In dieser Studie führten 37 adulte Patienten mit einer Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) ein Delay Discounting (DD) - Paradigma aus, während gleichzeitig mittels Funktioneller-Nahinfrarotspektroskopie (fNIRS) die Gehirnaktivität der „Regions of Interest“ (ROIs) des Orbitofrontalen-Kortex (OFC) und des Dorsolateralen-Präfrontalen-Kortex (dlPFC) gemessen wurde. Mittels Fragebögen und eines Delay Discounting Tasks (DDT) wurden zusätzlich Verhaltensparameter erhoben und flossen in den Auswertungsprozess mit ein. Vorausgegangene Untersuchungen weisen auf ein hypofunktionel-les dopaminerges System bei ADHS-Patienten hin, welches mit der ADHS-Pathogenese in Zusammenhang gebracht wird. Vor allem im Präfrontalen-Kortex (PFC), bestehend unter anderem aus OFC und dlPFC, erfolgt die Metabolisierung von Dopamin durch die Catechol-O-Methyltransferase (COMT). Hierbei hängt die Metabolisierungsgeschwindigkeit vom genetischen COMT-Val158Met- Polymorphismus ab. Die Einflussnahme dieses COMT-Val158Met-Polymorphismus auf die kortikale Aktivität der ROIs und Impulsivität ist ebenfalls Gegenstand dieser Dissertation („Imaging Genetics“). Adulte ADHS Patienten zeigten eine verstärkte Aktivität des OFC der Entscheidungskategorie „verzögert“ im Verhältnis zu der Entscheidungskategorie „sofort“. Die gemessene Impulsivität korrelierte mit der kortikalen Gehirnaktivität „DD-Kontrast“. Es konnte kein Zusammenhang zwischen Verhaltensparameter und Gehirnaktivität mit dem COMT-Polymorphismus gezeigt werden. Die erhöhte Aktivität des OFC bei der Entscheidungskategorie verzögert unterstützt die These der „Delay Aversion“ des „Dual Pathway Model“. Eine enge Konnektivität der stark dopaminerg innervierten kortiko-striataler Strukturen in Form des OFC und der Amygdala, welche Einfluss auf die ADHS-Pathogenese nehmen, erscheint somit plausibel. / In this study 37 adult subjects with ADHD (Attention Deficit Hyperactivity Disorder) performed a validated Delay Discounting (DD) paradigm. By using near-infrared-spectroskopy (NIRS) functional brain activation in the regions of interest (ROIs) was measured. The ROIs are represented by the Orbito-Frontal-Cortex (OFC) and the Dorsolateral Prefrontal Cortex (dlPFC). Additionally questionnaires with relation to behaviour and a Delay Discounting Task (DDT) were interpreted. Former studies indicate a hypo-functional dopaminergic system in ADHD pathology. Mainly the Prefrontal Cortex (PFC), including the OFC and the dlPFC, metabolizes dopamine with the Catechol-O-Methyltransferase (COMT). Velocity of this metabolism depends on the COMT-Val158Met-polymorphism. This effect is generally known by the term “imaging genetics”. Adult ADHD subjects showed a stronger activation in the OFC in the DD category “delayed” than in the category “now”. Measured impulsivity correlated with the cortical brain activity “DD-Kontrast”. No significant relation between the COMT polymorphism an the cortical brain activity or behaviour could be shown. The stronger activation of the OFC in the category “delayed” underlines the thesis of “Delay Aversion” from the “Dual Pathway Model”. A close connectivity between the dopaminergic corticostriatal brain regions of the amygdala and the OFC, which have an influence to the ADHD pathology, seem to be a plausible approach.

Bullying research has grown tremendously throughout the years, and yet, there is a lack of research investigating the biological underpinnings of bullying victimization and perpetration. The single nucleotide polymorphism catechol-O-methyltransferase (COMT) Val158Met is an important candidate gene that has been demonstrated to interact with environmental factors and play an important role in emotion processing. However, it remains unknown whether COMT Val158Met influences youth and adolescents’ involvement as both targets and perpetrators of bullying, considering bully-victims are found to struggle with emotion regulation. To address this knowledge gap, the role of COMT Val158Met on the joint trajectories of bullying victimization and perpetration was investigated in a longitudinal community sample. A latent class growth analysis (LCGA) was used to identify distinct patterns of bullying victimization and perpetration across the ages 10 to 18 years (n = 648). A three-class solution was chosen for bullying victimization where most participants were reflected in a trajectory of low decreasing bullying victimization (74%), followed by moderate stable trajectory of bullying victimization (23%) and a final group following a high stable trajectory of bullying victimization (3%). A two-class solution was chosen for bullying perpetration. As predicted, most participants were reflected in the low stable bullying perpetration group (83%) and a small group followed a moderate increasing/decreasing trajectory of bullying perpetration (16.4%). Dual trajectory models revealed distinct subgroup of individuals involved in bullying either as targets, perpetrators, or bully-victims. Conditional probabilities results suggest that highly victimized youth would in time perpetrate against others while remaining targets of high levels of perpetration (i.e., target to bully-victim), whereas youth moderately victimized were more likely to be uninvolved in bullying perpetration. There was no significant difference in allelic variations (i.e., any Met allele vs Val/Val) of COMT Val158Met between bully-victims and children uninvolved in bullying. Implications of these findings are discussed from a differential susceptibility model. Gaining an understanding of the mechanisms behind the impact of bullying victimization and perpetration on children and adolescent will help provide insight and support for school and clinical prevention and intervention efforts.

La esquizofrenia está considerada un síndrome clínico heterogéneo con una etiopatogenia de origen multifactorial, en el que se incluyen factores ambientales, caracteriales y genéticos. A pesar de que más del 50% de la variabilidad de la enfermedad se puede deber a uno o varios factores genéticos, sólo un número limitado de variantes de riesgo genético y con un efecto muy débil han podido ser identificados. Muchos de ellos no han podido reproducirse tanto por la diversidad de las muestras y poblaciones estudiadas como por su asociación a diversas enfermedades mentales. Parte de esta heterogeneidad ha intentado ser solventada mediante el uso de endofenotipos o fenotipos intermedios y marcadores biológicos, usados como marcadores de vulnerabilidad genética. El gen de la Catecol-O-Metil Transferasa (COMT), que codifica un enzima catabolizador de dopamina en el córtex prefrontal ha sido estudiado como uno de los genes candidatos más prometedores en el estudio de la etiopatogenia de la esquizofrenia, especialmente el polimorfismo rs4680 (COMT Val158Met). La posibilidad de asociar alteraciones en la regulación dopaminérgica prefrontal se encontraría refrendada por la hipótesis dopaminérgica revisada, según la cual, en la esquizofrenia existiría un desequilibrio dopaminérgico, con un incremento en la función dopaminérgica subcortical D2 y un déficit de estimulación D1 cortical. El polimorfismo COMT Val158Met no ha podido confirmar su asociación con esquizofrenia, existiendo en todo caso un riesgo muy débil asociado al alelo hiperfuncionante Val158. El estudio de endofenotipos y marcadores biológicos ha sugerido la asociación del polimorfismo con alteraciones cognitivas, neurofisiológicas, neuroanatómicas y a fenotipos clínicos como agresividad, suicidio, síntomas psicóticos, edad de inicio y respuesta clínica, encontrándose resultados heterogéneos, así como la existencia de una modulación del riesgo de asociación por el consumo de cannabis. Gran parte de la heterogeneidad puede explicarse por problemas metodológicos, relacionados con la validez y representatividad de las muestras, que podrían solventarse con la recogida sistemática de variables en muestras epidemiológicas en fases iniciales de la enfermedad. Partiendo de la hipótesis de la existencia de una alteración dopaminérgica prefrontal en la esquizofenia, el alelo Val158 del gen COMT estaría asociado a una expresión de síntomas psicóticos más graves, especialmente los negativos y a factores de mal pronóstico. Igualmente el consumo de cannabis podría modular este riesgo, incrementando el riesgo o contrarrestando los factores protectores. El objetivo principal fue estudiar la asociación de la presentación clínica y evolución a las seis semanas de tratamiento antipsicótico de pacientes con un primer episodio de psicosis y las variantes del polimorfismo COMT Val158Met así como su interacción con el consumo de cánnabis premórbido. Los objetivos secundarios fueron estudiar la incidencia de esquizofrenia y validar la representatividad de la muestra, analizar la relación entre el polimorfismo Val158Met y sintomatología clínica, edad de inicio, respuesta al tratamiento y estimar la presencia de interacciones gen-ambiente con el consumo de cánnabis premórbido. Para ello, se reclutaron 174 pacientes consecutivos con un primer episodio de psicosis de esquizofrenia, trastorno esquizofreniforme, trastorno esquizoafectivo, trastorno psicótico breve o trastorno psicótico no especificado, incluidos dentro del programa PAFIP, diseñado para la detección y tratamiento de los casos incidentes en la comunidad de Cantabria de Febrero 2001 a Febrero 2005. Los pacientes fueron evaluados con una entrevista semiestructurada, las escalas SANS, SAPS, HDRS, CDS, YMRS y la entrevista SCID-I. Fueron seguidos durante las primeras seis semanas de tratamiento antipsicótico de asignación aleatoria (olanzapina, risperidona o haloperidol). El genotipo del polimorfismo rs4680 se determinó en muestras de sangre venosa. Un primer estudio mostró una incidencia tratada de 1.38/10000 y la asociación de esta incidencia a factores de riesgo como edad menor de 25 años, sexo masculino, estado marital soltero, desempleo nivel educativo primario, ambiente urbano y consumo de cannabis. Un segundo estudio encontró una asociación del alelo Val158 con sintomatología negativa al inicio y edad de inicio temprana, diagnóstico de esquizofrenia y duración de psicosis sin tratar prolongada en mujeres. En un tercer estudio se mostró la asociación del consumo de cánnabis premórbido con edad de inicio más temprana y una interacción entre consumo de cannabis y el genotipo, de modo que el consumo de cannabis contrarresta el efecto protector del alelo 158 Met. Finalmente, en un cuarto estudio se confirmó la persistencia de la asociación del genotipo Val158Met con mayor sintomatología negativa tras seis semanas de tratamiento, no encontrando diferencias en cuanto a la respuesta clínica. Los resultados muestran que el polimorfismo COMT Val158Met pueden estar asociados a una edad de inicio más temprana y una mayor gravedad de síntomas negativos. Del mismo modo, el consumo de cánnabis premórbido se asocia a una menor edad de inicio y se encuentra un patrón de interacción con el polimorfismo, eliminando los efectos protectores del alelo Met158. Los hallazgos sugieren la importancia del polimorfismo COMT Val158Met y del consumo de cannabis en la etiopatogenia de la esquizofrenia, que podría explicarse por la disminución de trasmisión dopaminérgica prefrontal. / The schizophrenia is considered a heterogeneous syndrome which has multifactorial causes, including environmental, characterial and genetic factors. Despite the fact that 50% of the variability of the illness is explained by genetic factors, only a limited number of genetic variants have been identified as weak risk factors. Most of them have not been replicated because of the heterogeneity of the studied samples and the association with other mental illnesses. This variability has been tried to be solved by the use of endophenotypes and biological markers, as indicators of genetic vulnerability. Catechol-O-Methyltransferase gene, that codifies a dopamine degradation enzyme active in prefrontal cortex, has been studied as one of the most promising candidates in the etiopathogenesis of schizophrenia, particularly the rs4860 polymorphism (Val158Met). The possible association with an altered prefrontal dopaminergic transmission would be supported by the revised dopaminergic theory. Following this theory, there is a dopaminergic disequilibrium in schizophrenia, with an increase in subcortical D2 dopaminergic transmission and a deficit in D1 cortical stimulation. COMT Val158Met polymorphism has not consistently associated with schizophrenia. The study of endophenotypes and biological markers has suggested associations with cognitive deficits, neurophysiologic and neuroanatomic markers and with clinical phenotypes, such as aggressiveness, suicide, psychotic symptoms, age of onset and clinical response. It also has been reported an interaction with cannabis in the modulation of the risk of psychosis. This heterogeneity could be explained by methodological biases, related to the validity and representativeness of the studied samples and may be solved with the systematic study of epidemiological samples of patients in the initial phases of psychosis. Following the hypothesis of the existence of an altered prefrontal dopaminergic transmission, the Val158 allele in the COMT gene would be associated with more severe psychotic symptoms, particularly negative symptoms and with poor prognostic factors. Likewise, the premorbid use of cannabis could modulate this risk, increasing the risk or counteract the protective factors. The main objective was to study the association between the clinical onset and evolution in the first 6 weeks of treatment and the COMT Val158Met polymorphism as well as the interaction with premorbid cannabis use. The secondary objectives were to study the incidence of schizophrenia and validate the representativeness of the sample, to analyse the relation between the Val158Met polymorphism and clinical symptoms, age of onset, clinical response to treatment and to estimate the presence of gen-environment interactions with the premorbid cannabis use. 174 consecutive first episode psychosis patients with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder or psychosis non-otherwise specified were included in the PAFIP program. The program was designed for the detection and treatment of all cases in the region of Cantabria, form February 2001 to February 2005. The patients were assessed with a semi-structured interview, SANS, SAPS, HDRS, CDS, YMRS scales and the SCID-I interview. They were followed up to 6 weeks and treated with a randomly assigned antipsychotic (olanzapine, risperidone or haloperidol). Rs4680 polymorphism was assessed in peripheric blood samples. A first study showed a treated incidence of 1.38/10000 and the association with several risk factors such as age under 25 years, male gender, single marital status, unemployment, primary educational level, urban environment and cannabis use. A second study found an association between the Val158 allele and negative symptoms severity at onset, early age of onset, schizophrenia diagnosis and longer duration of untreated psychosis in females. A third study showed an association between premorbid cannabis use and early age of onset and an interaction between cannabis use and genotype, indicating that the cannabis use counter act the protective effect of the Met158Met allele in age of onset. Finally, in a fourth study the association between the Val158 allele and negative symptoms was confirmed after 6 weeks of treatment, although no relation was found with clinical response. The results showed that the COMT Val158Met polymorphism could be associated with an earlier age of onset and a higher severity of negative symptoms. Likewise, the premorbid use of cannabis was associated with an earlier age of onset and there was found a gene-environmental interaction, deleting the protective effect of the Met158 Allele. These findings suggest the importance of COMT Val158Met polymorphism and premorbid cannabis use in the etiopathogenesis of the schizophrenia that could be explained by a decrease in the prefrontal dopaminergic transmission.

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