Introdução: As psicoses funcionais são transtornos psiquiátricos cuja principal característica é a perda da capacidade de julgar apropriadamente a realidade em decorrência de alterações na esfera do pensamento, percepção, emoção, movimento e comportamento. A esquizofrenia é o principal destes quadros, com curso crônico e/ou deteriorativo nas esferas social e ocupacional, gerando enormes custos pessoais e financeiros para os pacientes e cuidadores em todo o mundo. Estudos prévios têm mostrado a existência de prejuízos cognitivos em pacientes com transtornos psicóticos já no início da doença, sendo estes mais graves na esquizofrenia. Há evidências de que estes prejuízos são tanto inerentes aos próprios processos da doença quanto secundários ao tratamento. O presente estudo procurou caracterizar o perfil cognitivo de pacientes com psicoses de início recente (n=56), até 3 anos após o primeiro contato com serviços de saúde mental, sendo 34 com esquizofrenia e 22 com psicoses afetivas. Tais grupos de pacientes tiveram seu desempenho cognitivo comparado com o de um grupo controles saudável (n=70), recrutados a partir das mesmas áreas geográficas de São Paulo, Brasil. Até o momento, a maioria dos estudos foi realizada em países em desenvolvimento. Metodologia: A investigação utilizou ampla bateria de testes neuropsicológicos composta por 12 testes agrupados em 8 domínios cognitivos destinados a avaliar respectivamente amplitude atencional, velocidade de processamento da informação, memória verbal, memória visual, memória de trabalho, fluência verbal, funções executivas e funcionamento intelectual. O nível de significância foi de p < 0.05. Resultados: O desempenho do grupo de pacientes com psicoses foi pior do que o dos controles em todas as tarefas cognitivas, com diferenças estatisticamente significativas nas tarefas de velocidade de processamento da informação, memória verbal, fluência verbal e funcionamento intelectual, sendo os déficits mais graves no domínio da memória verbal (p < 0.001). Os grupos esquizofrenia e psicoses afetivas não diferiram significativamente quando comparados entre si. A inclusão do grupo controle na comparação mostrou que os pacientes com esquizofrenia tiveram desempenho significativamente pior do que os controles, o que não ocorreu entre os controles e as psicoses afetivas. A investigação da influência das variáveis demográficas e clínicas mostrou que o desempenho cognitivo foi beneficiado pela escolaridade, na maioria das funções; a idade atual maior teve associação negativa com a memória visual e fluência verbal; gênero masculino teve correlação positiva com a memória de trabalho, tempo de latência para produção de resposta não-convencional, e negativa com a quantidade de erros frente à necessidade de controle de respostas impulsivas.O padrão de tratamento descontínuo beneficiou o desempenho em tarefas de memória verbal, e prejudicou o desempenho na tarefa de antecipação espacial. O abuso/dependência de substâncias não mostrou correlação com nenhuma tarefa, o que ocorreu na análise de regressão. O início do transtorno em idades mais precoces não mostrou prejudicar o desempenho dos pacientes na maioria das tarefas. O tempo de duração de psicose não tratada (duration of untreated psychosis, DUP) mostrou correlação negativa com o tempo de latência para respostas não-convencionais no grupo das psicoses, influenciando negativamente o desempenho nas tarefas de vocabulário, memória verbal imediata e tardia, e a quantidade de respostas impulsivas. No grupo da esquizofrenia, a maior DUP esteve associada a piores resultados nas tarefas de raciocínio não-verbal, memória verbal imediata e tardia, e quantidade de erros no teste de antecipação espacial. Os sintomas negativos influenciaram negativamente os resultados em várias provas, o que não ocorreu com os sintomas positivos. Conclusão: Pacientes com psicoses funcionais de início recente apresentaram prejuízos cognitivos evidentes em comparação aos controles saudáveis. Confirmou-se também a existência de funcionamento cognitivo semelhante entre amostras de países desenvolvidos e em desenvolvimento através de bateria cognitiva ampla. Os prejuízos cognitivos estenderam-se a várias funções, configurando tendência a perfil de déficits generalizados. Embora tenha havido tendência a maior gravidade de déficits no grupo da esquizofrenia, não encontramos diferenças significativas entre os subgrupos diagnósticos, confirmando a presença de déficits cognitivos nas psicoses de início recente, particularmente nas de natureza não-afetiva. / Background and Purpose: Functional psychoses are psychiatric disorders which have as their main characteristic a loss of the ability to properly judge the reality due to alterations of thought, perception, emotion, movement and behavior. The main psychotic disorder is schizophrenia, which usually as a chronic and / or deteriorating course in social and occupational relationships, generating enormous personal and financial costs for the patients and their caretakers all over the world. Previous studies have shown the presence of cognitive deficits in patients at the onset of psychoses, more severely in schizophrenia. There are evidences that those deficits are both related to disease processes and to treatment effects. The present work sought to characterize the neuropsychological profile of patients with recent onset psychoses (n=56), up to 3 years after their first contact with Mental Health Service Care 34 with schizophrenia and 22 with affective psychoses. These patient groups had their results compared to a healthy control group (n=70) recruited from the same geographic area of São Paulo City, Brazil. So far, most studies of neuropsychological functioning in patients with recent onset psychoses have been conducted in high-income countries. Method: The cognitive assessment was conducted using a neuropsychological battery comprising 12 tests, grouped into 8 cognitive domains aimed at assessing respectively intellectual functioning, attentional span, information processing speed, verbal memory, visual memory, working memory, verbal fluency and executive functioning. The significance level was set at p < 0.05. Results: The performance of the psychosis group was worse than that of controls in all cognitive tasks, with statistically significant differences detected in information processing speed, verbal memory, verbal fluency and intellectual functioning tasks, most seriously in the verbal memory domain (p < 0.001). When compared against each other, the schizophrenia and affective psychoses subgroups were not significantly different. The inclusion of the control group in the analysis showed that patients with schizophrenia had significantly worse performance than controls, while such difference was not noticed when controls and affective psychoses groups were compared against. The influence of demographic variables and clinic data showed that cognitive performance was significantly associated with level of schooling in most cognitive tasks; visual memory and verbal fluency were negatively affected by age (deficit increased with age); male gender showed a positive relationship to executive memory and lag time for non-conventional answers, and a negative relationship to mistakes in impulsive answer control needs. Treatment discontinuity was related to better performance in tasks such as verbal memory, but with worse performance in the anticipation space test. Substance abuse or dependence did not influence significantly the performance in any of the tasks individually, but this occurred in the regression analysis. Earlier age of psychosis onset was non significantly related to performance of patients in any of the tasks. The duration of untreated psychoses (DUP) showed negative correlation with the lag time for non-conventional answers in the psychoses group, influencing the performance in tasks as vocabulary, immediate and delayed verbal memory, and the amount of impulsive responses negatively. In schizophrenia group, DUP was associated to worse results in non - verbal reasoning, immediate and late verbal memory, and error quantity in anticipation space test. Several activities were negatively influenced by negative symptoms, what did not occurred with positive symptoms. Conclusion: Patients with recent onset psychosis clearly display cognitive deficits when compared to healthy controls. The existence of similar cognitive functioning between samples studied in developed and developing countries was confirmed through wide cognitive test sets. Cognitive impairment was detected in multiple tasks, showing a widespread trend of deficit profiles. Although there was a tendency towards high severity deficits in the schizophrenia group, we could not find major differences amongst diagnoses subgroups. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non- affective nature.

A avaliação neuropsicológica de portadores de doença de Parkinson (DP) tem sido de fundamental importância para definição de resultados em procedimentos clínicos, cirúrgicos experimentais ou para diagnóstico de demência nestes doentes. No entanto, ainda não existe consenso quanto aos testes neuropsicológicos necessários e padrões de comprometimento esperados. Este estudo objetivou comparar a produtividade das funções neuropsicológicas entre portadores da Doença de Parkinson, em diferentes estágios da doença, em relação aos indivíduos normais. Foram analisados 60 sujeitos (32 homens e 28 mulheres), emparelhados em relação à idade (média de 65,6 +-9,2) e instrução (média de 5,9 =- 4,0), distribuídos entre normais (n=20) e portadores de DP ambulatoriais, nos estágios leve a moderado (n=20) ou moderado a grave (n=20), de acordo com a escala Hoehn & Yahr. A bateria utilizou 24 testes neuropsicológicos abrangendo as funções de raciocínio, percepção visuoespacial, visuoconstrução, linguagem, memória, atenção e função executiva. Os resultados apontaram diferenças significantes (p < 0,01) entre vários testes e em todas as funções, exceto linguagem. Alguns instrumentos se mostraram mais adequados e outros se mostraram pouco indicados para avaliar estes doentes. Diferenças entre os estágios da doença só se evidenciaram nos testes que exigiam destreza motora. Este trabalho estabelece a adequação dos instrumentos e propõe uma bateria específica para avaliação destes doentes. A investigação de estados situacionais (nível cultural, sintoma afetivo e/ou limitações funcionais), manifestos na avaliação, permitiu estabelecer parâmetros para discriminar o modo como estas variáveis interferem na produção dos doentes de Parkinson. E conclui-se apresentando um método inovador de classificação para subsidiar com objetividade o diagnóstico neuropsicológico diferencial na DP. / The neuropsychological assessment of patients with Parkinson disease (PD) has been very important to define the results in clinical, experimental surgeries procedures or in the diagnostic of dementia of these patients. However, there is no consensus about the necessary neuropsychological tests and about the expected commitment patterns. This study aimed to compare the productivity of the neuropsychological functions among patients with Parkinson Disease, in different stages of the disease, in relation to normal people. Sixty subjects were assessed (32 men and 28 women), pared in relation to the age (average of 65.6 +- 9.2) and age of study (average of 5.9 +- 4.0), distributed among normal (n=20) and outpatients with PD, in the mild to moderate stages (n=20) or moderate to severe (n=20), according to Hoehn & Yahr Scale. The battery used 24 neuropsychological tests comprising the thinking, visuospatial perception, visuoconstruction, language, memory, attention and executive function. The results showed significant differences (p < 0.01) among many tests and in all the functions, except language. Some instruments were more suitable and others proved to be less indicated to assess these patients. Differences in the stages of the disease were highlighted in the tests that required motor ability. This work establishes the adequacy of the instruments and proposes a specific battery to assess these patients. The investigation of the situational state (cultural level, affective symptom and/or functional limitations), that appeared in the assessment, allowed to establish parameters to find out the way that these variables interfered in the Parkinson patients’ production. The work concludes presenting an innovative classification method to objectively subside the neuropsychological differential diagnosis for PD.

Foi estudado o efeito de priming negativo associado à supressão do distrator palavra-cor de Stroop (Estudo 1), à supressão do local (Estudo 2) e à identidade do distrator (Estudos 3 e 4). No Estudo 1 constatou-se que a prática prévia em palavras-cor eliminou o efeito da ordem das condições experimentais sobre o índice de priming negativo. No Estudo 2, o efeito de priming negativo foi observado somente no hemicampo direito. A execução concorrente de uma tarefa verbal eliminou os efeitos de lateralidade, mas o efeito de priming negativo permaneceu significante. Estes achados são discutidos em termos de processamento interhemisférico sob condições que exigiriam maior controle da atenção. Os estudos 3 e 4 apresentam tarefas de comparação de pares de dígitos. A versão de papel e lápis da tarefa de comparação de dígitos permitiu avaliar de maneira simples e rápida o efeito de priming negativo. A versão computadorizada, revelou uma interação entre os componentes espacial e de identidade. Ambos os grupos de adultos jovens e idosos revelaram priming negativo nas tarefas de Stroop e de localização espacial. Nas tarefas de identificação do alvo somente os adultos jovens mostraram efeito de priming negativo. Os presentes achados são consistentes com a proposta de mecanismos inibitórios diferenciados na supressão da identidade e de localização espacial. / The development of sensitive and simple tests for the assessment of the negative priming effect has theoretical relevance to the elucidation of selective attention models, and also practical and potential clinical implications. The negative priming effect has been regarded as an index of inhibitory attentional processing and was proposed for the detection of syndromes that involve cognitive impairment. Diminished negative priming was reported in studies of individual differences, developmental stage, and clinical populations. However, evidences suggest that tasks requiring responses to the color feature, location or object identity of the stimuli may comprise distinct types of negative priming tasks. The following studies presents data for computerized and paper-and-pencil tasks to examine negative priming for Stroop color-word, location and identity distractors. All four studies take into account aging effects across the tasks. For comparisons between age-groups, proportional performance scores (ratio) were used. A first study employed a reading-sheet Stroop-color-word task, in which the participant is asked to name the colors of the ink in which words with incongruent color names have been printed. Color-word interference is indicated by increased time to complete the conflicting color-word condition compared with a nonconflicting condition with patches of color or strings of Xs. The greater strength of the interference, when the target ink-color of the present stimulus is the distracting color name of the previous stimulus, is attributed to the negative priming effect. A pilot experiment showed that the order of the list conditions containing unrelated and related stimuli affected the negative priming index. The analysis of data demonstrated that a practice trial in color naming of conflicting color-words before the color-word conditions eliminated the effect of the order of the lists. In addition, there was a reliable Stroop reverse interference after practice in color naming, as indicated by the fact that the incongruent color-ink affected post-test word-reading, whereas it had no effect in the pretest word-reading. With practice procedure, older and younger subjects did not differ in their proportional interference scores, whereas the negative priming and reverse effects were increased for older adults. Study 2 examined the negative-priming effect in a spatial localization task under single- and dual-task conditions. The task required the subject to detect the location of a target letter, ‘O’, while ignoring a distractor letter, ‘X’, when it was present. Significant negative-priming effects were observed under both task conditions, with increased response times for trials in which target location had matched the location of the distractor on the preceding. The magnitude of the negative priming effect was not different for older and younger adults. The performance in the single-task condition showed laterality effects with a right visual field advantage for control and target-alone trials, but not for related trials. In consequence, in the single-task condition, negative priming was observed only for targets displayed in the right hemifield. However, a concurrent digit span task, with a load level that had shown no affect on the dual-task coordination capacity, eliminated the laterality effects, but the negative priming effect remained. These results are considered as neuropsychological evidence that interhemispheric processes may operate under more controlled conditions. Studies 3 and 4 examined negative priming by using an identity-based task that required participants to select the greater of two-digits display or the digit that was paired with an asterisk. Study 3 presents data for a computerized version of the task. Negative-priming was expressed as a slowing in the time to name the digit that had been ignored in the preceding trial, compared to control trials with consecutive targets and distractors always different. Analysis of data revealed that negative priming was reliable only for younger adults, and only when target probe and distractor prime appeared at the same location, suggesting that suppression for location of distractor was underpinning the negative priming effect. However, response latencies for the control trials were facilitated when the target probe and the distractor prime shared the same location. Thus, local suppression affected negative priming for attended distractors with a cost in the response latency for ignored-repetition trials and with a gain in response latency for control trials when the locus of target-probe and distractor-prime was the same. In contrast, older adults’ performance showed local suppression for both ignored-repetition and control trials. This may explain the lack of negative priming for older adults in the digit-comparison task. Study 4 presents data for a new paper-and-pencil version of the digit-comparison task to obtain a practical measure of negative priming that do not require cumbersome technical equipment. In that task, subjects were asked to circle digits that were paired with asterisks and the greater of two digits in a series of digit pairs listed on a sheet of paper. For younger participants, but not for older participants, the time to complete the sheet with related pairs was slower than for unrelated pairs. In addition, the reduced scores of negative priming in older adults were associated with the lowest sustained attention scores from Toulouse-Piéron test. These results suggest that older adults’ performance in the digit-comparison task were mainly related to flexibility and sustained attentional scores, and the lower sustained attentional coefficient seemed to be the best predictor of diminished or reversed negative priming in older adults. Younger adults showed reliable negative priming across all tasks. In contrast, older adults showed negative priming in Stroop and spatial tasks, when compared with younger subjects performance, but reduced negative priming in identity suppression tasks. The findings are consistent with neurophysiological and behavioural evidence that identity and location suppressing may rely on separate inhibitory mechanisms, and that not all of these processes are weakened by factors associated with age.

Apathy is characterised by a lack of motivation towards goal directed behaviour and is a symptom of various neurodegenerative diseases. There are various tools that can be used to assess apathy but a caveat of these is that they usually assess it as a unidimensional concept. Apathy has been recognised to have a multidimensional substructure. The Dimensional Apathy Scale is the only comprehensive measure designed to quantify neurobiologically-based subtypes, called Executive, Emotional and Initiation apathy. The first aim of this study was to explore multidimensional apathy, and its associations with demographic variables, in healthy, community dwelling adults. Secondly, multidimensional apathy was explored in neurodegenerative diseases, specifically Amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD). For each disease group, the validity and reliability of both the self rated and carer rated DAS were also determined. Finally, the association between specific apathy subtype impairments and executive dysfunction was explored in ALS patients. Four hundred healthy community dwelling adults, eighty-three ALS patients (seventy-five carers), thirty-four PD patients (thirty carers) and forty-nine AD patients (eighty-nine carers) were recruited for the questionnaire study. In the healthy community dwelling adults, Executive apathy decreased with age, whereas Emotional increased with age. Gender differences were also shown with higher apathy in males on Emotional apathy. There were also employment differences, in that Executive apathy was higher in unemployed individuals compared to those who were employed. Emotional apathy showed difference in type of employment, where full time employed individuals were significantly more apathetic than those employed part time. These findings were taken into account in selecting the appropriate control samples to match our patient groups. In the patient groups, ALS patients were found to be significantly more impaired on the Initiation subscale when compared to controls. Furthermore, Initiation apathy was found to be the most frequent impairment above abnormality cut-off on the carer rated DAS. PD patients were significantly more impaired on Executive and Initiation apathy when compared to controls. These two subscales were most frequently above abnormality cut-off in the carer rated DAS. Finally, AD patients were significantly more impaired on all subscales when compared to controls and, on the carer rated DAS, global impairment over all subscales was most often reported as above abnormality cut-off. Additionally in AD, there was a significant disparity between carer and patient ratings on Executive and Initiation apathy, indicating patients’ impaired awareness. When comparing patient groups, there was a significant difference between carer rated apathy subtype impairments for each patient group. Validity and reliability of the DAS was found to be robust when compared to standard measures of apathy and depression. In the experimental study, a sample of ALS patients (and their carers) and healthy controls (and their informants) were recruited to complete a battery of neuropsychological tests, the DAS, other apathy and depression measures. ALS patients were impaired on tasks of executive functioning when compared to controls. Furthermore, apathy subtype deficits were associated with executive dysfunction in ALS. In conclusion, apathy is a multidimensional concept that manifests in different subtype profiles dependent on neurodegenerative disease. This has further implications for understanding and assessment of cognitive dysfunction and neuropsychiatric symptoms, such as apathy, in ALS and other neurodegenerative disease patient groups.

Dramatic changes occur across childhood and adolescence in the activity and connectivity of an amygdala-medial prefrontal cortex circuit critical for emotional learning and regulation. However, little is currently known about how neuroplasticity within the circuit changes during development in the human. Experiences that occur during developmental sensitive periods of increased neuroplasticity have the capacity to sculpt neural function with lifelong consequences for cognition and behavior, though. This dissertation will therefore investigate when and how experience may shape amygdala-medial prefrontal cortex functional circuitry (Aim 1) and what the implications of experience-dependent circuitry development are for emotion regulation behaviors (Aim 2) across childhood, adolescence, and adulthood in three studies. Study 1 (previously published as Gabard-Durnam, Gee et al., 2016) posits and tests the long-term phasic molding hypothesis that tonic amygdala-prefrontal cortex functional connectivity, the functional architecture of the brain, is shaped during development by recurring stimulus-elicited connectivity in the circuitry using prospective examination of these connectivities’ development across childhood and adolescence. Study 1 also tests whether the ability of amygdala-prefrontal cortex stimulus-elicited connectivity to shape the amygdala-prefrontal cortex resting-state functional architecture changes across development, reflecting changing plasticity of the circuitry. Study 2 examines how the timing and duration of an early adverse experience, parental deprivation, interacts with genetically-driven differences in neuroplasticity levels indexed by the Brain-Derived Neurotrophic Factor val66met polymorphism to influence the developmental trajectory of amygdala-prefrontal cortex functional architecture using a population of previously-institutionalized children and adolescents and a never-institutionalized comparison sample. Study 2 further examines how the experience- and plasticity-related changes to the functional architecture influence both concurrent and future internalizing symptomatology across childhood and adolescence. Study 3 builds on the first two developmental studies by explicitly testing whether childhood is a sensitive period for medial prefrontal cortex-mediated regulatory signal learning through a retrospective design in adults. Study 3 additionally assesses the effects of developmental experience on adult emotion regulation behavior and physiology. My findings at the levels of brain circuitry, behavior, physiology, and genetics together delineate a period of increased sensitivity to the environment within prefrontal cortex-amygdala functional circuitry from infancy through childhood, modifiable by genetically-conferred variation in plasticity and the nature of the early environment. Moreover, experiences occurring during the sensitive period have consequences for future emotion regulation behavior both during development and lasting into young adulthood. Together, these findings demonstrate how experience-dependent development has enduring effects on amygdala-prefrontal cortex circuitry function and affective behavior.

Vocal communication relies on the ability of listeners to identify, process, and respond to vocal sounds produced by others in complex environments. In order to accurately recognize these signals, animals’ auditory systems must robustly represent acoustic features that distinguish vocal sounds from other environmental sounds. In this dissertation, I describe experiments combining acoustic, behavioral, and neurophysiological approaches to identify behaviorally relevant vocalization features and understand how they are represented in the brain. First, I show that vocal responses to communication sounds in songbirds depend on the presence of specific spectral signatures of vocalizations. Second, I identify an anatomically localized neural population in the auditory cortex that shows selective responses for behaviorally relevant sounds. Third, I show that these neurons’ spectral selectivity is robust to acoustic context, indicating that they could function as spectral signature detectors in a variety of listening conditions. Last, I deconstruct neural selectivity for behaviorally relevant sounds and show that it is driven by a sensitivity to deep fluctuations in power along the sound frequency spectrum. Together, these results show that the processing of behaviorally relevant spectral features engages a specialized neural population in the auditory cortex, and elucidate an acoustic driver of vocalization selectivity.

Objective: Neuropsychology models of anorexia nervosa (AN) propose that cognitive difficulties including poor Emotion Recognition (ER) and set-shifting ability may be central to the development and maintenance of eating pathology. This study aimed to test the central positions of such models by assessing specific ER difficulties in AN as well as the relationship between ER deficits and set-shifting performance. Methods: Fifty-one women were assessed (25 with AN; M = 28.20 SD = 8.69 and 26 control M = 21.27 SD = 5.10) on a novel measure of ER, a set-shifting test and self-report questionnaires concerning co-morbid factors. Results: The data did not reveal a global difference in ER or set-shifting performance between groups. Specific hypotheses of ER deficits in AN were also not met as performance on individual emotions was comparable between groups. There was an unexpected negative correlation between disgust recognition and set-shifting performance, however, this was only significant across the whole sample. ER performance was not related with any confounding factors. Conclusions: Despite an abundance of research supporting the position of social cognitive difficulties in AN, the current study failed to find global or specific deficits in ER in the present sample. Similarly, ER performance was not related to set-shifting as proposed by neuropsychological models of AN aetiology. Possible explanations for a lack of difference observed using this novel ER task are explored and future directions for evaluating ER in AN are discussed.

A rat model of novelty-seeking phenotype predicts vulnerability to nicotine relapse where locomotor reactivity to novelty is used to rank high (HR) versus low (LR) responders. This dissertation examines the neuropeptidergic and structural substrates of the expression of locomotor sensitization to a low dose nicotine challenge and associated social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Data show the long-lasting nature of behavioral sensitization to nicotine and abstinence-related social anxiety-like behavior in nicotine pre-trained HRs compared to saline pre-trained controls. Moreover, this behavior is accompanied by an imbalance between the brain antistress/antianxiety, i.e., neuropeptide Y (NPY), and stress, i.e., corticotrophin releasing factor (CRF) systems in the amygdala. Moreover, a deficit in NPY signaling marked with decreased NPY and increased NPY Y2 receptor (Y2R) mRNA levels is observed in the hip pocampus, along with mossy fiber reorganization in nicotine pre-trained HRs. Furthermore, a Y2R antagonist administered 1 wk of abstinence reverses these behavioral, molecular and morphological effects in nicotine-exposed HRs. Additionally, the role of amygdalar synaptic plasticity in longlasting social withdrawal is also investigated by assessing brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in HRs following a behaviorally-sensitizing nicotine regimen. A persistent increase in BDNF and spinophilin mRNA levels in the basolateral amygdala (BLA) is observed in nicotine pre-trained HRs even across a long (3-wk) abstinence spanning into young adulthood. This strongly suggests BDNFmediated long-lasting neuroplasticity within the BLA that may regulate abstinence-related negative affect in HRs. / Moreover, a cannabinoid receptor 1 (CB1R) antagonist, AM251 treatment during a short (1-wk) abstinence is ineffective in reversing social anxiety, nicotine-induced neuroplasticity and the neuropeptidergic changes in the amygdala, although it is effective in reversing the expression of locomotor sensitization to challenge nicotine even following a long (3-wks) abstinence. Furthermore, the identical AM251 treatment given during the late phase of a long (3-wk) abstinence further augments social withdrawal and associated BLA plasticity in nicotine pre-trained HRs. These findings implicate neuropeptidergic and neuroplastic changes in the hippocampus and the amygdala in vulnerability to the long-lasting behavioral effects of nicotine in the novelty-seeking phenotype. / by Cigdem Aydin. / Thesis (Ph.D.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

Introdução: As psicoses funcionais são transtornos psiquiátricos cuja principal característica é a perda da capacidade de julgar apropriadamente a realidade em decorrência de alterações na esfera do pensamento, percepção, emoção, movimento e comportamento. A esquizofrenia é o principal destes quadros, com curso crônico e/ou deteriorativo nas esferas social e ocupacional, gerando enormes custos pessoais e financeiros para os pacientes e cuidadores em todo o mundo. Estudos prévios têm mostrado a existência de prejuízos cognitivos em pacientes com transtornos psicóticos já no início da doença, sendo estes mais graves na esquizofrenia. Há evidências de que estes prejuízos são tanto inerentes aos próprios processos da doença quanto secundários ao tratamento. O presente estudo procurou caracterizar o perfil cognitivo de pacientes com psicoses de início recente (n=56), até 3 anos após o primeiro contato com serviços de saúde mental, sendo 34 com esquizofrenia e 22 com psicoses afetivas. Tais grupos de pacientes tiveram seu desempenho cognitivo comparado com o de um grupo controles saudável (n=70), recrutados a partir das mesmas áreas geográficas de São Paulo, Brasil. Até o momento, a maioria dos estudos foi realizada em países em desenvolvimento. Metodologia: A investigação utilizou ampla bateria de testes neuropsicológicos composta por 12 testes agrupados em 8 domínios cognitivos destinados a avaliar respectivamente amplitude atencional, velocidade de processamento da informação, memória verbal, memória visual, memória de trabalho, fluência verbal, funções executivas e funcionamento intelectual. O nível de significância foi de p < 0.05. Resultados: O desempenho do grupo de pacientes com psicoses foi pior do que o dos controles em todas as tarefas cognitivas, com diferenças estatisticamente significativas nas tarefas de velocidade de processamento da informação, memória verbal, fluência verbal e funcionamento intelectual, sendo os déficits mais graves no domínio da memória verbal (p < 0.001). Os grupos esquizofrenia e psicoses afetivas não diferiram significativamente quando comparados entre si. A inclusão do grupo controle na comparação mostrou que os pacientes com esquizofrenia tiveram desempenho significativamente pior do que os controles, o que não ocorreu entre os controles e as psicoses afetivas. A investigação da influência das variáveis demográficas e clínicas mostrou que o desempenho cognitivo foi beneficiado pela escolaridade, na maioria das funções; a idade atual maior teve associação negativa com a memória visual e fluência verbal; gênero masculino teve correlação positiva com a memória de trabalho, tempo de latência para produção de resposta não-convencional, e negativa com a quantidade de erros frente à necessidade de controle de respostas impulsivas.O padrão de tratamento descontínuo beneficiou o desempenho em tarefas de memória verbal, e prejudicou o desempenho na tarefa de antecipação espacial. O abuso/dependência de substâncias não mostrou correlação com nenhuma tarefa, o que ocorreu na análise de regressão. O início do transtorno em idades mais precoces não mostrou prejudicar o desempenho dos pacientes na maioria das tarefas. O tempo de duração de psicose não tratada (duration of untreated psychosis, DUP) mostrou correlação negativa com o tempo de latência para respostas não-convencionais no grupo das psicoses, influenciando negativamente o desempenho nas tarefas de vocabulário, memória verbal imediata e tardia, e a quantidade de respostas impulsivas. No grupo da esquizofrenia, a maior DUP esteve associada a piores resultados nas tarefas de raciocínio não-verbal, memória verbal imediata e tardia, e quantidade de erros no teste de antecipação espacial. Os sintomas negativos influenciaram negativamente os resultados em várias provas, o que não ocorreu com os sintomas positivos. Conclusão: Pacientes com psicoses funcionais de início recente apresentaram prejuízos cognitivos evidentes em comparação aos controles saudáveis. Confirmou-se também a existência de funcionamento cognitivo semelhante entre amostras de países desenvolvidos e em desenvolvimento através de bateria cognitiva ampla. Os prejuízos cognitivos estenderam-se a várias funções, configurando tendência a perfil de déficits generalizados. Embora tenha havido tendência a maior gravidade de déficits no grupo da esquizofrenia, não encontramos diferenças significativas entre os subgrupos diagnósticos, confirmando a presença de déficits cognitivos nas psicoses de início recente, particularmente nas de natureza não-afetiva. / Background and Purpose: Functional psychoses are psychiatric disorders which have as their main characteristic a loss of the ability to properly judge the reality due to alterations of thought, perception, emotion, movement and behavior. The main psychotic disorder is schizophrenia, which usually as a chronic and / or deteriorating course in social and occupational relationships, generating enormous personal and financial costs for the patients and their caretakers all over the world. Previous studies have shown the presence of cognitive deficits in patients at the onset of psychoses, more severely in schizophrenia. There are evidences that those deficits are both related to disease processes and to treatment effects. The present work sought to characterize the neuropsychological profile of patients with recent onset psychoses (n=56), up to 3 years after their first contact with Mental Health Service Care 34 with schizophrenia and 22 with affective psychoses. These patient groups had their results compared to a healthy control group (n=70) recruited from the same geographic area of São Paulo City, Brazil. So far, most studies of neuropsychological functioning in patients with recent onset psychoses have been conducted in high-income countries. Method: The cognitive assessment was conducted using a neuropsychological battery comprising 12 tests, grouped into 8 cognitive domains aimed at assessing respectively intellectual functioning, attentional span, information processing speed, verbal memory, visual memory, working memory, verbal fluency and executive functioning. The significance level was set at p < 0.05. Results: The performance of the psychosis group was worse than that of controls in all cognitive tasks, with statistically significant differences detected in information processing speed, verbal memory, verbal fluency and intellectual functioning tasks, most seriously in the verbal memory domain (p < 0.001). When compared against each other, the schizophrenia and affective psychoses subgroups were not significantly different. The inclusion of the control group in the analysis showed that patients with schizophrenia had significantly worse performance than controls, while such difference was not noticed when controls and affective psychoses groups were compared against. The influence of demographic variables and clinic data showed that cognitive performance was significantly associated with level of schooling in most cognitive tasks; visual memory and verbal fluency were negatively affected by age (deficit increased with age); male gender showed a positive relationship to executive memory and lag time for non-conventional answers, and a negative relationship to mistakes in impulsive answer control needs. Treatment discontinuity was related to better performance in tasks such as verbal memory, but with worse performance in the anticipation space test. Substance abuse or dependence did not influence significantly the performance in any of the tasks individually, but this occurred in the regression analysis. Earlier age of psychosis onset was non significantly related to performance of patients in any of the tasks. The duration of untreated psychoses (DUP) showed negative correlation with the lag time for non-conventional answers in the psychoses group, influencing the performance in tasks as vocabulary, immediate and delayed verbal memory, and the amount of impulsive responses negatively. In schizophrenia group, DUP was associated to worse results in non - verbal reasoning, immediate and late verbal memory, and error quantity in anticipation space test. Several activities were negatively influenced by negative symptoms, what did not occurred with positive symptoms. Conclusion: Patients with recent onset psychosis clearly display cognitive deficits when compared to healthy controls. The existence of similar cognitive functioning between samples studied in developed and developing countries was confirmed through wide cognitive test sets. Cognitive impairment was detected in multiple tasks, showing a widespread trend of deficit profiles. Although there was a tendency towards high severity deficits in the schizophrenia group, we could not find major differences amongst diagnoses subgroups. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non- affective nature.

執行功能指代一系列高水平的認知加工過程。情緒狀態被證明對執行功能具有重要影響。然而，以往研究大多關注消極情緒的影響效應。本研究則借助實驗操作（研究1）和行為問卷（研究2），以國內青少年為被試，考察並比較了不同動機強度的積極情緒如何作用執行功能。此外，執行功能、積極情緒作為獨立的兩個變量，均被證明能夠有效預測青少年的問題行為與社交技能，但是以往鮮有研究探討它們對於這些結果變量的共同預測效力，據此，研究2還對這一問題作了分析。 / 研究1包括兩個實驗，分別考察有/無動機傾向（實驗1）與高/低動機強度的積極情緒（實驗2）對執行功能的影響效應。兩個實驗均為隨機對照設計，並用數字字母任務、Go/No-go任務、Flanker任務、線索回憶任務、N-back任務來測量基本的執行功能，包括定勢轉換、抑制能力、工作記憶刷新。實驗1隨機向每個被試呈現具有不同情感色彩的視頻短片，以此誘發：中性狀態、有動機傾向的積極情緒（興趣）、無動機傾向的積極情緒（逗樂、寧靜）以及動機強度不同的兩種消極情緒（緊張、厭惡）。實驗2則誘發中性狀態以及高/低動機強度的興趣。兩個實驗均測量了情緒誘發前後被試的生理喚醒作為控制變量。研究2用問卷評估了執行功能、不同動機強度的積極情緒、外向/內向的問題行為、五種基本的社交技能，並用回歸模型分析變量間的關係。 / 研究1結果顯示在控制了生理喚醒的效應后：（1）興趣仍顯著損害了所有執行任務表現，興趣動機強度越高，損害越傾向於嚴重；（2）相比中性狀態，逗樂與寧靜均未對執行任務表現造成顯著影響；（3）厭惡較之緊張，前者傾向於更嚴重地損害執行任務表現。研究2的重要結果有，在控制了性別、年齡與大五人格特質的效應后：（1）不論動機強度如何，積極情緒越多就傾向於導致執行功能越差；（2）執行功能在積極情緒與結果變量之間發揮中介作用。可見，動機強度調節著情緒對執行功能的影響效應。研究結果的理論及實踐啓發將在論文中作討論。 / Executive functions (EFs),an umbrella term encompassing various high-level cognitive processes, play an important role in child and adolescent development. Extensive evidence indicates that emotions exert great impact on EFs. However, previous studies mostly concerned the effects of negative emotions on EFs. The primary purpose of this study was to add to the literature by examininghow EFs were influenced by positive emotions that varied in motivational intensity among Chinese adolescents, using an experiment (Study 1) and through behavioral means (Study 2). Given that EFs and positive emotions have been separately proven as strong predictors to problem behaviors and social skills, Study 2 also explored their joint effect in predicting these outcome variables. / Study 1 comprised two experiments, which respectively compared the effects of motivating versus non-motivating positive emotions (Experiment 1 ) and of high-versus low-motivating positive emotions (Experiment 2). Both experiments employed the randomized controlled design and utilized the Number-Letter task, the Go/No-go task, the Flanker task, the Cued Recall task, and the N-back task to assess the fundamental EFs, i.e., set shifting, inhibition-related functioning, and working memory updating. Experiment 1 used film clips to induce hilarity, serenity, interest, anxiety, disgust, and neutral state. Whereas hilarity and serenity are non-motivating positive emotions, interest is the typical motivating positive emotion. Disgust has higher motivational intensity than anxiety. In Experiment 2, three emotional states were induced: low-motivating interest, high-motivating interest, and neutral state. Participants’ physiological arousal (i.e., blood pressure and pulse rate) were measured both before and after the emotion induction in two experiments, in order to control the potential influence of physiological arousal on executive performance. / In Study 2, behavioral measures were used to assess motivating/non-motivating positive emotions, EFs, externalizing/internalizing behaviors, and five basic social skills (i.e., social adaptability, social perception, social confidence, social expressiveness, and impression management). Regression analyses were conducted to explore the interrelationship between these constructs. / Results of Study 1 revealed that after controlling for physiological arousal: (1) interest impaired performance in all five executive tasks, with higher motivational intensity tending to aggravate the impairment; (2) hilarity and serenity, as compared with neutral state, did not cause significantly discrepant performance across all five executive tasks; (3) disgust, as compared with anxiety, tended to cause more severely impaired EFs. Results of Study 2 included that after controlling for demographic and personality variables: (1) high degree of motivating/non-motivating positive emotions tended to predict poor EFs; (2) EFs mediated the relationship between motivating/non-motivating positive emotions and behavioral social outcomes. These results confirmed that motivational intensity modulated the influences of emotions on EFs.Emotions high in motivational tendency were more likely to impair EFs. Possible explanation is that such emotions are linked with specific action urges to acquire desired objects, which could impel the individual to focus cognitive resources on the goal-pursuit and thus narrow down the flexibility and complexity of cognitive processing. Practical implications in simultaneously intervening emotionality and EFs to enhance children and adolescents’ behavioral social functioning will be discussed. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhou, Ya. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 100-113). / Abstracts also in Chinese; appendixes includes Chinese.