COMT val158met Polymorphism and Neural Pain Processing

A functional polymorphism (val158met) of the gene coding for Catechol-O-methyltransferase (COM) has been demonstrated to be related to processing of emotional stimuli. Also, this polymorphism has been found to be associated with pain regulation in healthy subjects. Therefore, we investigated a possible influence of this polymorphism on pain processing in healthy persons as well as in subjects with markedly reduced pain sensitivity in the context of Borderline Personality Disorder (BPD). Fifty females (25 patients with BPD and 25 healthy control participants) were included in this study. Genotype had a significant – though moderate - effect on pain sensitivity, but only in healthies. The number of val alleles was correlated with the BOLD response in several pain-processing brain regions, including dorsolateral prefrontal cortex, posterior parietal cortex, lateral globus pallidus, anterior and posterior insula. Within the subgroup of healthy participants, the number of val alleles was positively correlated with the BOLD response in posterior parietal, posterior cingulate, and dorsolateral prefrontal cortex. BPD patients revealed a positive correlation between the number of val alleles and BOLD signal in anterior and posterior insula. Thus, our data show that the val158met polymorphism in the COMT gene contributes significantly to inter-individual differences in neural pain processing: in healthy people, this polymorphism was more related to cognitive aspects of pain processing, whereas BPD patients with reduced pain sensitivity showed an association with activity in brain regions related to affective pain processing

EEG Source Imaging Indices of Cognitive Control Show Associations with Dopamine System Genes.

Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness

Interaction of catechol O-methyltransferase and serotonin transporter genes modulates effective connectivity in a facial emotion-processing circuitry

Imaging genetic studies showed exaggerated blood oxygenation level-dependent response in limbic structures in carriers of low activity alleles of serotonin transporter-linked promoter region (5-HTTLPR) as well as catechol O-methyltransferase (COMT) genes. This was suggested to underlie the vulnerability to mood disorders. To better understand the mechanisms of vulnerability, it is important to investigate the genetic modulation of frontal-limbic connectivity that underlies emotional regulation and control. In this study, we have examined the interaction of 5-HTTLPR and COMT genetic markers on effective connectivity within neural circuitry for emotional facial expressions. A total of 91 healthy Caucasian adults underwent functional magnetic resonance imaging experiments with a task presenting dynamic emotional facial expressions of fear, sadness, happiness and anger. The effective connectivity within the facial processing circuitry was assessed with Granger causality method. We have demonstrated that in fear processing condition, an interaction between 5-HTTLPR (S) and COMT (met) low activity alleles was associated with reduced reciprocal connectivity within the circuitry including bilateral fusiform/inferior occipital regions, right superior temporal gyrus/superior temporal sulcus, bilateral inferior/middle prefrontal cortex and right amygdala. We suggest that the epistatic effect of reduced effective connectivity may underlie an inefficient emotion regulation that places these individuals at greater risk for depressive disorders

Emotsionaalsete näoilmete taju ja töömälu variatiivsuse allikad

Väitekirja elektrooniline versioon ei sisalda publikatsiooneKuidas mõjutavad emotsionaalsed näoilmed seda, mis jääb lühiajaliselt meelde ja mis mitte? Näiteks, kas naeratav või kuri pilk õpetajalt matemaatikatunnis võib segada peast arvutamist või hoopis soodustab seda? Miks mõned inimesed ei erista näoilmeid (nagu kurbus, viha ja rõõm) kuigi hästi? Mis on näoilmete taju ja töömälu variatiivsuse allikad? Doktoritöös testisin neist küsimustest inspireeritud hüpoteese. Töömälu ehk lühiajaline mälu on tunnetusprotsess, mis aitab tajutud informatsiooni siduda varasemate teadmistega ning kasutada seda lühiajaliselt ülesande täitmiseks. Töömälu on igasuguse eesmärgipärase tegevuse aluseks. Uurisin: 1) näoilmetest tulenevat mõju (tähendus vs füüsikalised omadused), 2) neurobioloogia panust, sh dopamiini, noradrenaliini ja serotoniini süsteemide biomarkerite ja soo seoseid sooritusega, 3) emotsionaalsete seadumuste (ärevuse, depressiivsuse) mõju. Kuue uuringu tulemustele tuginedes koostasin teoreetilise mudeli, mis kirjeldab näoilmete taju ja töömälu variatiivsuse allikaid. Uuringud I, III, IV, V ja VI viisin läbi Eesti Laste Isiksuse, Käitumise ja Tervise Uuringu raames kogutud andmetel, kokku osales 507 inimest (25 aastased). Uuring II sisaldas kolme eksperimenti, kus osales kokku üle 200 vabatahtliku inimese Tartust ja Tallinnast (vanuses 18-50). Tulemused näitasid, et positiivne ja motiveeriv kontekst (naeratavad või rõõmsad näod) soodustavad mälu sooritust, aga mitte kõrge depressiivsusega inimestel. Lisaks selgus, et madal serotoniini tase (mida kaudselt peegeldab madal vereliistakute monoamiini oksüdaasi aktiivsus) seostub sõltumata näoilmest parema töömälu soorituskiirusega, aga ainult siis kui dopamiinitase on keskmine või kõrge, aga mitte liiga kõrge. Tööst ilmnes ka, et mehed ja naised ei erine töömälu soorituses, küll aga näoilmete tajumises, arvestada tuleb sealjuures ka genotüüpi. Üllatavaks tulemuseks oli see, et varasem sotsiaalärevuse diagnoos ennustas ebatäpsemat sooritust vihase näoilme äratundmisel võrreldes kontrollgrupiga ja nendega, kellel oli katse ajal sotsiaalärevuse diagnoos. Kokkuvõtteks, ei leidu lihtsat “retsepti” näoilmete taju ja töömälu soorituse selgitamiseks. Tulemused aitavad aga mõista, miks inimesed on nii erinevad näoilmete tajumisel ja nende mäletamiselHow do emotional facial expressions affect what is remembered for a short time and what is not? For example, can a smiling or angry look from a teacher in a mathematics class help or hinder task performance? Why cannot some people discriminate between facial expressions (e.g. sad, angry and happy)? What are the sources of variation in perception and working memory for facial emotional expressions? In my dissertation, I tested hypotheses inspired by these questions. Working memory (WM), or short-term memory, is a process of cognition that binds perceived information to previous knowledge and use it in a purposeful manner to perform a task. Working memory is the foundation of any goal-oriented activity. I studied the effects that come from: 1) facial stimulus qualities (meaning vs. physical properties), 2) neurobiology, including associations between dopamine, serotonin and noradrenaline system biomarkers, and sex, 3) emotional dispositions (anxiety, depression). Based on the results from six studies, I developed a theoretical model that describes the sources of variation in perception and working memory for facial emotional expressions. Studies I, III, IV, V and VI were conducted as part of the Estonian Children Personality, Behaviour and Health Study, a total of 507 subjects (25 years old) participated. Study II consisted of three experiments with more than 200 volunteers from Tartu and Tallinn (aged 18-50). The results showed that a positive and motivating context (smiling or happy faces) enhanced memory performance, but not in people with high depression. Additionally, low serotonin (as reflected by low platelet monoamine oxidase activity) was associated with better WM performance regardless of facial expression, but only at an average or high, but not too high dopamine level. Men and women did not differ in WM performance. Sex difference was present only in interaction with genotype in perception of facial expressions. Surprisingly, past diagnosis of social anxiety disorder in contrast to controls, and acute social anxiety predicted inaccurate recognition of angry faces. In conclusion, there is no simple “recipe” that would explain perception and WM performance for facial expressions. However, the results help to understand why people are so different in perceiving and remembering facial expressions.https://www.ester.ee/record=b542767

The Catechol-O-Methyltransferase (COMT) val158met Polymorphism Affects Brain Responses to Repeated Painful Stimuli

Despite the explosion of interest in the genetic underpinnings of individual differences in pain sensitivity, conflicting findings have emerged for most of the identified "pain genes". Perhaps the prime example of this inconsistency is represented by catechol-O-methyltransferase (COMT), as its substantial association to pain sensitivity has been reported in various studies, but rejected in several others. In line with findings from behavioral studies, we hypothesized that the effect of COMT on pain processing would become apparent only when the pain system was adequately challenged (i.e., after repeated pain stimulation). In the present study, we used functional Magnetic Resonance Imaging (fMRI) to investigate the brain response to heat pain stimuli in 54 subjects genotyped for the common COMT val158met polymorphism (val/val = n 22, val/met = n 20, met/met = n 12). Met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures, including the periaqueductal gray matter, lingual gyrus, cerebellum, hippocampal formation and precuneus. These effects were observed only for high intensity pain stimuli after repeated administration. In spite of our relatively small sample size, our results suggest that COMT appears to affect pain processing. Our data demonstrate that the effect of COMT on pain processing can be detected in presence of 1) a sufficiently robust challenge to the pain system to detect a genotype effect, and/or 2) the recruitment of pain-dampening compensatory mechanisms by the putatively more pain sensitive met homozygotes. These findings may help explain the inconsistencies in reported findings of the impact of COMT in pain regulation.United States. National Institutes of Health (R01AT005280)United States. National Institutes of Health (R21AT00949)United States. National Institutes of Health (KO1AT003883)United States. National Institutes of Health (R21AT004497)National Center for Complementary and Alternative Medicine (U.S.) (PO1-AT002048)United States. National Institutes of Health (M01-RR-01066)United States. National Institutes of Health (UL1 RR025758-01)United States. National Institutes of Health (P41RR14075)United States. National Institutes of Health (DE-FG03-99ER62764)Swedish Society for Medical Researc

Electrophysiological Signatures of Fear Conditioning: From Methodological Considerations to Catecholaminergic Mechanisms and Translational Perspectives

Fear conditioning describes a learning mechanism during which a specific stimulus gets associated with an aversive event (i.e., an unconditioned stimulus; US). Thereby, this initially neutral or arbitrary stimulus becomes a so-called “conditioned” stimulus (CS), which elicits a conditioned threat response. Fear extinction refers to the decrease in conditioned threat responses as soon as the CS is repeatedly presented in the absence of the US. While fear conditioning is an important learning model for understanding the etiology and maintenance of anxiety and fear-related disorders, extinction learning is considered to reflect the most important learning process of exposure therapy. Neurophysiological signatures of fear conditioning have been widely studied in rodents, leading to the development of groundbreaking neurobiological models, including brain regions such as the amygdala, insula, and prefrontal areas. These models aim to explain neural mechanisms of threat processing, with the ultimate goal to improve treatment strategies for pathological fear. Recording intracranial electrical activity of single units in animals offers the opportunity to uncover neural processes involved in threat processing with excellent spatial and temporal resolution. A large body of functional magnetic resonance imaging (fMRI) studies have helped to translate this knowledge about the anatomy of fear conditioning into the human realm. fMRI is an imaging technique with a high spatial resolution that is well suited to study slower brain processes. However, the temporal resolution of fMRI is relatively poor. By contrast, electroencephalography (EEG) is a neuroscientific method to capture fast and transient cortical processes. While EEG offers promising opportunities to unravel the speed of neural threat processing, it also provides the possibility to study oscillatory brain activity (e.g., prefrontal theta oscillations). The present thesis contains six research manuscripts, describing fear conditioning studies that mainly applied EEG methods in combination with other central (fMRI) and peripheral (skin conductance, heart rate, and fear-potentiated startle) measures. A special focus of this thesis lies in methodological considerations for EEG fear conditioning research. In addition, catecholaminergic mechanisms are studied, with the ultimate goal of opening up new translational perspectives. Taken together, the present thesis addresses several methodological challenges for neuroscientific (in particular, EEG) fear conditioning research (e.g., appropriate US types and experimental designs, signal-to-noise ratio, simultaneous EEG-fMRI). Furthermore, this thesis gives critical insight into catecholaminergic (noradrenaline and dopamine) mechanisms. A variety of neuroscientific methods (e.g., EEG, fMRI, peripheral physiology, pharmacological manipulation, genetic associations) have been combined, an approach that allowed us (a) to translate knowledge from animal studies to human research, and (b) to stimulate novel clinical directions

The Role of COMT in Schizophrenic-Like Cognitive Impairment and Social Functioning in Children with 22q11 Deletion Syndrome

Schizophrenia is a severe psychiatric disorder that is hypothesized to represent the most extreme manifestation of a continuum of impairment referred to as schizotypy. As such, many of the cognitive, clinical, behavioral, and neuroanatomical features of schizophrenia should be present and detectable in nonpsychotic individuals who share this vulnerability. Recent findings have led to a renewed interest in the role that the gene that codes for catechol-O-methyltransferase (COMT) plays in the development and expression of schizotypy and schizophrenia. Specifically, an amino-acid polymorphism (Val158Met) in the COMT gene has been associated with schizophrenia based on linkage and association studies, with schizotypy in nonpsychotic adults, and with performance on dopamine-mediated prefrontal functioning in healthy adults and in patients with schizophrenia. Since abnormal functioning in dopaminergic pathways is thought to be associated with schizophrenia, COMT activity may play a role in schizophrenia pathogenesis and expression. The COMT gene is housed at 22q11.2, which maps to the commonly deleted region in 22q11 Deletion Syndrome (22q11DS), a syndrome that is associated with a highly elevated risk for the development of psychosis. The present study investigated the relationship of COMT genotype with neuropsychological impairment and social functioning in a nonpsychotic sample of children with 22q11DS. As hypothesized, participants with the Val allele performed worse on some measures of prefrontal functioning than participants with the Met allele. Additionally, participants with the Val allele exhibited schizophrenic-like social and behavioral deficits. Finally, associations between social and cognitive functioning and a haplotype that has been linked to schizophrenia were examined in patients with 22q11DS

Association of COMT, BDNF and 5-HTT functional polymorphisms with personality characteristics.

Background: The real impact of genetic factors on personality is still unknown, even if in literature about 50% of variance in personality traits are considered genetically determined. The determination of the genetic variance in personality traits could promote psychological well-being and the prevention of psychopathologies, because there are many experimental evidences showing that mental illness is associated to personality. Numerous studies have showed that Catechol-O-methyltransferase (COMT), brain derived neurotrophic factor (BDNF) and serotonin transporter (5-HTT) are genes whose variants are associated with personality traits. This aim of this study is the investigation of the association between personality traits and 5-HTTLPR/rs255315-HTT promoter variant, COMT Val158Met and BDNF Val66Met gene polymorphisms. Methods: The sample was composed by 132 healthy female students. Genomic DNA was extracted from buccal swab, while personality was assessed with Cloninger's Temperament and Character Inventory-Revised (TCI-R). Linear discriminant analysis was used to analyze how personality characteristics can differentiate individuals in relation to their genetic polymorphisms. Results: Data showed that the temperament trait Reward Dependence discriminated individuals with different BDNF variants; Novelty Seeking and Harm Avoidance discriminated individuals with different 5HTTLPR variants; Persistence discriminated individuals with different COMT variants. Conclusions: Since these traits are connected to psychological diseases as depression, social anxiety, anorexia and obsessive-compulsive disorders of personality, the study of their genetic component can be used as intermediary issue to better define the connection between genes and predisposition toward maladaptive behavior and mental illness