNAD/HC, the FCAD group also had decreased fALFF in the orbitofrontal cortex (OFC) and thalamus, and increased OFC-hippocampus connectivity. In the FCNAD group, brain activities (pACC/DMPFC) and connection (precuneus-thalamus) had correlations only with symptoms; in the FCAD group, brain activities (OFC, pACC/DMPFC) and connectivities (OFC-hippocampus/precentral gyrus-thalamus) showed correlations with both constipation symptoms and anxiety/depressive status ratings. Mediation analysis indicated that the relationship between abdominal distension and OFC activity was completely mediated by anxiety in FCAD. CONCLUSIONS: These findings provide evidence of differences in brain activity and functional connectivity between FCAD and FCNAD, potentially providing important clues for improving treatment strategies.

Resting activity of the hippocampus and amygdala in obese individuals predicts their response to food cues.

Obese individuals exhibit brain functional abnormalities in multiple regions implicated in reward/motivation, emotion/memory, homeostatic regulation, and executive control when exposed to food cues and during rest. However, it remains unclear whether abnormal brain responses to food cues might account for or relate to their abnormal activity in resting state. This information would be useful for understanding the neural mechanisms behind hyperactive responses to food cues, a critical marker of obesity. Resting-state functional magnetic resonance imaging (RS-fMRI) and a cue-reactivity fMRI task with high- (HiCal) and low-caloric (LoCal) food cues were employed to investigate brain baseline activity and food cue-induced activation differences in 44 obese participants (OB), in 37 overweight participants (OW), and in 37 normal weight (NW) controls. One-way analyses of variance showed there was a group difference in the left hippocampus/amygdala activity during resting state and during food-cue stimulation (pFWE < 0.05); post-hoc tests showed the OB group had both greater basal activity and greater food cue-induced activation than the OW and NW groups; OW had higher activity in the hippocampus/amygdala than the NW group, which was only significant during resting state. In the OB group, resting-state activity in the left hippocampus/amygdala was positively correlated with activation induced by HiCal food cues, and both of these measures correlated with body mass index (BMI). Mediation analysis showed that the relationship between BMI and hippocampus/amygdala response to HiCal food cues was mediated by their resting-state activity. These findings suggest a close association between obesity and brain functional abnormality in the hippocampus/amygdala. They also indicate that resting-state activity in the hippocampus/amygdala may impact these regions' responses to food cues.

Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential.

CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the synthesis of nucleic acids, active intermediates, and cell membranes. Meanwhile, the important role of CAD in various physiopathological processes has also been emphasized. Deregulation of CAD-related pathways or CAD mutations cause cancer, neurological disorders, and inherited metabolic diseases. Here, we review the structure, function, and regulation of CAD in mammalian physiology as well as human diseases, and provide insights into the potential to target CAD in future clinical applications.

Ghrelin reductions following bariatric surgery were associated with decreased resting state activity in the hippocampus.

BACKGROUND/OBJECTIVE: Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery to treat obesity, and involves removal of the gastric fundus where ghrelin is mainly produced. Ghrelin stimulates appetite and regulates food intake through its effect on the hypothalamus and hippocampus (HIPP). While ghrelin's role on the hypothalamus has been explored, little is known about its role on HIPP. We tested the hypothesis that LSG-induced reductions in ghrelin levels would be associated with changes in HIPP activity. SUBJECTS/METHODS: Brain activity was measured with amplitude of low-frequency fluctuations (ALFF) captured with resting-state functional magnetic resonance imaging (fMRI) in 30 obese participants, both before and after 1-month of LSG, and in 26 obese controls without surgery that were studied at baseline and 1-month later. A two-way analysis of variance (ANOVA) was performed to model the group and time effects on ALFF and resting-state functional connectivity. RESULTS: One-month post-LSG there were significant decreases in appetite, body mass index (BMI), fasting plasma ghrelin and leptin levels, anxiety, and ALFF in HIPP and ALFF increases in posterior cingulate cortex (PCC, PFWE < 0.05). Decreases in HIPP ALFF correlated positively with decreases in fasting ghrelin and anxiety, and increases in PCC ALFF correlated positively with decreases in anxiety. Seed-voxel correlation analysis showed stronger connectivity between HIPP and insula, and between PCC and dorsolateral prefrontal cortex (DLPFC) post-LSG. CONCLUSIONS: These findings suggest that ghrelin effects in HIPP modulate connectivity with the insula, which processes interoception and might be relevant to LSG-induced reductions in appetite/anxiety. Role of LSG in PCC and its enhanced connectivity with DLPFC in improving self-regulation following LSG requires further investigation.