COMT Val(158)Met genotypes differentially influence subgenual cingulate functional connectivity in healthy females

Brain imaging studies have cons stently shown subgenual Anterior Cingulate Cortical (sgACC) involvement in emotion processing. catechol-O-methyltransferase (COMT) Val(158) and Met(158) polymorphisms may influence such emotional brain processes in specific ways. Given that resting-state fMRI (rsfMRI) may increase our understanding on brain functioning, we integrated genetic and rsfMRI data and focused on sgACC functional connections. No studies have yet investigated the influence of the COMT Val(158)Met polymorphism (rs4680) on sgACC resting-state functional connectivity (rsFC) in healthy individuals. A homogeneous group of 61 Caucasian right-handed healthy female university students, all within the same age range, underwent isfMRI. Compared to Met158 homozygotes, Val(158) allele carriers displayed significantly stronger rsFC between the sgACC and the left parahippocampal gyrus, ventromedial parts of the inferior frontal gyrus (IFG), and the nucleus accumbens (NAc). On the other hand, compared to Val(158) homozygotes, we found in Met(158) allele carriers stronger sgACC rsFC with the medial frontal gyrus (MEG), more in particular the anterior parts of the medial orbitofrontal cortex. Although we did not use emotional or cognitive tasks, our sgACC rsFC results point to possible distinct differences in emotional and cognitive processes between Val(158) and Met(158) allele carriers. Hovvever, the exact nature of these directions remains to be determined

Sleep and its oscillatory characteristics in overnight learning : what is the role of plasticity genes BDNF and COMT?

Sleep is crucial for memory function. Sleep not only protects memories from wake-time interference, but it also actively transfers them from temporal storage to more permanent representations in the neocortex. This consolidation process of declarative memories is believed to be facilitated by certain oscillations during non-rapid eye movement (NREM) sleep, that is, sleep spindles, slow oscillations (SO) and sharp-wave ripples. Recent experiments in humans have demonstrated the importance of inter-oscillation synchrony on memory retention. Do all individuals equally share the memory benefits of sleep? Certain gene polymorphisms, such as BDNF Val66Met and COMT Val158Met, have been attributed with implications on synaptic plasticity, neuroanatomy and functional brain activation within memory-related brain networks. Behavioral studies have found relative mnemonic advantages to associate with the alleles that reportedly promote brain plasticity, i.e. ValBDNF and MetCOMT. Moreover, homeostatic sleep drive is moderated by BDNF Val66Met and COMT Val158Met. However, the role of these polymorphisms in memory retention over sleep has been scarcely studied. In this thesis, overnight memory for verbal and visual material was studied. Specific focus was put on how sleep spindles and their phasic synchrony with slow oscillations associate with memory performance. Importantly, it was questioned whether genetic predisposition for neural plasticity (BDNF Val66Met and COMT Val158Met) interacts with overnight memory and the related consolidation mechanisms. The studies in this thesis were conducted either on an adolescent (~17 y) cohort or on a sample consisting of young adults. Sleep was recorded with an ambulatory polysomnography in all studies. It was found that memory outcome – both verbal cued recall and picture recognition – was strongly associated with fast sleep spindles and their accurate coupling with the depolarized ‘upstate’ of SOs. BDNF Val66Met moderated the associations between sleep oscillations and visual recognition memory: memory outcome was robustly predicted by fast sleep spindles and their SO-coupling only in ValBDNF homozygotes but not MetBDNF carriers. In addition, memory performance in the ValBDNF homozygote group was seen more vulnerable to extended wake during the retention period. COMT Val158Met did not moderate the associations between sleep variables and recognition accuracy. In conclusion, the relation between sleep and memory may depend on inheritance. Genetic propensity for synaptic plasticity possibly enhances the effect of events that promote sleep-dependent consolidation. The findings question whether the benefits of sleep on memory are constant and equal across individuals.Uni on välttämätöntä muistin toiminnalle. Uni ei ainoastaan suojaa muistoja valveajan sekoittumiselta, vaan se myös aktiivisesti siirtää niitä väliaikaisesta muistivarastosta pysyviksi edustuksiksi aivokuorelle. Tiettyjen NREM-unen (non-rapid eye movement) aikaisten aivoaaltojen, eli unisukkuloiden, hitaiden aaltojen sekä hippokampusväreiden, uskotaan aktiivisesti edistävän tätä muistojen konsolidoitumista. Tutkimukset ihmisillä ovat osoittaneet, että aaltojen välinen synkronia on oleellista muistojen säilymiselle. Ovatko unen muistihyödyt yhtäläiset yksilöiden välillä? Tietyt geenipolymorfismit, kuten BDNF Val66Met ja COMT Val158Met, on aiemmassa tutkimuksessa yhdistetty aivoyhteyksien muovautuvuuteen, aivoanatomiaan sekä -toimintaan niissä rakenteissa, jotka tukevat muistitoimintoja. Alleelien, joiden oletetaan edistävän aivojen plastisuutta (ValBDNF ja MetCOMT), on käyttäytymisen tasolla havaittu assosioituvan suhteelliseen etuun muistisuoriutumisessa. Tämän lisäksi on raportoitu, että BDNF Val66Met sekä COMT Val158Met vaikuttavat unipaineen säätelyyn. Tästä huolimatta näiden polymorfismien roolia unen ja muistamisen yhteydessä on tutkittu vain vähän. Tämä väitöskirja tutki kielellistä ja näönvaraista muistamista yön yli. Erityisesti keskityttiin siihen, kuinka unisukkulat sekä niiden vaihesynkronia hitaiden aaltojen kanssa assosioituvat muistisuoriutumiseen. Lisäksi tarkasteltiin, onko perinnöllinen taipumus aivojen plastisuuteen (BDNF Val66Met ja COMT Val158Met) yhteydessä yön yli muistamiseen (näönvarainen tunnistus) ja unen aikaisiin konsolidaatiomekanismeihin. Väitöskirjan tutkimukset toteutettiin joko nuorista (~17 v) koostuvassa kohortissa tai nuorten aikuisten otoksessa. Genotyyppiin liittyvät tutkimukset koskivat nuorten otosta. Kaikissa tutkimuksissa unta mitattiin polysomnografialla. Muistitulos – sekä kielellinen, vihjeenvarainen muistaminen että kuvien tunnistus – oli selvästi yhteydessä unisukkuloihin sekä siihen, kuinka tarkasti unisukkulat ajoittuivat hitaisiin aaltoihin. BDNF Val66Met vaikutti aivoaaltojen ja näönvaraisen tunnistusmuistin yhteyksiin: yhteys ilmeni ainoastaan ValBDNF-homotsygooteilla, mutta ei MetBDNF-alleelin kantajilla. Lisäksi ValBDNF-homotsygooteilla runsas valve näytti haittaavan muistisuoriutumista. COMT Val158Met ei vaikuttanut unimuuttujien ja tunnistustarkkuuden yhteyksiin. Tulokset viittaavat siihen, että unen ja muistin yhteys saattaa jossain määrin riippua perimästä. Geneettinen taipumus aivoplastisuuteen saattaa voimistaa unen aikaisten konsolidaatiomekanismien vaikutusta. Tämä kyseenalaistaa ajatuksen siitä, että unen hyödyt olisivat muuttumattomat sekä jokaiselle yhtäläiset

The relationship between alexithymia and hypnotic susceptibility: A review of the literature

Elméleti háttér: Számos klinikai megfigyelés és kutatási eredmény utal rá, hogy a hipnózis iránti fogékonyság és az alexitímia hátterében közös — részben azonos, részben ellentétes irányban ható — mechanizmusok működnek. Ennek ellenére csak néhány tanulmány található a szakirodalomban, ami közvetlenül a két konstruktum kapcsolatával foglalkozik. Úgy tűnik, hogy a disszociatív hajlam, a fantáziakészség, az empátia és a mások érzelmeinek azonosítására való képesség mind a hipnábilitás, mind az alexitímia szempontjából meghatározó jelentőségűek. Ezek a tulajdonságok (a disszociáció kivételével) egy tágabb kategória, a mentalizációs készség elemeinek tekinthetők. Neuroanatómiai, neurofiziológiai és pszichogenetikai kutatások eredményei pedig azt sugallják, hogy az alacsony hipnotikus válaszkészség és az alexitímia központi idegrendszeri és neuroendokrin korrelátumai átfednek egymással. Célkitűzés: A hipnotikus fogékonyság és az alexitímia közös tényezőinek azonosítása. Módszer: Releváns szakirodalmi tanulmányok áttekintése és elemzése. Eredmények: A hipnózis iránti fogékonyság és az alexitímia egyaránt kapcsolatban áll a disszociációval. A magasabb hipnábilitás erősebb, a magasabb alexitímia gyengébb képzeleti bevonódással és aktivitással függ össze. Úgy tűnik, a hipnábilis/”lexitímiás” (nem alexitímiás) személyek mind a saját, mind mások érzelmeit inkább képesek azonosítani és azokra reagálni, mint az alacsony hipnábilitású/alexitímiás személyek. A két konstruktum hátterében átfedő (legnagyobbrészt ellentétes) neuroendokrin, neurofiziológiai és pszichogenetikai mechanizmusok állnak. Következtetések: A szakirodalmi adatok alapján feltételezzük, hogy a hipnábilitás és az alexitímia egymással összefüggő jelenségek, de kapcsolatuk nem lineáris. Feltételezzük, hogy köztük a mentalizációra való képesség és a másodlagos, elhárító funkciójú disszociáció közvetít. Összefüggésük feltárása további empirikus vizsgálatot igényel. A hipnábilitás és az alexitímia viszonyának megértése elősegítheti egyes mentális és pszichoszomatikus betegségek hatékonyabb hipnoterápiás kezelését

Schizophrenia-like Cognitive, Trait and DNA Markers in Regular Cannabis Users

Rationale: Converging evidence suggests that cannabis use can induce psychosis and is a distinct risk factor for schizophrenia. Taken together with the effects of Tetrahydrocannabinol (THC) on neural systems, dopamine and endocannabinoids it is likely that cannabis use may also produce sub- clinical psychosis-linked changes in a much larger number of regular recreational users; observable in schizophrenia-sensitive assessments. Use of the drug by individuals with genetic risk factors for schizophrenia appears to magnify the chances of pathology, and so changes in recreational users with one or more of these genetic markers may be more evident or pronounced. Method: 50 cannabis users and 50 non cannabis users were assessed in each of two studies. Study one assessed selective attention in the Latent Inhibition (LI) and Kamin Blocking (KB) paradigms and examined schizophrenia-linked traits using the short form of the Schizotypal Personality Questionnaire (the SPQ-B; Raine and Benishay, 1995). Study two assessed executive control (using an Anti-Saccade Test), decision-making (using the Iowa Gambling Task), and selective/sustained attention and inhibitory control (Continuous Performance Test). Study two included additional personality measures to explore paranoia, emotional processing, ambivalence and impulsivity. Across both studies, the relative contribution of seven genetic risk markers in five candidate genes for schizophrenia (DAOA, COMT, NRG1, FAAH and CNR1) were assessed. Key Results: Cannabis use was associated with abolished latent inhibition and significantly riskier decision making, especially in those who used the drug more frequently. Cannabis users reported significantly higher scores for psychosis-linked personality traits and there was a dose-response effect with heavier users experiencing more of these schizotypal traits. Some key trends existed in the genotyping data for the cannabis group. The psychosis-risk C allele in the NRG1 gene was linked to higher SPQ-B scores and more errors on the AST; and was also associated with longer use of cannabis. Cannabis users without the protective three-way T-G-G haplotype COMT gene had higher scores for the SPQ-B disorganised thinking subscale than users with the protective haplotype. Discussion: The data in this thesis suggests that cannabis users are showing differences in brain inhibitory function and decision-making akin to previous research with schizophrenic patients, their first degree relatives and high schizotypy scorers. Exposure to THC may contribute to changes in individuals by pushing them further along a schizophrenia-spectrum resulting in the display of more psychotic-like traits and cognitive dysfunction at sub-clinical levels. These preliminary findings need expansion and replication, particularly with regards to the COMT three-way haplotype

Bihevioralnogenetičke osnove petofaktorskog modela ličnosti

Petofaktorski model ličnosti pretpostavlja da se osobine ličnosti mogu razumeti u terminima bazičnih pet domena: neuroticizma, ekstraverzije, otvorenosti ka iskustvu, prijatnosti i savesnosti. Pošto je razvoj ličnosti posledica složenih odnosa gena i sredine, osnovno teorijsko i istraživačko pitanje savremene bijevioralne genetike jeste na koji način geni i sredina oblikuju osobine. Osnovni ciljevi istraživanja bili su ispitivanje genskih i sredinskih faktora koji doprinose objašnjenju individualnih razlika na domenima i aspektima petofaktorskog modela ličnosti i veze između genotipova HTR1A, TPH2, BDNF, COMT, DRD2 i OXTR gena, njihovih epistatičkih efekata i dimenzija ličnosti petofaktorskog modela. U Studiji 1 učestvovala su 362 monozigotna i 210 dizigotna blizanaca iz Republike Srbije (M = 24,88; SD = 6,94). U Studiji 2 učestvovalo je 474 ispitanika iz Studije 1 (M = 24,48; SD = 7,58). Korišćeni instrumenti su revidirani NEO-PI-R inventar ličnosti (Costa & McCrae, 2019, adaptacija Knežević et al., 2004), zigotnost procenjena iz DNK bukalnog brisa i pojedinačni nukleotidni polimorfizmi HTR1A (rs6295), TPH2 (rs4570625), BDNF (rs6265), COMT (rs4680), DRD2 (rs1800497) i OXTR (rs53576) gena. Rezultati Studije 1 ukazuju na to da osobine ličnosti petofaktorskog modela pokazuju značajne aditivne genske i nedeljene sredinske doprinose, kao i da neki aspekti unutar domena imaju jake zajedničke osnove, dok su neki drugi gotovo nezavisni. Studija 2 sugeriše da serotoninski, dopaminski, oksitocin i moždani neurotrofni faktor sistemi gena leže u osnovi kompleksnih ponašanja, sa potencijalno različitim efektima na pojedinačne osobine ličnosti. Uloga dopaminskog genskom sistema najznačajnija je za domen ekstraverzije, otvorenosti ka iskustvu i savesnosti, serotoninski sistem učestvuje u mehanizmima povezanim sa povlačenjem i ihnibicijom, ali ima potencijalno značajnu ulogu u obradi i pozitivnih i negativnih stimulusa, dok moždani neurotrofni faktor pokazuje ulogu u kognitivnoj eksploraciji i plasticitetu ostalih sistema. Teorijske i praktične implikacije dobijenih rezultata komentarisane su u radu

Bihevioralnogenetičke osnove petofaktorskog modela ličnosti

Petofaktorski model ličnosti pretpostavlja da se osobine ličnosti mogu razumeti u terminima bazičnih pet domena: neuroticizma, ekstraverzije, otvorenosti ka iskustvu, prijatnosti i savesnosti. Pošto je razvoj ličnosti posledica složenih odnosa gena i sredine, osnovno teorijsko i istraživačko pitanje savremene bijevioralne genetike jeste na koji način geni i sredina oblikuju osobine. Osnovni ciljevi istraživanja bili su ispitivanje genskih i sredinskih faktora koji doprinose objašnjenju individualnih razlika na domenima i aspektima petofaktorskog modela ličnosti i veze između genotipova HTR1A, TPH2, BDNF, COMT, DRD2 i OXTR gena, njihovih epistatičkih efekata i dimenzija ličnosti petofaktorskog modela. U Studiji 1 učestvovala su 362 monozigotna i 210 dizigotna blizanaca iz Republike Srbije (M = 24,88; SD = 6,94). U Studiji 2 učestvovalo je 474 ispitanika iz Studije 1 (M = 24,48; SD = 7,58). Korišćeni instrumenti su revidirani NEO-PI-R inventar ličnosti (Costa & McCrae, 2019, adaptacija Knežević et al., 2004), zigotnost procenjena iz DNK bukalnog brisa i pojedinačni nukleotidni polimorfizmi HTR1A (rs6295), TPH2 (rs4570625), BDNF (rs6265), COMT (rs4680), DRD2 (rs1800497) i OXTR (rs53576) gena. Rezultati Studije 1 ukazuju na to da osobine ličnosti petofaktorskog modela pokazuju značajne aditivne genske i nedeljene sredinske doprinose, kao i da neki aspekti unutar domena imaju jake zajedničke osnove, dok su neki drugi gotovo nezavisni. Studija 2 sugeriše da serotoninski, dopaminski, oksitocin i moždani neurotrofni faktor sistemi gena leže u osnovi kompleksnih ponašanja, sa potencijalno različitim efektima na pojedinačne osobine ličnosti. Uloga dopaminskog genskom sistema najznačajnija je za domen ekstraverzije, otvorenosti ka iskustvu i savesnosti, serotoninski sistem učestvuje u mehanizmima povezanim sa povlačenjem i ihnibicijom, ali ima potencijalno značajnu ulogu u obradi i pozitivnih i negativnih stimulusa, dok moždani neurotrofni faktor pokazuje ulogu u kognitivnoj eksploraciji i plasticitetu ostalih sistema. Teorijske i praktične implikacije dobijenih rezultata komentarisane su u radu

Investigating the relationship between emotion and cognition during adolescence : genes and behaviour

Emotions provide the motivational aspect to conscious, goal-directed cognition. When they become disruptive, interfering with attainment or well-being, we rely on the ability to regulate them, facilitated by cognitive control. Exactly how emotion and cognition relate to each other is still unclear, particularly during adolescence, a time when structural and hormonal changes may accentuate the importance of their interactions. This thesis explores the relationship between emotion and cognition during adolescence using the Avon Longitudinal Study of Parents and Children, a longitudinal population-based cohort. Chapter 3 characterises cognitive ability and emotional behaviour across adolescence, finding modest associations between constructs, the largest being between externalising and working memory. Using an independent adult sample, Chapter 4 finds emotional behaviours to be differently related to emotion regulation strategies, and, using an emotional variant of the N—back, that externalising again associates with working memory, and internalising with emotional distraction. Chapter 5 employs a longitudinal design to assess directional associations and finds that early adolescent externalising and internalising predict later adolescent working memory. Chapter 6 reports six genome-wide association studies evaluating genetic relationships between cognitive and emotion measures; phenotypic relations between working memory and externalising replicate genetically, but a contrasting relationship is found with internalising. Chapter 7 investigates whether these measures predict academic achievement and find working memory to be a robust predictor, while emotion measures explain small amounts of unique variance. Chapter 8 reports the first genome-wide association study of national standardised school assessments of English, maths and science attainment and finds strong genetic contributions to attainment from cognitive measures and differential relationships with emotion measures. Across studies cognitive and emotional behaviour measures emerged as independent and diverse, highlighting the importance of considering specific roles of cognitive and emotional processes in academic achievement and mental health, as well as investigating their unique genetic bases

Analysis of speech and language, social-emotional and cognitive development of patients with heterozygous microdeletion of the region q11.2 of chromosome 22.

Sažetak: Sindrom delecije 22q11.2 (22q11.2DS) karakteriše prisustvo heterozigotne mikrodelecije regiona q11.2 na hromozomu 22. Pokazano je da deca sa 22q11.2DS često kasne na polju govorno-jezičkog, socio-emocionalnog i kognitivnog razvoja. Kako u literaturi nema podataka o ovim sposobnostima kod bolesnika sa 22q11.2DS govornika južno-slovenskih jezika, u okviru ove doktorske disertacije analizirane su govorno-jezičke, kognitivne i socio-emocionalne sposobnosti bolesnika sa 22q11.2DS izvornih govornika srpskog jezika. Dijagnoza 22q11.2DS postavljena je na osnovu prisustva najmanje dve od pet najčešćih fenotipskih karakteristika 22q11.2DS (urođene srčane malformacije konotrunkalnog tipa (KSM), facijalna dismorfija, aplazija/hipoplazija timusa, rascep nepca, hipokalcemije). Za detekciju mikrodelecije 22q11.2 primenjene su fluorescentna in situ hibridizacija (FISH) i metoda višestrukog umnožavanja proba koje je zavisno od ligacije (MLPA). Na osnovu rezultata FISH i/ili MLPA metoda, bolesnici sa kliničkom dijagnozom 22q11.2DS svrstani su u eksperimentalne grupe E1 (kod kojih je detektovana mikrodelecija 22q11.2) i E2 (kod kojih mikrodelecija 22q11.2 nije detektovana). Familijarna forma 22q11.2DS utvrđena je kod četiri porodice. Kako su kod svih bolesnika grupa E1 i E2 detektovane KSM i kako one mogu da utiču na razvoj govorno-jezičkih, kognitivnih i socio-emocionalnih sposobnosti istraživanjem su bila obuhvaćena i bolesnici sa nesindromskim KSM kod kojih mikrodelecija 22q11.2 nije detektovana FISH metodom (grupa E3). Govorno-jezičke, kognitivne i socioemocionalne sposobnosti bolesnika grupa E1, E2 i E3 su poređene sa ovim sposobnostima vršnjaka urednog govorno-jezičkog, socio-emocionalnog i kognitivnog razvoja, dobrog zdravstvenog stanja bez prisutnih hroničnih bolesti (grupa K). Rezultati istraživanja su pokazali da bolesnici grupe E1 imaju lošije govorno-jezičke sposobnosti u poređenju sa bolesnicima grupa E2 i E3 i ispitanicima grupe K. Niži nivo psihofizioloških sposobnosti detektovan je kod bolesnika grupe E1 u poređenju sa bolesnicima grupa E2 i E3 i ispitanicima grupe K...22q11.2 deletion syndrome (22q11.2DS) is caused by a heterozygous microdeletion of region q11.2 of chromosome 22. It has been shown that speech and language, cognitive and socio-emotional impairments are very common in children with 22q11.2DS. To the best of our knowledge, there are no published data about these abilities in children with 22q11.2DS, native speakers of South-Slavic languages. Therefore, the main goal of this Doctoral Dissertation is to analyze speech and language, cognitive and socio-emotional abilities of children with 22q11.2DS, monolingual native speakers of the Serbian language. Enrollment of patients was based on the presence of at least two out of the five major characteristics of 22q11.2DS (congenital heart malformations (CHM), facial dysmorphism, thymic aplasia/hypoplasia, palatal clefts and hypocalcemia). Fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) have been applied in order to detect 22q11.2 microdeletion. Based on FISH/MLPA results, patients with phenotypic features of 22q11.2DS were divided into experimental groups E1 (with 22q11.2 microdeletion) and E2 (without the 22q11.2 microdeletion). A familial form of 22q11.2DS was detected in four families. Patients with non-syndromic CHM (group E3) were included in the study since literature data implies that these children may exhibit a speech and language, cognitive and socioemotional impairments. Applying FISH, 22q11.2 microdeletion was not detected in these patients. Speech-language, cognitive and socio-emotional abilities of patients from the groups E1, E2 and E3 were compared to their age peers with proper speechlanguage, cognitive and socio-emotional development, and good general health condition without chronic diseases (group K). Obtained results revealed that patients from group E1 have less developed speech and language skills and psychophysiological abilities compared to patients from group E2 and E3 and children from group K. Also, cognitive abilities of 38.9% of patients from group E1, 18.8% of patients from group E2 and 25% of patients from group E3 did not reach levels expected for their calendar age..