Neuroreceptor availability and cerebral morphology in human obesity

Obesity is a major challenge to human health worldwide. Little is known about the brain mechanisms that are associated with overeating and obesity in humans. In this project, multimodal neuroimaging techniques were utilized to study brain neurotransmission and anatomy in obesity. Bariatric surgery was used as an experimental method for assessing whether the possible differences between obese and non-obese individuals change following the weight loss. This could indicate whether obesity-related altered neurotransmission and cerebral atrophy are recoverable or whether they represent stable individual characteristics. Morbidly obese subjects (BMI ≥ 35 kg/m2) and non-obese control subjects (mean BMI 23 kg/m2) were studied with positron emission tomography (PET) and magnetic resonance imaging (MRI). In the PET studies, focus was put on dopaminergic and opioidergic systems, both of which are crucial in the reward processing. Brain dopamine D2 receptor (D2R) availability was measured using [11C]raclopride and µ-opioid receptor (MOR) availability using [11C]carfentanil. In the MRI studies, voxel-based morphometry (VBM) of T1-weighted MRI images was used, coupled with diffusion tensor imaging (DTI). Obese subjects underwent bariatric surgery as their standard clinical treatment during the study. Preoperatively, morbidly obese subjects had significantly lower MOR availability but unaltered D2R availability in several brain regions involved in reward processing, including striatum, insula, and thalamus. Moreover, obesity disrupted the interaction between the MOR and D2R systems in ventral striatum. Bariatric surgery and concomitant weight loss normalized MOR availability in the obese, but did not influence D2R availability in any brain region. Morbidly obese subjects had also significantly lower grey and white matter densities globally in the brain, but more focal changes were located in the areas associated with inhibitory control, reward processing, and appetite. DTI revealed also signs of axonal damage in the obese in corticospinal tracts and occipito-frontal fascicles. Surgery-induced weight loss resulted in global recovery of white matter density as well as more focal recovery of grey matter density among obese subjects. Altogether these results show that the endogenous opioid system is fundamentally linked to obesity. Lowered MOR availability is likely a consequence of obesity and may mediate maintenance of excessive energy uptake. In addition, obesity has adverse effects on brain structure. Bariatric surgery however reverses MOR dysfunction and recovers cerebral atrophy. Understanding the opioidergic contribution to overeating and obesity is critical for developing new psychological or pharmacological treatments for obesity. The actual molecular mechanisms behind the positive change in structure and neurotransmitter function still remain unclear and should be addressed in the future research.Neuroreseptorit ja aivojen rakenne lihavuudessa Lihavuudesta on tullut yksi maailman suurimmista terveysongelmista. Lihavuuteen liittyvistä aivojen toiminnan ja rakenteen muutoksista tiedetään kuitenkin toistaiseksi melko vähän. Tässä tutkimuksessa selvitettiin aivojen välittäjäainetoiminnan ja rakenteen eroja lihavien ja normaalipainoisten henkilöiden välillä. Lihavuusleikkauksen ja sitä seuraavan laihtumisen aiheuttamia aivojen välittäjäainetoiminnan ja tiheyden muutoksia arvioimalla voitiin päätellä, ovatko aivomuutokset jo olemassa ennen lihavuuden syntyä vai ovatko ne lihavuuden aiheuttamia. Vaikeasti lihavien henkilöiden (BMI ≥ 35 kg/m2) aivoja verrattiin normaalipainoisten henkilöiden (BMI:n keskiarvo 23 kg/m2) aivoihin käyttämällä positroniemissiotomografiaa (PET) ja magneettiresonanssikuvantamismenetelmiä (MRI). PET-tutkimuksissa käytettiin kahta radioisotoopilla leimattua merkkiainetta, joista [11C]raklopriidi sitoutuu dopamiinin D2-reseptoreihin ja [11C]karfentaniili µ-opioidireseptoreihin. Kummatkin reseptorit ovat keskeisessä asemassa aivojen mielihyväjärjestelmän toiminnassa. MRI-tutkimuksissa käytettiin analyysimenetelminä vokselipohjaista morfometriaa (voxel-based morphometry, VBM) sekä diffuusiotensorikuvantamista (diffusion tensor imaging, DTI). Lihaville tutkittaville tehtiin tutkimuksen aikana lihavuusleikkaus aiemman hoitosuunnitelman mukaisesti. Ennen lihavuusleikkausta lihavilla tutkittavilla oli selvästi vähemmän µ-opioidireseptoreja mielihyväjärjestelmän keskeisissä osissa, kuten tyvitumakkeissa, insulassa ja talamuksessa, mutta dopamiinin D2-reseptorien määrä oli sama kuin normaalipainoisilla tutkittavilla. Lisäksi näiden reseptorijärjestelmien välinen yhteys oli häiriintynyt lihavilla tutkittavilla aivojuovion etuosassa. Lihavuusleikkauksen aiheuttaman laihtumisen jälkeen µ-opioidireseptorien määrä palautui samalle tasolle kuin normaalipainoisilla. Dopamiinireseptorien määrässä ei tapahtunut muutosta. Magneettitutkimuksissa kävi ilmi, että lihavilla tutkittavilla aivojen harmaan ja valkean aineen tiheydet olivat pienemmät kuin normaalipainoisilla tutkittavilla. Eroa löytyi erityisesti mielihyvään ja ruokahaluun liittyvillä alueilla. Myös valkean aineen radastoissa oli vaurion merkkejä. Leikkauksen jälkeen tapahtui palautumista laajasti valkean aineen alueilla mutta myös selvästi pienemmillä harmaan aineen alueilla. Tulokset osoittavat, että opioidijärjestelmä liittyy keskeisesti lihavuuteen ja liikasyömiseen. Opioidijärjestelmän poikkeava toiminta on todennäköisesti lihavuuden aiheuttamaa ja saattaa ylläpitää haitallista syömiskäyttäytymistä. Lisäksi lihavuudella on haitallisia vaikutuksia aivojen rakenteeseen. Lihavuusleikkaus palauttaa opioidijärjestelmän ennalleen ja korjaa lihavuuden aiheuttamaa aivokudoksen harventumaa. Opioidijärjestelmän merkityksen ymmärtäminen on välttämätöntä lihavuuden uusien psykologisten ja farmakologisten hoitomuotojen kehittämisessä. Solutason mekanismit leikkauksen aiheuttamien muutosten taustalla ovat kuitenkin edelleen epäselvät, ja niihin tulisi keskittyä jatkotutkimuksissa.Siirretty Doriast

Auditory Mismatch Responses to Emotional Stimuli in 3-Year-Olds in Relation to Prenatal Maternal Depression Symptoms

Maternal depression symptoms are common in pregnant women and can have negative effects on offspring's emotional development. This study investigated the association between prenatal maternal depression symptoms (assessed with the Edinburgh Postnatal Depression Scale at 24 weeks of gestation) and auditory perception of emotional stimuli in 3-year-olds (n = 58) from the FinnBrain Birth Cohort Study. Using electroencephalography (EEG), we examined mismatch responses for happy, sad, and angry sounds presented among neutral stimuli. A positive association between maternal depression symptoms and the emotional mismatch responses in an early time window (80-120 ms) was found, indicating that brain responses of children of mothers with depressive symptoms were weaker to happy sounds, though the results did not survive Bonferroni correction. There were no clear associations in the sad and angry emotional categories. Our results tentatively support that the 3-year-old children of mothers with depression symptoms may be less sensitive to automatically detect happy sounds compared to children whose mothers do not display symptoms of depression.Peer reviewe

Development of a preliminary conceptual model of the patient experience of chronic kidney disease: a targeted literature review and analysis

BackgroundPatient-reported outcome (PRO) instruments should capture the experiences of disease and treatment that patients consider most important in order to inform patient-centred care and product development. The aim of this study was to develop a preliminary conceptual model of patient experience in chronic kidney disease (CKD) based on a targeted literature review and to characterize existing PRO instruments used in CKD.MethodsPubMed, EMBASE and Cochrane databases and recent society meetings were searched for publications reporting signs/symptoms and life impacts of CKD. Concepts identified in the literature review were used to develop a preliminary conceptual model of patient experience of CKD, overall, and within patient subpopulations of differing CKD causes, severities and complications. PRO instruments, identified from PRO databases, CKD literature and CKD clinical trials, were assessed for content validity, psychometric strength and coverage of concepts in the literature review.ResultsIn total, 100 publications met criteria for analysis; 56 signs/symptoms and 37 life impacts of CKD were identified from these sources. The most frequently mentioned signs/symptoms were pain/discomfort (57% of publications) and tiredness/low energy/lethargy/fatigue (42%); the most commonly reported life impacts were anxiety/depression (49%) and decrements in physical functioning (43%). Signs/symptoms and life impacts varied across the subpopulations and were more frequent at advanced CKD stages. The preliminary conceptual model grouped signs/symptoms into seven domains (pain/discomfort; energy/fatigue; sleep-related; gastrointestinal-related; urinary-related; skin-/hair-/nails-related; and other) and life impacts into six domains (psychological/emotional strain; cognitive impairment; dietary habit disruption; physical function decrements; interference with social relationships; and other). Eleven PRO instruments were considered to be promising for use in CKD; all had limitations.ConclusionsAlthough preliminary, the proposed conceptual model highlights key PROs for people with CKD and is intended to spur development of more tailored PRO instruments to assess these concepts

Maternal sleep quality during pregnancy is associated with neonatal auditory ERPs

Poor maternal sleep quality during pregnancy may act as a prenatal stress factor for the fetus and associate with neonate neurocognition, for example via fetal programming. The impacts of worsened maternal sleep on neonatal development and, more specifically on neonatal auditory brain responses, have not been studied. A total of 155 mother-neonate dyads drawn from the FinnBrain Birth Cohort Study participated in our study including maternal self-report questionnaires on sleep at gestational week 24 and an event-related potential (ERP) measurement among 1-2-day-old neonates. For sleep quality assessment, the Basic Nordic Sleep Questionnaire (BNSQ) was used and calculated scores for (1) insomnia, (2) subjective sleep loss and (3) sleepiness were formed and applied in the analyses. In the auditory ERP protocol, three emotionally uttered pseudo words (in happy, angry and sad valence) were presented among neutrally uttered pseudo words. To study the relations between prenatal maternal sleep quality and auditory emotion-related ERP responses, mixed-effects regression models were computed for early (100-200 ms) and late (300-500 ms) ERP response time-windows. All of the selected BNSQ scores were associated with neonatal ERP responses for happy and angry emotion stimuli (sleep loss and sleepiness in the early, and insomnia, sleep loss and sleepiness in the late time-window). For sad stimuli, only maternal sleep loss predicted the neonatal ERP response in the late time-window, likely because the overall ERP was weakest in the sad condition. We conclude that maternal sleep quality during pregnancy is associated with changes in neonatal auditory ERP responses.Peer reviewe

Local Coordination Environments and Vibrational Dynamics of Protons in Hexagonal and Cubic Sc-Doped BaTiO3 Proton-Conducting Oxides

The proton local coordination environments and vibrational dynamics associated with the two order of magnitude change in proton conductivity in hydrated forms of hexagonal and cubic structured BaTi1-xScxO3Hx (0.16 < x < 0.7) were investigated using optical spectroscopy, neutron spectroscopy, and first-principles calculations. Whereas the cubic structure compositions display a single proton site, we show that protons occupy three distinct sites in compositions exhibiting the hexagonal structure. The principal site is characterized by interoctahedral hydrogen bonds, while two additional low occupancy sites are similar to those in the cubic structure, with classic intraoctahedral geometry. Furthermore, the proton hydrogen bond strength increases with decreasing scandium doping level. We infer from this that the stronger, more energetic hydrogen bonds in the hexagonal structure, resulting from proton sites with lower symmetry (lower multiplicity), are predominantly responsible for the significant reduction in macroscopic conductivity between cubic and hexagonal BaTi1-xScxO3Hx materials, rather than simply the absolute number of protons. Our findings are highly relevant to the field, clarifying the advantages of high-symmetry structures with high-multiplicity proton sites to favorable properties in ceramic proton-conducting oxides

Auditory Mismatch Responses to Emotional Stimuli in 3-Year-Olds in Relation to Prenatal Maternal Depression Symptoms

Maternal depression symptoms are common in pregnant women and can have negative effects on offspring’s emotional development. This study investigated the association between prenatal maternal depression symptoms (assessed with the Edinburgh Postnatal Depression Scale at 24 weeks of gestation) and auditory perception of emotional stimuli in 3-year-olds (n = 58) from the FinnBrain Birth Cohort Study. Using electroencephalography (EEG), we examined mismatch responses for happy, sad, and angry sounds presented among neutral stimuli. A positive association between maternal depression symptoms and the emotional mismatch responses in an early time window (80–120 ms) was found, indicating that brain responses of children of mothers with depressive symptoms were weaker to happy sounds, though the results did not survive Bonferroni correction. There were no clear associations in the sad and angry emotional categories. Our results tentatively support that the 3-year-old children of mothers with depression symptoms may be less sensitive to automatically detect happy sounds compared to children whose mothers do not display symptoms of depression.</p

Mesolimbic opioid-dopamine interaction is disrupted in obesity but recovered by weight loss following bariatric surgery

Obesity is a growing burden to health and the economy worldwide. Obesity is associated with central mu-opioid receptor (MOR) downregulation and disruption of the interaction between MOR and dopamine D-2 receptor (D2R) system in the ventral striatum. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying 20 healthy non-obese and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and D2R availability were measured using positron emission tomography (PET) with [C-11]carfentanil and [C-11]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed on obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery. In the control subjects, MOR and D2R availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but the unaltered association in dorsal caudate (r = .43). The association between MOR and D2R availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss. Bariatric surgery and concomitant weight loss recover the interaction between MOR and D2R in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioral interventions for treating obesity

Preoperative brain μ-opioid receptor availability predicts weight development following bariatric surgery in women

Bariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors leading to postoperative weight loss or weight regain remain elusive. Alterations in the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) systems are associated with obesity and appetite control, and the magnitude of initial brain receptor system perturbation may predict long-term surgical weight loss outcomes. We tested this hypothesis by studying 19 morbidly obese women (mean BMI 40) scheduled to undergo bariatric surgery. We measured their preoperative MOR and D2R availabilities using positron emission tomography with [11C]carfentanil and [11C]raclopride, respectively, and then assessed their weight development association with regional MOR and D2R availabilities at 24-month follow-up. MOR availability in the amygdala consistently predicted weight development throughout the follow-up period, but no associations were found for D2R. This is the first study to our knowledge to demonstrate that neuroreceptor markers prior to bariatric surgery are associated with postoperative weight development. Postoperative weight regain may derive from dysfunction in the opioid system, and weight loss outcomes after bariatric surgery may be partially predicted based on preoperative brain receptor availability, opening up new potential for treatment possibilities

Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and blood flow

Aims: Bariatric surgery is the most effective treatment to tackle morbid obesity and type 2 diabetes, but the mechanisms of action are still unclear. The objective of this study was to investigate the effects of bariatric surgery on intestinal fatty acid (FA) uptake and blood flow. Materials and Methods: We recruited 27 morbidly obese subjects, of whom 10 had type 2 diabetes and 15 were healthy age-matched controls. Intestinal blood flow and fatty acid uptake from circulation were measured during fasting state using positron emission tomography (PET). Obese subjects were re-studied 6 months after bariatric surgery. The mucosal location of intestinal FA retention was verified in insulin resistant mice with autoradiography. Results: Compared to lean subjects, morbidly obese subjects had higher duodenal and jejunal FA uptake (P </p