CATECHOL-O-METHYL TRANSFERASE AND SCHIZOPHRENIA

Catechol-O-methyl transferase (COMT) is an enzyme involved in the degradation of dopamine. The most commonly examined polymorphism within the COMT gene is Val108/158Met polymorphism, which results in three to fourfold difference in COMT enzyme activity. It is particularely important in prefrontal cortex, since COMT activity is the most important regulator of the prefrontal dopamine function. Given the association between schizophrenia and decreased dopamine activity in the prefrontal cortex, it is not surprising that Val108/158Met polymorphism is among the most extensively investigated polymorphisms in schizophrenia. According to different studies, Val allele may be a small risk factor for schizophrenia. There is also some evidence that Val108/158Met polymorphism influences the age of onset of schizophrenia, cognitive function, severity of psychotic symptoms, as well as efficacy and adverse events of antipsychotics. Heterogenity of patient population has undoubtedly influenced the results of these studies. Interaction of Val108/158Met polymorphism with other genes and environmental factors is an important avenue for future research

Influence of the COMT Genotype on Working Memory and Brain Activity Changes During Development

Background: The Valine158Methionine (Val158Met) polymorphism of the COMT gene leads to lower enzymatic activity and higher dopamine availability in Met carriers. The Met allele is associated with better performance and reduced prefrontal cortex activation during working memory (WM) tasks in adults. Dopaminergic system changes during adolescence may lead to a reduction of basal dopamine levels, potentially affecting Met allele benefits during development. Methods: We investigated the association of COMT genotype with behavioral (n = 322) and magnetic resonance imaging data (n = 81–84) collected during performance of a visuospatial WM task and potential changes in these effects during development (reflected in age × genotype interactions). Data were collected from a cross-sectional and longitudinal typically developing sample of 6- to 20-year-olds. Results: Visuospatial WM capacity exhibited an age × genotype interaction, with a benefit of the Met allele emerging after 10 years of age. There was a parallel age × genotype interaction on WM-related activation in the right inferior frontal gyrus and intraparietal sulcus (IPS), with increases in activation with age in the Val/Val group only. Main effects of COMT genotype were also observed in the IPS, with greater gray matter volumes bilaterally and greater right IPS activation in the Val/Val group compared with the Met carriers. Conclusions: These results suggest that COMT genotype effects on WM brain activity and behavior are not static during development. The full developmental picture should be considered when trying to understand the impact of genetic polymorphisms on the mature cognition of healthy adult or psychiatric populations

Functional connectivity in healthy subjects is nonlinearly modulated by the COMT and DRD2 polymorphisms in a functional system-dependent manner

The dopamine system is known to modulate brain function in an inverted U-shaped manner. Recently, the functional networks of the brain were categorized into two systems, a "control system" and a "processing system." However, it remains unclear whether the inverted U-shaped model of dopaminergic modulation could be applied to both of these functional systems. The catechol-O-methyltransferase (COMT) and dopamine D2 receptor (DRD2) were genotyped in 258 healthy young human subjects. The local and long-range functional connectivity densities (FCDs) of each voxel were calculated and compared in a voxel-wise manner using a two-way (COMT and DRD2 genotypes) analysis of covariance. The resting-state functional connectivity analysis was performed to determine the functional networks to which brain regions with significant FCD differences belonged. Significant COMT × DRD2 interaction effects were found in the local FCDs of the superior portion of the right temporal pole (sTP) and left lingual gyrus (LG) and in the long-range FCDs of the right putamen and left medial prefrontal cortex (MPFC). Post hoc tests showed nonlinear relationships between the genotypic subgroups and FCD. In the control system, the sTP and putamen, components of the salience network, showed a U-shaped modulation by dopamine signaling. In the processing system, however, the MPFC of the default-mode network and the LG of the visual network showed an inverted U-shaped modulation by the dopamine system. Our findings suggest an interaction between COMT and DRD2 genotypes and show a functional system-dependent modulation of dopamine signaling

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

BIOLOGICAL BASIS OF VARIABILITY IN DOPAMINE AVAILABILITY ON FRONTOSTRIATAL BRAIN FUNCTION IN ADOLESCENCE

Neurodevelopmental studies indicate a protracted development through adolescence of brain systems underlying incentive-driven behaviors including prefrontal cortex (PFC) and the striatum. These systems support the executive control of behavior as well as motivationally driven behaviors and may contribute to vulnerabilities in the emergence of psychopathology. The PFC and striatum may support cognition and motivation through the function of the neurotransmitter dopamine. Dopamine (DA) availability is increased during the adolescent period in human and animals and play an important role in mediating individual differences in risk-taking behaviors. This dissertation seeks to examine the moderating role of genetically mediated DA availability on frontostriatal brain function in adolescence. To this end, we genotyped individuals between the ages of 10 and 20 for common functional polymorphisms in three genes that have a direct influence on synaptic DA availability. In addition, we calculated a multilocus composite score in order to assess additive effects of our three genetic loci. We used functional magnetic resonance imaging (fMRI) to assess brain function. The purpose of our first study was to examine the integrity of frontostriatal networks using resting state functional connectivity. We then look more directly at the role of frontostriatal brain function on incentive-driven behaviors using a rewarded inhibitory control task that has a known developmental signature . Overall we found a moderating influence of DA availability on age-related changes in key frontostriatal circuitry suggesting that the maturation of brain function in adolescence may in part be mediated by inter-individual variability in DA signaling. Overall, the genotypes by age interactions highlight a unique DA-driven brain profile in adolescence. This suggests that a genetically mediated brain phenotype characterized in adolescence may differ significantly from that in adulthood. This has strong implications regarding the variability observed in adolescent risk-taking behaviors as well as predictions of later adult behavior

Hétérogénéité neuropsychologique et corrélats structurels du trouble déficit de l'attention / hyperactivité

Previous models of Attention Deficit / Hyperactivity Disorder (ADHD) such as Barkley’s or Brown’s conceptualized ADHD as essentially a developmental impairment of executive function. Against this view, it is now recognized that ADHD is a heterogeneous disorder, involving multiple deficits and multiple neuronal pathways. Despite this current theoretical framework, most structural brain imaging studies in ADHD have compared groups of children with ADHD with typically developing children, without trying to identify subgroups within the diagnostic category. This approach has yielded heterogeneous findings, possibly due to inter-studies variations in the type and number of comorbidities, the percentage of medicated participants included, the number of girls included, and/or methodological and statistical differences. Patients participating in these studies were also often exposed to methylphenidate, and potential medication effects on grey matter volumes are still unclear in certain brain regions such as the frontal lobe, despite a therapeutic action involving the preferential activation of catecholamine neurotransmission within the prefrontal cortex. In this thesis, we used voxel-based morphometry to study the influence of two important risk factors for the development of comorbid conditions in ADHD. The first of these two factors was gender, and the second a genetic polymorphism of the Catechol-O-methyltransferase gene known to put children with ADHD at risk for developing a conduct disorder (Val158Met). We also compared grey matter volumes in children with ADHD exposed to methylphenidate, never-medicated children with ADHD and typically developing children. These experimental studies were part of a more general discussion of ADHD neuropsychological and neurobiological heterogeneity. In our study exploring the influence of gender on the structural correlates of ADHD, we report for the first time a gender-by-diagnosis interaction, with grey matter volume differences in boys and girls with ADHD in midline cortical structures, involved in emotional regulation and part of the default mode network. We propose that these differences may contribute to explain why girls with ADHD more often develop inattentive and internalizing symptoms, whereas externalizing symptoms are predominant in boys with ADHD. In our study investigating the effects of Val158Met in ADHD, we report the first evidence of a COMT-related genetic modulation of ADHD-related grey matter volume alterations. Indeed, children with ADHD at higher risk for developing a conduct disorder (children homozygotes for the Val158 allele) presented increased grey matter volumes in the caudate nucleus when compared with typically developing children, whereas children carrying a Met158 allele presented with decreased grey matter volumes in the right inferior frontal cortex, a region known for its key role in attention. Finally, we measured grey matter volumes in medicated children with ADHD, never-medicated children with ADHD and typically developing children using both whole-brain voxel-based morphometry and automated tracing procedures in chosen regions of interest. We document potential methylphenidate-related grey matter volume normalization and deviation in previously unexplored frontal and temporal regions, and report a positive association between treatment history and grey matter volume in the nucleus accumbens, a key region for reward processing. Our first two experimental studies therefore contribute to a better understanding of the influence of important sources of within-category heterogeneity, while the third helps clarifying the potential confounding effect of medication exposure in previous structural brain imaging studies in ADHD.Succédant à une théorisation centrée sur le rôle des déficits des fonctions exécutives, les modèles contemporains du trouble déficit de l'attention / hyperactivité (TDAH) mettent en avant l’hétérogénéité d’une catégorie diagnostique impliquant des déficits neuropsychologiques, voies cérébrales et mécanismes étiopathogéniques multiples. En dépit de cette évolution, la majorité des études d'imagerie cérébrale des corrélats structurels du trouble menées à ce jour ont été conduites au niveau de la catégorie diagnostique, sans spécification supplémentaire. Cette approche comparant en moyenne un groupe de patients avec TDAH à un groupe de sujets sains a donné des résultats très variables d'une étude à l'autre, la comparaison inter-étude étant toutefois rendue difficile par la présence de facteurs confondants, tels que des différences en terme de régions d’intérêt examinées, de comorbidités acceptées chez les patients, de pourcentages de sujets masculins et féminins, de fenêtre d’âge sélectionnée, de méthodologie d'analyse ou encore de pourcentage de patients traités par méthylphénidate. Dans ce doctorat, nous nous sommes appuyés sur la morphométrie voxel-à-voxel pour isoler l’influence sur les volumes de matière grise de deux facteurs d’hétérogénéité intra-catégorielle dans le TDAH : le genre d’une part, et un polymorphisme génétique (Val158Met du gène Catéchol-O-méthyltransferase (COMT)) d’autre part ; ces deux facteurs présentant l’intérêt de moduler le risque associé de développer un trouble de type externalisé. Nous avons également comparé les volumes de matière grise d’enfants avec TDAH ayant reçu un traitement par méthylphénidate, de patients n'ayant jamais été exposé à la médication, et de sujet sains. Ces recherches expérimentales ont été inscrites dans une discussion plus générale de l’hétérogénéité des résultats de la littérature structurelle consacrée au TDAH et des sources neuropsychologiques de cette hétérogénéité. Dans notre étude des effets du genre sur les volumes de matière grise dans le TDAH, nous reportons pour la première fois une interaction entre genre et diagnostic, avec des corrélats structurels du trouble différents chez les garçons et les filles avec TDAH dans des régions de la ligne médiane du cerveau, impliquées à la fois dans la régulation émotionnelle et dans le fonctionnement du mode de réseau par défaut. Nous suggérons que ces différences structurelles pourraient contribuer aux différences de risque associé pour les troubles internalisés et externalisés présentées par les garçons et filles avec TDAH. Dans notre étude explorant l'influence du polymorphisme Val158Met sur les volumes de matière grise, nous mettons en évidence une modulation génétique des corrélats structurels du trouble : les sujets homozygotes pour l'allèle Val158, identifiés dans la littérature comme à risque pour le développement d'un trouble des conduites, présentent des volumes de matière grise supérieurs dans le noyau caudé comparativement aux sujets sains, tandis que les patients avec TDAH porteurs d'un allèle Met158 présentent des volumes de matière grise plus faibles dans le cortex préfrontal inférieur droit, une région cruciale pour les processus de contrôle attentionnel. Enfin, dans notre étude des corrélats structurels de l'exposition au méthylphénidate, nous reportons un effet potentiellement normalisateur du traitement sur les volumes de matière grise de l'insula et du pole temporal, des volumes de matière grise plus faibles chez les patients traités comparativement aux sujets sains dans le gyrus frontal moyen et dans le gyrus précentral, et une association entre volume de matière grise dans le nucleus accumbens gauche et durée d'exposition au méthylphénidate chez les sujets traités. (...

Monoaminergic and Neurotrophic Gene Variation Associated with Fronto-Limbic Circuitry affect Mood and Cognitive Recovery Post-TBI

Following traumatic brain injury (TBI), ~80% of individuals will experience cognitive deficits, and ~50% will experience post-TBI depression (PTD). Identifying individual risk patterns for these complications is important for preventive treatment and early intervention. In uninjured populations, individuals with depression have distinct accompanying cognitive deficits. Importantly, dysregulation of fronto-limbic regions may, in part, explain the co-occurrence of both depressive and cognitive symptoms. The work presented investigates biological factors that influence survival after severe TBI, and among survivors, the presence and severity of PTD and/or cognitive deficits. The scientific framework under which this work was completed proposes targeted interactions between monoaminergic and neurotrophic gene variation that may lead to cognitive deficits and depressive symptoms. In addition to cognition, serotonergic (5-HT) and dopaminergic (DA) signaling both contribute to depressed mood and anhedonia, suggesting genetic variation in their signaling pathways may modulate PTD risk. Brain-derived neurotrophic factor (BDNF), a ubiquitous neurotrophin involved in neuronal survival and synaptic plasticity, is implicated in depression and cognitive dysfunction, and BDNF interacts with 5-HT/DA signaling in mood and cognitive processes. The work presented examines monoaminergic-neurotrophic biomarkers for predicting PTD risk and cognitive deficits. Serum and cerebrospinal fluid (CSF) BDNF levels, and fronto-limbic atrophy, were examined as possible biomarkers of PTD and cognitive deficits. A battery of targeted genes were examined for their proposed roles in survival, depression, cognition, and/or modulation of fronto-limbic connectivity. The data show variation within monoaminergic genes was associated with PTD incidence (serotonin transporter, 5-HTTLPR) and cognitive deficits post-TBI (dopamine D2 receptor, DRD2 and COMT). When investigating BDNF associations with PTD, we discovered that variation in BDNF interacts with MONOAMINERGIC AND NEUROTROPHIC GENE VARIATION ASSOCIATED WITH FRONTO-LIMBIC CIRCUITRY AFFECT MOOD AND COGNITIVE RECOVERY POST-TBI Michelle D. Failla, PhD University of Pittsburgh, 2014 v age to influence TBI survival, and acute BDNF levels were consistent biomarkers for TBI survival. Among TBI survivors, acute BDNF levels were associated with chronic cognitive performance and depressive symptoms severity, suggesting early neurotrophic support may facilitate chronic recovery. Investigating fronto-limbic regional brain volumes identified significant relationships to PTD and suggested non-uniform fronto-limbic atrophy patterns that may explain PTD susceptibility. Overall, this work supports that monoaminergic-neurotrophin genetic variability affects individual risk for PTD and related cognitive deficits, possibly through relationships with fronto-limbic circuitry

Polimorfismos genéticos humanos y adicción a drogas de abuso: implicación del SNP C385 del gen FAAH en el consumo de riesgo de alcohol en jóvenes adultos

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Psicología, leída el 05/11/2014Fac. de PsicologíaTRUEunpu