<p>Deep brain stimulation (DBS) is an established treatment for movement disorders that has been implanted in more than 40,000 patients worldwide. Despite the successes of DBS, its mechanisms of action are not well understood. Early descriptions of the mechanisms of DBS focused on whether DBS excited or inhibited neurons in the stimulated nucleus. However, changes in the <italic>patterns</italic> of neuronal activity, and not just changes in the rate of neuronal activity, play a major role in the pathology of movement disorders. Therefore, we hypothesized that the temporal pattern of stimulation might be an important factor in determining the effectiveness of DBS. The purpose of this dissertation was to use temporally <italic>irregular</italic> patterns of stimulation (non-regular interpulse intervals) to probe the mechanisms of thalamic DBS in suppressing tremor. The clinical tremor measurements reported in this dissertation represent the first tremor data published during stimulation with temporally <italic>irregular</italic> stimulus trains in human subjects. First, we tested the effects of paired-pulse DBS on tremor suppression in human subjects with essential tremor and on the responses of a computational model of thalamic neurons. DBS was more effective at reducing tremor when pulses were evenly spaced than when there were large differences between intrapair and interpair pulse intervals, suggesting that tremor suppression is dependent on the <italic>pattern</italic> of DBS and not just the average rate of stimulation. Increasing the difference between the intrapair and interpair intervals in the computational model rendered model neurons more likely to fire synchronous bursts. Second, we quantified the effects of the degree of regularity of temporally random stimulus trains in human subjects with tremor. We pioneered an innovative preparation to conduct these experiments--during surgery to replace the implantable pulse generator--which allowed us to establish a direct connection to implanted DBS leads under stable conditions. Stimulus trains were less effective at relieving tremor as the temporal spacing between stimulus pulses in DBS trains became more irregular. However, the reasons for the decreased efficacy of the temporally irregular stimulus trains was not clear. Third, we evaluated the contributions of `<italic>pauses</italic>,' `<italic>bursts</italic>,' and `<italic>irregularity, per se</italic>' to the inability of irregular stimulus trains to suppress tremor. Stimulus trains with <italic>pauses</italic> were significantly less effective at suppressing tremor than stimulus trains without <italic>pauses</italic>, while there were no significant changes in tremor suppression between trains with <italic>bursts</italic> and those without <italic>bursts</italic>, or between trains that were <italic>irregular</italic> and those that were <italic>periodic</italic>. We also developed a computer-based biophysical model of a thalamic network to simulate the response of thalamic neurons to the same temporal patterns of DBS. Trains that effectively suppressed tremor in human subjects also suppressed fluctuations in transmembrane potential at the frequency associated with burst-driven cerebellar inputs to the thalamus. Both clinical and computational findings indicate that DBS suppresses tremor by masking cerebellar burst-driven input to the thalamus.</p><p>The work in this dissertation bridges an important gap between the hypothesis that high-frequency DBS masks pathological activity in the cerebello-thalamo-cortical circuit and the experimentally observed finding that DBS in the subthalamic area suppresses tremor more effectively than DBS in the Vim thalamus proper. We provided experimental and computational evidence that the mechanism of DBS is to mask the burst-driven cerebellar inputs to the thalamus. Hence, the most relevant neuronal targets for effective tremor suppression are the afferent cerebellar fibers that terminate in the thalamus.</p> / Dissertation

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 63-82).

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

The experiments reported in the present thesis investigated the effects of lesions to the anterior nuclei of the thalamus (ATN) on the acquisition of two spatial, working memory tasks performed on the eight-arm radial maze. In the task used in Experiment 1 and 2, the animals were required to discriminate and remember all the eight arms of the maze simultaneously. Lesions of the ATN produced impairments in the acquisition of this task, but the degree of impairment depended on the amount of damage within this region. In the task used in Experiment 3, the animals were required to discriminate and remember only two arms at once. Lesions of the ATN were shown to impair its acquisition even though performance was facilitated by the addition of visual intra-arms cues. These experiments suggest that the ATN may be involved in spatial learning and in the retention of non-specific information over time.

Thesis (Ph. D. in Neuroscience)--Vanderbilt University, Aug. 2006. / Title from title screen. Includes bibliographical references.

Thesis (Ph.D.)--University of Florida, 2004. / Title from title page of source document. Document formatted into pages; contains 96 pages. Includes Vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Florida, 2005. / Typescript. Title from title page of source document. Document formatted into pages; contains 119 pages. Includes Vita. Includes bibliographical references.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 88-92). Also available via the World Wide Web.

The auditory thalamus or medial geniculate body (MGB) is the final brain structure for acoustic information processing prior to, and functioning in reciprocity with, auditory cortex. MGB neurons process and gate aspects of acoustic stimuli, functions which depend partly on GABAergic inhibition. To characterize these properties, the inhibitory neurotransmitters involved and how they may be altered in the aged MGB, specific aims sought to: 1) determine the presence of functional high affinity GABAA receptors (GABAARs) in the MGB, 2) determine whether GABAAR function is altered with age and 3) determine to what degree MGB neurons of awake young and aged rats display stimulus-specific adaptation (SSA). Inhibitory neurotransmission is essential for accurate coding of acoustic information in the central auditory system, but appears disrupted in the aged. The present study required the development of a slice preparation that permitted whole cell recordings from juvenile, young adult and aged rat MGB neurons. The presence of high affinity GABAARs and the impact of aging on synaptic and high affinity GABAAR function were examined. Low concentrations of gaboxadol (GABAAR agonist) activated a gabazine-sensitive (GABAAR antagonist) tonic current, providing support for the expression of functional high affinity GABAARs in the MGB. Activation of high affinity GABAARs expressed by MGB neurons decreased input resistance, hyperpolarized resting membrane potential, reduced evoked firing rates and induced a transition from tonic to burst firing mode. In aged MGB neurons there was a significant 50.4% reduction in GABAAR-mediated tonic Cl- current. Synaptic GABAAR inhibition appeared differentially affected by age in lemniscal and non-lemniscal auditory thalamus although gramicidin perforated patch-clamp recordings indicated neuronal Cl- homeostasis was unaltered with age. Anesthetized rodent MGB single units show SSA, during which the firing rate in response to repetitive stimuli decreases/adapts over time but low probability stimuli (i.e. novel) continue to elicit robust responses. To examine the presence of SSA in the MGB of awake rats, a multichannel single unit recording preparation was implemented. This approach involved implanting young and aged rats with an array of four individually-advanceable tetrodes in order to evaluate SSA by recording responses to a frequency oddball paradigm and a random/non-random frequency range paradigm. Single units in the MGB of awake FBN rats were found to display SSA, which was stronger in the non-lemniscal than lemniscal regions of the MGB. SSA was most dramatic at lower intensities where 27 of 57 (47%) young adult single units and 28 of 54 (52%) aged single units displayed SSA. However, there were no significant age-related differences in average magnitude or time course of SSA of MGB single units studied. Data from aims 1 and 2 provide the initial description of functional high affinity GABAARs in the rodent MGB and the plasticity of these receptors with age. These data suggest that GABAAR subtype-selective agonists or modulators could be used to augment MGB inhibitory neurotransmission, possibly improving speech understanding for a subset of elderly individuals. Findings from aim 3 were the first to show that SSA by MGB neurons is not dependent on arousal level nor on the anesthetized state, but is a common response in the MGB of awake rats. SSA did not appear to be overtly altered in the aged auditory thalamus of awake rats.

Orientador: Fernando Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-18T18:20:03Z (GMT). No. of bitstreams: 1 Pedro_Tatiane_M.pdf: 1473821 bytes, checksum: a5814a9d00faf77f9e24efe5ced0e38b (MD5) Previous issue date: 2011 / Resumo: A Doença de Alzheimer (DA) caracteriza-se, por um quadro demencial com declínio das funções cognitivas como perda de memória, alterações no comportamento, linguagem e atenção, bem como desorientação em tempo e espaço, em conseqüência da degeneração lenta e progressiva de neurônios colinérgicos do núcleo basal de Meynert, da formação de placas insolúveis de proteína beta-amilóide entre as células nervosas e, dentro delas, de redes neurofibrilares de proteína tau. É a principal causa de demência na população idosa, sendo responsável por cerca de 60 a 70% de todas as demências. Sua prevalência vem aumentando seguidamente por conta do aumento da população idosa. O Comprometimento Cognitivo Leve Amnéstico (CCLa) é um estado dito "pré-demencial", com alteração em pelo menos uma esfera cognitiva, mas sem prejuízo da vida social ou ocupacional. Em nosso estudo, avaliamos 3 grupos de 15 indivíduos: um grupo de controles normais, um grupo com DA leve e um grupo de CCLa. Avaliamos o padrão de atrofia cerebral desses pacientes em relação a controles por volumetria através de segmentação manual (softaware Display) do corpo caloso, tálamo e estruturas mesiais temporais (hipocampo e córtex entorrinal). Avaliamos também o padrão de atrofia correlacionados com os testes neuropsicológicos, como o Teste de Nomeação de Boston (TNB), Teste de Mini Exame Mental (MEEM), Teste de nomeação de figuras Digit Spand (direto) e Spani (indireto), Teste de Similaridade do CAMCOG e Fluência Verbal (FV) para categoria animais além de outros domínios cognitivos. Na comparação entre pares de grupos, observamos: (no primeiro grupo em relação ao segundo): DA leve x CCLa- atrofia no córtex entorrinal esquerdo; DA leve x Controle -atrofia no tálamo direito, hipocampo e córtex entorrinal bilateral; CCla x Controle -atrofia no hipocampo bilateral e córtex entorrinal direito. O volume do corpo caloso correlacionou- se com Digit spand e BNT, o volume do tálamo direito com MEEM; o volume do tálamo esquerdo com Digit Spand;o hipocampo direito com CAMCOG, Digit spand, FV e RAVALTA7; o volume do hipocampo esquerdo com Digit Spani, FV e RAVALA7; o córtex entorrinal direito com MEEM. Não houve correlação entre o córtex entorrinal esquerdo e os demais testes. Este estudo confirma o acometimento do tálamo e corpo caloso, na DA leve e CCLa. A correlação anatomo funcional da atrofia das estruturas estudadas e testes cognitivos, pode vir a contribuir em estudos futuros na busca de marcadores diagnósticos para a CCLa e DA leve / Abstract: Alzheimer's Disease (AD) is characterized by dementia with cognitive decline. Its prevalence has been increasing as the general population is aging. Amnestic Mild Cognitive Impairment (aMCI) is a condition called "pre-dementia", with changes in at least one cognitive sphere but no impairment in occupational or social life. We studied three groups of 15 individuals: a normal control group, a group with mild AD and a group with aMCI. This study assessed the patterns of brain atrophy in these patients, comparing them to controls, by manual segmentation volumetry (software Display) of the corpus callosum, thalamus and mesial temporal structures (the hippocampus and entorhinal cortex). We also evaluated the pattern of atrophy correlated with neuropsychological tests, such as Boston Test (BNT), Test of Mini Mental Examination (MMSE), Digit Spandi (forward) and Spani (indirect) picture naming tests, CAMCOG similartiy test and Verbal Fluency (VF) for animal category and other cognitive domains. The comparison between groups revealed (always in the first relative to the second pair): mild AD vs aMCI - atrophy in the left entorhinal cortex; mild AD vs Control - atrophy in right thalamus, bilateral hippocampus and entorhinal cortex; aMCI vs Control - bilateral atrophy in the hippocampus and right entorhinal cortex. The volume of the corpus callosum correlated with the Digit spand, RAVLTRC_FP BNT and the volume of the right thalamus with MMSE, the volume of the left thalamus with age, and Digit Spandi RAVLTA7, the right hippocampus with age, MMSE, CAMCOG, BNT, Digit Spani, FV and RAVALTA7, and RAVLT_RC RAVLT_RC_FP; the volume of the left hippocampus with MMSE, Digit Span, FV, and BNT RAVALA7: the right entorhinal cortex with MMSE, visuospatial, digit span, verbal fluency, BNT, RAVLTA7, the entorhinal cortex left with Spatial and Visuo RAVLA7, there was no correlation between the left entorhinal cortex and other tests on the simple correlation. This study confirms the link between the thalamus and corpus callosum, mild AD and aMCI. The anatomic-functional correlation of atrophy in the structures studied here with cognitive tests, may contribute for future studies in search of diagnostic markers for aMCI and mild Alzheimr's Disease / Mestrado / Neurociencias / Mestre em Fisiopatologia Médica