The basal ganglia are a set of subcortical nuclei in the forebrain of vertebrates that are highly conserved among mammals. Classically, dysfunction in the basal ganglia has been linked to motor abnormalities. However, it is now widely recognized that in addition to their role in motor behavior, these set of nuclei play a role in reinforcement learning and motivated behavior as well as in many diseases that present with abnormal motivation. In this dissertation, I first provide a review of the literature that describes the current state of research on the basal ganglia and the background for the original studies I later present. I describe the anatomy and physiology of the basal ganglia, including how structures are interconnected to form two parallel pathways, the direct and the indirect pathways. I further review published studies that have investigated how the basal ganglia regulate motor behavior and motivation. And finally, I also summarize findings on how disruption in basal ganglia circuitry function has been linked to a number of neuropsychiatric diseases, with special focus on the symptoms of schizophrenia. I then present original data and discuss the results of three studies investigating basal ganglia function and behavior. In the first study, I investigated the bridging collaterals, axon collaterals of direct-pathway medium spiny neurons (dMSNs) in the striatum that target the external segment of the globus (GPe), the canonical target of indirect-pathway medium spiny neurons (iMSNs). Previous work in the Kellendonk laboratory has linked these collaterals to increased dopamine D2 receptor (D2R) function and increased striatal excitability, as well as to abnormal locomotor response to stimulation of the direct pathway. I expanded on these findings by first demonstrating that bridging collaterals form synaptic contacts with GPe cells. I was also able to generate a viral vector to selectively increase excitability in specific populations of MSNs. I used this virus to show that chronically increasing excitability of the indirect pathway, but not the direct pathway, leads to a circuit-level change in connectivity by inducing the growth of bridging collaterals from dMSNs in the GPe. I also confirmed that increased density of bridging collaterals are associated with an abnormal locomotor response to stimulation of striatal dMSNs and further demonstrated that chronic pharmacologic blockade of D2Rs can rescue this abnormal locomotor phenotype. Furthermore, I found that motor training reverses the enhanced density of bridging collaterals and partially rescue the abnormal locomotor phenotype associated with increased collaterals, thereby establishing a new link between connectivity in the basal ganglia and motor learning. In the second study, I conducted a series of experiments in which I selectively increased excitability of the direct or indirect pathway in specific striatal sub-regions that have been implicated in goal-directed behavior, namely the DMS and NA core. I found that this manipulation was not sufficient to induce significant effects in different behavioral assays of locomotion and motivation, including the progressive ratio and concurrent choice tasks. These findings also suggest that increased bridging collateral density does not have a one-to-one relationship with the motivational deficit of D2R-OEdev mice, as previously hypothesized. In the third and final study, my original aim was to determine whether the motivational deficit of D2R-OEdev mice, induced by upregulation of D2Rs in the striatum, could be reversed by acutely activating Gαi-coupled signaling in the indirect pathway in these animals. I found that this manipulation increased motivation in D2R-OEdev mice but also in control littermates. This effect was due to energized behavioral performance, which, however, came at the cost of goal-directed efficiency. Moreover, selective manipulation of MSNs in either the DMS or NA core showed that both striatal regions contribute to this effect on motivation. Further investigation aimed at understanding how Gαi-coupled signaling affects striatal circuit function revealed that activating a Gαi-coupled receptor did not lead to a significant change in somatic MSN activity in vivo or to a change in neuronal excitability in vitro. In contrast, the GPe, which receives monosynaptic inhibition from the indirect pathway, showed disinhibited activity when Gαi signaling was activated in striatal iMSNs. In addition, as drug therapies for psychiatric diseases are not usually given acutely but involve long-term, continuous administrations, I also studied how chronically decreasing function of iMSNs would affect behavior. I showed that chronically activating a Gαi-coupled receptor in iMSNs does not lead to a measurable effect on locomotion or motivation, a behavioral desensitization response that can be recovered within 48 h and may be due to receptor desensitization to the drug or circuit-level compensation to a chronic decrease in iMSN function. Finally, I conclude this dissertation with a general discussion addressing how the findings from each study can be related to each other to provide a more complete understanding of how basal ganglia function regulate behavior, how disruption in the basal ganglia can underlie neuropsychiatric disease, and how strategies to target basal ganglia function should be employed to treat disorders of motivation. I conclude this dissertation by proposing new avenues of research for further exploring my findings.

The acute nervous system toxicity of organophosphate (OP) pesticides is well described. However, the reported long-term effects of OP pesticides on the nervous system are inconsistent. This inconsistency may be due to imprecise estimates of pesticide exposure, variability of central nervous system (CNS) and peripheral nervous system (PNS) assessment, small samples, and poor control of confounding. The primary goal of this research was to examine the association between long-term OP pesticide use on CNS and PNS function among pesticide applicators. An additional goal was to examine the association between high pesticide exposure events (HPEEs), which typically do not result in acute toxicity, and CNS function. Study participants were recruited from among applicators enrolled in the Agricultural Health Study (AHS) in Iowa and North Carolina. In 2006-2008, 701 male pesticide applicators completed a battery of neurobehavioral (NB) and neurological tests. Information about individual pesticide use was obtained from previous AHS interviews and a questionnaire administered during NB testing. Associations between pesticide use and neurological outcomes were estimated with linear and logistic regression models while controlling for covariates. When associations were examined between agent-specific pesticide use and nine NB tests, significantly poorer performance was observed on four tests and significantly better performance on five tests. Additionally, for some pesticides, we observed differential associations by state, suggesting that regional differences in pesticide practices may influence neurotoxicity. Overall, our results did not provide strong evidence that OP pesticide use was associated with adverse NB test performance. A history of at least one HPEE was reported by 23 percent of participants. Significant adverse associations were observed between HPEEs and two of the nine NB tests. Participants with HPEEs were, on average, 4.9 seconds slower on a test of visual scanning/processing, and 2.2 seconds slower on a test of visual scanning/motor speed. Overall, small but meaningful associations were observed between HPEEs and adverse CNS function. When associations were examined between pesticide use and PNS function, five of six neurological physical examination outcomes were associated with ever-use of one or more OP pesticides. Odds ratios ranged from 1.9 to 3.1. However, mostly null associations were observed between OP pesticide use and electrophysiological tests, hand strength, sway speed and vibrotactile threshold. This study provides some evidence that long-term exposure to OP pesticides is associated with impaired PNS function. In summary, our results suggest that exposure to a few individual OP pesticides as well as HPEEs may contribute to adverse neurological function. The observed exposure-effect associations were present after adjustment for confounding and were independent of past-diagnosed pesticide poisoning. We believe this research contributes important new evidence to an inconsistent literature. Reducing pesticide exposure and preventing HPEEs among pesticide applicators remain important public health goals.

No description available.

Thesis (Ph. D.)--University of California, San Diego, and San Diego State University, 2005. / Vita. Includes bibliographical references (leaves 211-233).

Thesis (Ph.D.)--Uppsala Universitet, 2009. / This website links to the complete document in PDF format. Title from title screen (viewed on November 21, 2009). Includes bibliographical references.

Schizophrenia is a complex mental disorder characterised by positive symptoms such as hallucinations and psychosis, negative symptoms such as avolition and anhedonia, and cognitive defects. Schizophrenia risk has a genetic component, and it is likely that this is caused by interaction between numerous genes with individually small effects. Environment also plays a role; factors associated with schizophrenia include drug use, prenatal stressors and living environment. Candidate genes linked to schizophrenia have been identified through recent GWAS of human populations with the disorder, including ANK3, TCF4 and CACNA1C. GWAS associations alone are not sufficient to identify these as definitive risk genes for the disease. In order to validate these findings, animal models (in particular the mouse) can be used to study the effect of mutations in these genes of interest. Knockouts of these genes in the mouse are lethal, so we have used the ENU mutagenesis DNA archive at MRC Harwell to screen for additional allelic variants expressing more subtle and varied behavioural phenotypes. Endophenotypes associated with schizophrenia and bipolar disorder, such as anxiety, cognitive deficits and sensorimotor gating deficits, can be characterised in these mutants and, together with molecular characterisation, this can validate these genes as risk factors. While mutations in Ank3 and Tcf4 proved to be non-functional, two mutations in Cacna1c have been associated with anxiety phenotypes and differences in EEG power spectra, as well as causing a cardiac phenotype.

Orientador: Vanda Maria Gimenes Gonçalves / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T15:33:08Z (GMT). No. of bitstreams: 1 Carvalho_MariaImaculadaMerlinde_M.pdf: 5079620 bytes, checksum: 57af6f7ff10156c4b75c019bc0f1d9e2 (MD5) Previous issue date: 2009 / Resumo: Essa pesquisa foi proposta tendo como objetivo o estudo dos sinais neurológicos, utilizando semiologia neurológica detalhada, em um grupo de escolares portadores de dislexia do desenvolvimento, comparados a um grupo sem queixa escolar. O grupo disléxico foi constituído por 12 escolares com diagnóstico de dislexia do desenvolvimento comprovada pelas avaliações neuropsicológica, fonoaudiológica e neurológica; projeto de pesquisa aprovado pelo Comitê de Ética em Pesquisa da instituição e os pais assinaram o Termo de Consentimento Livre e Esclarecido; idade cronológica mínima de 8 anos. O grupo controle foi composto por escolares bons leitores, sem dificuldades ou distúrbios de aprendizagem, indicados por professores e avaliados pela fonoaudióloga, pareados com os disléxicos por gênero e idade. Foram excluídos os escolares com diagnóstico de distúrbio de aprendizagem, com deficiência auditiva e visual, deficiência mental, síndromes genéticas ou grandes malformações, não comparecimento à primeira avaliação após três convocações sucessivas. Foram avaliados pelo Exame Neurológico Tradicional (ENT), Exame Neurológico Evolutivo (ENE) e Quick Neurological Screening Test II (QNST-II). O ENT foi normal em todos os escolares do grupo controle e em três do grupo disléxico; a alteração mais freqüente foi leve hipotonia muscular global ou localizada em membros superiores, observada em oito escolares como um achado isolado ou associado a outras alterações. O ENE foi normal em todos os escolares do grupo controle e alterado em todos do grupo disléxico. Nenhum participante apresentou dificuldade em equilíbrio dinâmico. Dentre os setores alterados os mais freqüentes foram persistência motora e tono muscular. As alterações detectadas foram heterogêneas, não constituindo um padrão ao exame do grupo disléxico. O QNST-II foi normal em todos os escolares do grupo controle e alterado em todos os participantes do grupo disléxico. O QNST-II identificou o grupo disléxico, com mediana de pontuação total 33 ± 11,95, classificado como desvio moderado e o grupo controle com pontuação total de 13,5 ± 4,57, classificado como normal, com diferença significativa entre os grupos (p-valor = 0,0005, teste de Wilcoxon). Alguns subtestes mostraram mediana de pontuação significativamente maior no grupo disléxico: habilidade manual, reconhecimento e reprodução de figuras, reprodução de formas na palma da mão, padrões sonoros, movimentos manuais reversos rápidos e repetitivos, extensão de braços e pernas, ficar em uma só perna, irregularidades comportamentais. Concluiuse que o uso desta técnica de avaliação neurológica acrescentou novos elementos semióticos no estudo do grupo disléxico. / Abstract: The objective was to propose a study of neurological signs, using detailed neurological semiology in a group of school aged children that had developmental dyslexia, compared to a group without learning disabilities. A group of 12 students were identified as dyslexic group, (1 girl and 11 boys), after neuropsychological, speech therapist and neurological evaluations. Ethical approval was obtained from the Research Ethics Committee of the institution and the families provided full informed consent; minimal chronological age of 8 years. They were matched on age and sex with the control group recruited in regular classroom placement, who were reading at grade level according to their school-teacher and the evaluation of the speech therapist. Those with learning disabilities, mental retardation, visual deficiency and hearing loss, genetic syndromes or malformations, or absence after three invitations were excluded. The Traditional Neurological Examination (TNE), Neurological Evolutional Examination (NEE) and Quick Neurological Screening Test II (QNST II) were used. The TNE was normal in the control group and in three of the dyslexic group. Muscular hypotonia was the most frequent alteration, observed in 8 schoolchildren. The NEE was normal in the control group and showed alterations in the entire dyslexic group. Nobody showed alteration in dynamic balance. The most altered items were the motor persistence and muscle tone. There was heterogeneous alterations, without a standard examination for the dislexic group. QNST II was normal in the control group and showed alterations in the entire dyslexic group. QNST II total scores correctly identified the dyslexic group, with median punctuation of total score 33 ± 11,95, classified as moderate discrepancy (MD) and the control group with 13,5 ± 4,57, classified as normal range (NR). The dyslexic group showed significantly higher scores than the control group (p-value = 0,0005, Wilcoxon test). Some subtests acted as a discriminator between the groups, with significantly higher scores in the dyslexic group in the subtests: hand skill, figure recognition and production, palm form recognition, sound patterns, rapidly reversing repetitive hand movements, arm and leg extension, stand on one leg, behavioral irregularities. We concluded that this technique of neurological evaluation added new semiotic elements in the study of the dyslexic group. / Mestrado / Neurologia / Mestre em Ciências Médicas

Introdução: Neurocistcercose (NC) é a doença parasitária do SNC mais frequente no mundo. Afeta mais de 50 milhões de pessoas. No entanto, algumas de suas manifestações clínicas, como comprometmento cognitivo e demência, ainda permanecem caracterizadas de modo incompleto, sem que haja estudos controlados disponíveis na literatura até o momento. Objetvos: Investigar a frequência e o perfil clínico do comprometimento cognitivo associado à NC ativa, comparando o desempenho em testes de avaliação cognitiva de pacientes com a doença ao de controles saudáveis (CS) e de pacientes com epilepsia criptogênica (EC). Métodos: Quarenta pacientes (idade média = 39,25 ± 10,50 anos), com diagnóstco de NC ativa segundo critérios absolutos à ressonância magnética (RM) de crânio e sem tratamento antiparasitário prévio foram submetdos à avaliação cognitiva e funcional extensas, sendo comparados a 49 CS e 28 pacientes com EC emparelhados por idade, nível educacional e frequência de crises epilépticas (grupo EC). Resultados: Pacientes com NC apresentaram comprometimento significativo em relação ao grupo CS nos testes que avaliam funções executivas, memória verbal e não verbal, praxia construtiva e fluência verbal (p<0,05). Demência foi diagnosticada em 12,5% dos pacientes com NC de acordo com os critérios do DSM-IV. Os doentes do grupo NC apresentaram desempenho significativamente inferior em testes de memória operacional, memória episódica verbal, funções executivas, nomeação, praxia construtiva e orientação visual-espacial, quando comparados àqueles do grupo EC. Não se encontrou correlação entre as alterações nos testes cognitivos nos pacientes com NC e os achados à RM (carga de doença, tipo e localização das lesões). Conclusões: Comprometimento cognitivo foi muito frequente na amostra de pacientes com NC avaliada, sendo que demência foi identificada em uma proporção significativa dos doentes. Estes dados aumentam o nosso conhecimento sobre a apresentação clínica da NC e sobre seu potencial impacto na saúde pública. / Introducton: Neurocysticercosis (NCYST) is the most frequent CNS parasitic disease worldwide, afecting more than 50 million people. However, some of its clinical findings, such as cognitive impairment and dementia, remain poorly characterized, with no controlled studies conducted so far. We investigated the frequency and the clinical profile of cognitive impairment and dementia in a sample of NCYST patents in comparison to cognitvely healthy controls (HC) and to cryptogenic epilepsy (CE) patents. Methods: Forty treatment-naïve NCYST patients aged 39.25 ± 10.50 years and fulfilling absolute criteria for definitive active NCYST on magnetic resonance imaging (MRI), underwent a comprehensive cognitive and functional evaluation and were compared to 49 HC and 28 CE patients of similar age, educational level, and seizure frequency. Results: NCYST patients displayed significant impairment in executive functions, verbal and non-verbal memory, constructive praxis, and verbal fluency when compared to HC (p<0.05). Dementia was diagnosed in 12.5% of NCYST patients according to the DSM-IV criteria. When compared to CE patients, NCYST patients presented altered working and episodic verbal memory, executive functions, naming, verbal fluency, constructive praxis, and visual-spatal orientation. No correlation emerged between cognitive scores and number, localization or type of NCYST lesions on MRI. Conclusions: Cognitive impairment was ubiquitous in this sample of active NCYST patients. Antepileptic drug use and seizure frequency could not account for these features. Dementia was present in a signifcant proportion of patients. These data broaden our knowledge on the clinical presentations of NCYST and its impact in public health

The present study is a cross-validation of the Validity-10 embedded symptom validity indicator from the Neurobehavioral Symptom Inventory (NSI) for the detection of questionable response validity during evaluation for mild traumatic brain injury (TBI). The sample and data derived from a three-site Veterans Affairs (VA) parent study to validate the TBI Clinical Reminder, a routine set of questions asked of all recently returned veterans at VA facilities to screen for history of TBI. In the parent study, veterans recently returned from Iraq and Afghanistan underwent an evaluation for TBI with a physician and completed an assessment battery including neuropsychological tests of cognitive performance and indicators of symptom and performance validity, psychiatric assessment measures, a structured interview for post-traumatic stress disorder (PTSD), and various behavioral health questionnaires. The present study estimated the test operating characteristics of Validity-10, using NSI results gathered during the physician evaluation to compute Validity-10 scores, and using results on several other measures of symptom and performance validity from the assessment battery as criteria for questionable response validity. Only individuals who had positive screen results for TBI on the TBI Clinical Reminder prior to full evaluation were included in the present sample. Sensitivity of Validity-10 to questionable validity was moderately high (.60 - .70) to excellent (.90 - 1.00) at high levels of specificity (> .80). Effects of different base rates of and different criteria for questionable validity on the utility of Validity-10 were explored as well. Chi-square analyses to determine the effect of PTSD symptoms on the utility of Validity-10 demonstrated overall classification accuracy in general, and false positive rate in particular, were relatively poorer when used with individuals who reported significant PTSD symptoms. Overall, these findings support the use of Validity-10 (at cut score Validity-10 ≥ 19) to identify those veterans being evaluation for mild TBI in the VA system who should be referred for comprehensive secondary evaluation by a clinical neuropsychologist using multiple forms of symptom and performance validity testing. Further studies of the effects of PTSD symptoms on the accuracy of Validity-10 for this purpose are recommended.

No description available.