Abstract The association between antipsychotics and brain volume changes in schizophrenia is not clear. Previous imaging studies have not examined benzodiazepine use, though it has been linked to cognitive impairment. The aim of this thesis was to examine the association between long-term antipsychotic and benzodiazepine use and brain structures in schizophrenia. Based on a systematic review and meta-analysis of previous studies on long-term antipsychotic use and brain changes in schizophrenia, a higher antipsychotic exposure associated with parietal lobe decrease and basal ganglia increase. Previous data on the topic is very heterogenous and the overall number of studies is small (N=34). Most reported findings were non-significant. In the Northern Finland Birth Cohort 1966, 38 cases with schizophrenia spectrum disorder participated in the longitudinal study at the ages of 24 and 43. In the cross-sectional study, 44 cases with schizophrenia and 35 cases with affective psychoses participated at the age of 43. Structural brain MRI scans were acquired from all participants an data on antipsychotic and benzodiazepine dose was collected using medical records and interviews. Illness severity and antipsychotic/benzodiazepine dose were included as confounders in the analyses. Higher scan-interval antipsychotic dose associated to volume increase in lateral ventricles and higher benzodiazepine dose associated to volume decrease in the caudate nucleus during the 9-year follow-up. In the 43-year study, higher lifetime antipsychotic dose associated to smaller nucleus accumbens volume in schizophrenia. In comparison, higher lifetime benzodiazepine dose associated to larger volumes of total gray matter, cerebral gray matter, and thalamus in affective psychoses. In analyses without illness severity and other medication as confounders, there were several statistically significant associations. It seems that long-term antipsychotic use may associate to structural brain changes in schizophrenia and some associations may be confounded by symptoms and the use of benzodiazepines. These findings underline the importance of taking benzodiazepine use and other confounding factors into account when studying the effects of antipsychotics on the brain. Further studies should focus on how these findings relate to cognition and functioning. / Tiivistelmä Psykoosilääkityksen yhteys skitsofreniassa tapahtuviin aivomuutoksiin on epäselvä. Aiemmat kuvantamistutkimukset eivät ole tutkineet bentsodiatsepiinien käyttöä, vaikka niiden käyttö on yhdistetty heikompaan kognititioon. Tämän tutkimuksen tarkoituksena oli selvittää pitkäaikaisen psykoosi- ja bentsodiatsepiinlääkityksen yhteyttä aivojen rakenteisiin skitsofreniassa. Systemaattisen katsauksen ja meta-analyysin perusteella suurempi psykoosilääkeannos liittyi päälakilohkon tilavuuden pienenemiseen sekä tyvitumakkeiden koon kasvuun skitsofreniassa pitkäaikaisseurannoissa. Aikaisempi kirjallisuus on erittäin heterogeenistä ja tutkimusten kokonaismäärä on pieni (N=34). Suurin osa löydöksistä ei ollut tilastollisesti merkitseviä. Pohjois-Suomen syntymäkohortti 1966 aineistossa 38 skitsofreniaspektrin psykoosia sairastavaa henkilöä osallistui pitkittäistutkimukseen 34 vuoden ja 43 vuoden iässä. Poikkileikkaustutkimuksessa 44 skitsofreniaa ja 24 mielialapsykoosia sairastavaa henkilöä osallistui tutkimukseen 43 vuoden iässä. Pään rakenteellinen magneettikuvaus tehtiin kaikille osallistujille. Tiedot psykoosilääkkeiden ja bentsodiatsepiinien annoksista kerättiin sairauskertomusmerkinnöistä ja haastatteluista. Taudin vakavuus ja psykoosilääkkeiden/bentosidatsepiinien annos huomioitiin sekoittavina tekijöinä. Korkeampi psykoosilääkeannos liittyi aivokammioiden koon kasvuun ja korkeampi bentsodiatsepiiniannos häntätumakkeen koon pienenemiseen 9 vuoden seurannassa. Poikkileikkaustutkimuksessa korkeampi elinaikainen psykoosilääkeannos liittyi pienempään makaavan tumakkeen tilavuuteen skitsofreniassa. Mielialapsykooseissa korkeampi elinaikainen bentsodiatsepiiniannos liittyi suurempaan koko aivojen harmaan aineen, isoaivojen harmaan aineen ja talamuksen tilavuuteen. Kun sekoittavia tekijöitä ei otettu huomioon, tilastollisesti merkitseviä yhteyksiä löytyi useammilta aivoalueilta Tutkimuksen perusteella psykoosilääkkeiden pitkäaikaiskäyttö saattaa liittyä aivojen rakenteellisiin muutoksiin skitsofreniassa. Bentsodiatsepiinien käyttö ja oireet voivat toimia sekoittavina tekijöinä. Löydökset korostavat sekoittavien tekijöiden huomioimisen tärkeyttä tutkittaessa psykoosilääkkeiden vaikutuksia aivoihin. Tulevaisuudessa tutkimusten tulisi selvittää, miten löydökset liittyvät kognitioon ja toimintakykyyn.

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As falsas memórias são um tipo falha de memória, em que o indivíduo pode (a) reconhecer como tendo visto antes um objeto ou evento que não tenha ocorrido ou (b) não reconhecer algo previamente presenciado. Estes são o falso reconhecimento e a rejeição errada. Segundo a teoria do rastro difuso, dois processos distintos agem em paralelo durante a memorização e reconhecimento, um sobre as informações literais (verbatim) e o outro sobre a essência do significado da palavra (gist). Neste trabalho é proposto um sistema modular de redes neurais artificiais que considera estes dois processos, características funcionais das estruturas cerebrais envolvidas na memorização e fluxo de informação análogo ao ocorrido no cérebro. O modelo neural é validado através de treinamento para armazenar e recuperar listas de palavras semanticamente relacionadas. Na formulação do modelo e da representação foram considerados a representação fonológica e significado das palavras, de forma a simular as computações ocorridas e os resultados obtidos em experimentos efetuados com sujeitos humanos. Nestes experimentos, 12 listas de aproximadamente 15 palavras, cada lista semanticamente relacionadas a um tema são ouvidas e, em seguida, algumas destas palavras, a palavra tema e outras palavras não relacionadas são também ouvidas e os indivíduos respondem se cada palavra fora ouvida previamente. Os resultados obtidos computacionalmente aproximam-se bastante dos resultados obtidos com sujeitos humanos, e o modelo produzido serve como base para estudo das influências dos diversos processos atuantes durante a memorização e reconhecimento. / False memories are a kind of memory failure, in which the subject may (a) recognize as known an never seen object or never happened fact or (b) don\'t recognize something that was already presented him. These are false memories and wrong rejections. According to false memory theory, two parallel processes act during memorization and recognition, one on verbatim information and other on gist information. In this work is proposed a artificial neural network model system that takes in account these two processes, functional issues about brain structures involved on memorization and the an information flow analog to the occurred in the brain. The neural model is validated by training to store in recover lists of semantically related words. In the model and representation scheme formulation, phonological and semantic informations were used intending to simulate brain computations and results of human subjects experiments. In such experiment, 12 lists of something about 15 semantically related words, are heard and, in the second step, in the sequence, many of these words, other related words and not related words are heard in a recognition test, when subjets say if that word was or was not heard during memorization steps. Results obtained from computer tests are very close of human results, and the produced model may be used as a tool for analysis of the influences of the many processes that take place during memorization and recognition.

As falsas memórias são um tipo falha de memória, em que o indivíduo pode (a) reconhecer como tendo visto antes um objeto ou evento que não tenha ocorrido ou (b) não reconhecer algo previamente presenciado. Estes são o falso reconhecimento e a rejeição errada. Segundo a teoria do rastro difuso, dois processos distintos agem em paralelo durante a memorização e reconhecimento, um sobre as informações literais (verbatim) e o outro sobre a essência do significado da palavra (gist). Neste trabalho é proposto um sistema modular de redes neurais artificiais que considera estes dois processos, características funcionais das estruturas cerebrais envolvidas na memorização e fluxo de informação análogo ao ocorrido no cérebro. O modelo neural é validado através de treinamento para armazenar e recuperar listas de palavras semanticamente relacionadas. Na formulação do modelo e da representação foram considerados a representação fonológica e significado das palavras, de forma a simular as computações ocorridas e os resultados obtidos em experimentos efetuados com sujeitos humanos. Nestes experimentos, 12 listas de aproximadamente 15 palavras, cada lista semanticamente relacionadas a um tema são ouvidas e, em seguida, algumas destas palavras, a palavra tema e outras palavras não relacionadas são também ouvidas e os indivíduos respondem se cada palavra fora ouvida previamente. Os resultados obtidos computacionalmente aproximam-se bastante dos resultados obtidos com sujeitos humanos, e o modelo produzido serve como base para estudo das influências dos diversos processos atuantes durante a memorização e reconhecimento. / False memories are a kind of memory failure, in which the subject may (a) recognize as known an never seen object or never happened fact or (b) don\'t recognize something that was already presented him. These are false memories and wrong rejections. According to false memory theory, two parallel processes act during memorization and recognition, one on verbatim information and other on gist information. In this work is proposed a artificial neural network model system that takes in account these two processes, functional issues about brain structures involved on memorization and the an information flow analog to the occurred in the brain. The neural model is validated by training to store in recover lists of semantically related words. In the model and representation scheme formulation, phonological and semantic informations were used intending to simulate brain computations and results of human subjects experiments. In such experiment, 12 lists of something about 15 semantically related words, are heard and, in the second step, in the sequence, many of these words, other related words and not related words are heard in a recognition test, when subjets say if that word was or was not heard during memorization steps. Results obtained from computer tests are very close of human results, and the produced model may be used as a tool for analysis of the influences of the many processes that take place during memorization and recognition.

This document is a critical synopsis of prior work by Michael Dwyer submitted in support of a PhD by published work. The selected work is focused on the application of quantitative magnet resonance imaging (MRI) analysis techniques to the study of multiple sclerosis (MS). MS is a debilitating disease with a multi-factorial pathology, progression, and clinical presentation. Its most salient feature is focal inflammatory lesions, but it also includes significant parenchymal atrophy and microstructural damage. As a powerful tool for in vivo investigation of tissue properties, MRI can provide important clinical and scientific information regarding these various aspects of the disease, but precise, accurate quantitative analysis techniques are needed to detect subtle changes and to cope with the vast amount of data produced in an MRI session. To address this, eight new techniques were developed by Michael Dwyer and his co-workers to better elucidate focal, atrophic, and occult/"invisible" pathology. These included: a method to better evaluate errors in lesion identification; a method to quantify differences in lesion distribution between scanner strengths; a method to measure optic nerve atrophy; a more precise method to quantify tissue-specific atrophy; a method sensitive to dynamic myelin changes; and a method to quantify iron in specific brain structures. Taken together, these new techniques are complementary and improve the ability of clinicians and researchers to reliably assess various key elements of MS pathology in vivo.