Atualmente se tem bem estabelecido o tratamento para Doença de Parkinson, dentre eles o DBS (Deep Brain Stimulation). Embora haja controvérsias, muitos estudos têm demonstrado os efeitos adversos do DBS sobre a cognição, humor e comportamento. Assim, este estudo buscou investigar a associação entre os prejuízos cognitivos no pós-operatório e a volumetria cerebral em pacientes parkinsonianos submetidos a DBS, verificando se a correlação entre ambos pode ser considerada fator de risco para os prejuízos encontrados no pós-operatório. Fizeram parte da população estudada 25 indivíduos, 80% do sexo masculino, que foram submetidos ao procedimento cirúrgico de estimulação cerebral profunda (DBS) no Hospital de Clínicas de Porto Alegre (HCPA), em Porto Alegre entre 2012 e 2015. Estes sujeitos foram submetidos a uma bateria de testes cognitivos, bem como a testes clínicos e a ressonância magnética computadorizada nos períodos pré e pós-operatório em 6 meses. Os dados foram analisados através de estatísticas descritivas, coeficiente de correlação de Pearson e Teste t. Os resultados serão considerados significativos a um nível de significância máximo de 5% (p≤ 0,05) e o software estatístico utilizado para a análise será o SPSS versão 20.0. Quanto aos aspectos cognitivos avaliados, somente a fluência verbal fonêmica mostrou redução significativa entre os períodos pré e pós-operatório (p=0,003). A transfixação dos ventrículos foi associada à perda na fluência verbal semântica (p=0,009) e na memória (p=0,016) no pós-operatório. A presença de lesão na substância branca foi associada ao maior prejuízo na função executiva (p=0,017), fluência verbal semântica (p=0,039) e memória (p=0,050). Conclusão: Os prejuízos na fluência verbal semântica e memória no pós-operatório foram associados à presença de lesão na substância branca e a transfixação dos ventrículos pelo cabo com 6 eletrodos. A perda na função executiva foi associada a presença de lesão na substância branca. Os danos na fluência verbal fonêmica no pós-operatório, embora difiram estatisticamente, não foram associados a quaisquer achados da RM. / Currently, the treatment for Parkinson's Disease has been well established, among them DBS (Deep Brain Stimulation). Although controversial, many studies have demonstrated the adverse effects of DBS on cognition, mood, and behavior. Thus, this study sought to investigate the association between cognitive impairment in the postoperative period and cerebral volume in patients with Parkinson's disease who underwent DBS, and whether the correlation between the two can be considered as a risk factor for the possible postoperative losses. Twenty-five subjects, 80% male, who underwent deep brain stimulation (DBS) at the Hospital de Clínicas in Porto Alegre, Porto Alegre, between 2012 and 2015, were submitted to a cognitive battery, as well as clinical trials and computerized magnetic resonance imaging in the preoperative and postoperative periods at 6 months. Data were analyzed through descriptive statistics, Pearson's correlation coefficient and t-test. The results will be considered significant at a maximum significance level of 5% (p≤0.05) and the statistical software used for analysis will be SPSS version 20.0. Concerning the cognitive aspects evaluated, only phonemic verbal fluency showed a significant reduction between the pre and postoperative periods (p = 0.003). The transfixation of the ventricles was associated with loss of semantic verbal fluency (p = 0.009) and memory (p = 0.016) in the postoperative period. The presence of lesion in the white matter was associated with greater impairment in executive function (p = 0.017), semantic verbal fluency (p = 0.039) and memory (p = 0.050). Conclusion: The losses in the semantic verbal fluency and memory in the postoperative period were associated with the presence of white matter lesion and the transfixation of the ventricles by the cable with electrodes. The loss of executive function was associated with the presence of injury in the white matter. Damage to phonemic verbal fluency in 8 the postoperative period, although statistically different, was not associated with any MRI findings.

abstract: The efficacy of deep brain stimulation (DBS) in Parkinson's disease (PD) has been convincingly demonstrated in studies that compare motor performance with and without stimulation, but characterization of performance at intermediate stimulation amplitudes has been limited. This study investigated the effects of changing DBS amplitude in order to assess dose-response characteristics, inter-subject variability, consistency of effect across outcome measures, and day-to-day variability. Eight subjects with PD and bilateral DBS systems were evaluated at their clinically determined stimulation (CDS) and at three reduced amplitude conditions: approximately 70%, 30%, and 0% of the CDS (MOD, LOW, and OFF, respectively). Overall symptom severity and performance on a battery of motor tasks - gait, postural control, single-joint flexion-extension, postural tremor, and tapping - were assessed at each condition using the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III) and quantitative measures. Data were analyzed to determine whether subjects demonstrated a threshold response (one decrement in stimulation resulted in ≥ 70% of the maximum change) or a graded response to reduced stimulation. Day-to-day variability was assessed using the CDS data from the three testing sessions. Although the cohort as a whole demonstrated a graded response on several measures, there was high variability across subjects, with subsets exhibiting graded, threshold, or minimal responses. Some subjects experienced greater variability in their CDS performance across the three days than the change induced by reducing stimulation. For several tasks, a subset of subjects exhibited improved performance at one or more of the reduced conditions. Reducing stimulation did not affect all subjects equally, nor did it uniformly affect each subject's performance across tasks. These results indicate that altered recruitment of neural structures can differentially affect motor capabilities and demonstrate the need for clinical consideration of the effects on multiple symptoms across several days when selecting DBS parameters. / Dissertation/Thesis / Ph.D. Bioengineering 2013

Movement disorders are a group of syndromes that often arise due to neurological abnormalities. Approximately 40 million Americans are affected by some form of movement disorder, significantly impacting patients’ quality of life and their ability to live independently. Deep brain stimulation (DBS) is one treatment that has shown promising results in the past couple decades, however, the currently used open-loop system has several drawbacks. By implementing a closed-loop or adaptive DBS (aDBS) system, the need for expensive parameter reprogramming sessions would be reduced, side-effects may be relieved, and habituation could be avoided. Several biomarkers, for example signals or activity derived from electroencephalogram (EEG), could potentially be used as a feedback source for aDBS. Here, we attempted to characterize cortical EEG potentials in healthy subjects performing six tasks that are difficult for those with movement disorders. Using a 32-channel EEG cap with an amplifier sampling at 500 Hz, we performed our protocol on 11 college-aged volunteers lacking any known movement disorder. For each task, we analyzed task-related power (TRP) changes, spectrograms, and topographical maps. In a finger movement exercise, we found task-related depression (TRD) in the delta band at the F4 electrode, as well as TRD at the C3 electrode in the alpha band during a pencil-pickup task, and TRD at the F3 electrode in the beta band during voluntary swallowing. While delta-ERD in the finger movement exercise was likely due to ocular artifact, the other significant results were in line with what relevant literature would predict. The findings from the work, in conjunction with a future study involving movement disorder patients, can provide insight into the use of EEG as a feedback source for aDBS. Keywords: EEG, electroencephalography, neurostimulation, deep brain stimulation, movement disorders, closed-loop DBS, adaptive DBS, aDBS

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Objective: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson’s disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of our study was therefore to evaluate whether 1) DAT availability changes within one year of STN-DBS and whether 2) the clinical outcome is predictable by DAT availability before surgical procedure (pre-op). Methods: Twenty-seven PD patients (age: 62.7 ± 8.9 years (y); duration of illness: 13.0 ± 4.9y; PD subtypes: akinetic-rigid n=11, equivalence n=13, tremor-dominant n=3) underwent [123I]FP-CIT single-photon emission computed tomography (SPECT) pre-op and one year after STN-DBS (post-op). DAT availability (specific-to-unspecific binding ratio, SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side. Results: 1) Unified Parkinson’s Disease Rating Scale (UPDRS) III (pre-op on: on medication; pre-op off: off medication; post-op on/on: on medication/on stimulation; post-op on/off: on medication/off stimulation) improved significantly (pre-op on: 25.6 ± 12.3, pre-op off: 42.3 ± 15.2, post-op on/off: 41.4 ± 13.2; post-op on/on: 16.1 ± 9.4; pre-op on vs. post-op on/on: p = 0.006) while L-dopa equivalent daily dose (LEDD) was reduced (pre-op 957 ± 440 mg, post-op 313 ± 189 mg; p < 0.001). SBR did not differ significantly before and one year after DBS, regardless of PD subtypes. 2) Pre-op DAT availability was not related to the change in UPDRS III but the change in DAT availability was significantly correlated with the change in UPDRS III (contralateral head of the caudate VOI: p=0.014, contralateral putamen VOI: p=0.018). Conclusion Overall, DAT availability did not change significantly after one-year of STN-DBS. However, on an individual base, the improvement in UPDRS III was associated with an increase of DAT availability while DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of pre-op DAT availability can become a reliable predictor for successful STN-DBS has to be evaluated in larger study cohorts.:Introduction 2 1.1 Parkinson’s Disease Pathophysiology 2 1.2 Parkinson’s Disease Clinical Manifestation 4 1.2.1 Parkinson’s Disease Diagnosis 5 1.2.1.1 Unified Parkinson’s Disease Rating Scale 5 1.2.1.2 Imaging 6 1.2.2 Parkinson’s Disease Subtypes 6 1.3 Parkinson’s Disease Therapy 7 1.3.1 Pharmacologic Therapy 7 1.3.2 Surgical Therapy – Deep Brain Stimulation 9 1.3.2.1 Patient Selection 9 1.3.2.2 Operative Technique 9 1.3.2.3 Efficacy 10 1.3.2.4 Complications 11 1.3.2.5 Mechanism of action 11 2 Publication 15 3 Summary of Work 23 3.1 Background 23 3.2 DAT availability changes after STN-DBS 24 3.3 Pre-op DAT availability predicts the clinical outcome 25 3.4 DBS has a neuroprotective effect 25 3.5 Limitations and future direction 26 3.6 Conclusion 26 4 References 27 5 Attachments 35 5.1 Index of Abbreviations 35 5.2 List of figures 36 5.3 Academic Contribution 37 5.4 Declaration of the independent writing of this thesis 39 5.5 Declaration of Submission 40 5.6 Curriculum Vitae 41 5.7 Acknowledgements 43

The aim of the research is to provide a computationally efficient neural network model for the study of deep brain stimulation efficacy in the treatment of Parkinson's disease. An Izhikevich neuron model was used to accomplish this task and four classes of neurons were modeled. The parameters of each class were estimated using a genetic algorithm with a fitness function based on spike frequency as a function of input current. After computing the optimal parameters the neurons were interconnected to form the network model. The estimated parameters were capable of replicating the normal firing characteristics for each type of neuron, but failed to replicate richer spiking characteristics such as post-inhibitory bursting and tonic firing. Without these characteristics, the network was unable to produce biologically feasible results. Findings indicate the Izhikevich model relies heavily on manual tuning and must be trained under an extensive set of conditions to allow for the majority of spiking characteristics to be learned. The use of the Izhikevich model in a network simulation will always be limited to the characteristics trained on a single neuron. When connected to the network the neuron may be exposed to a variety of unlearned conditions and therefore may not be capable of replicating biologically realistic behavior. / Electrical and Computer Engineering

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<p>  </p> <p>Disfluencies are a commonly reported speech symptom associated with Parkinson disease (PD), though the cause remains unknown. Studies have consistently reported that people with PD experience more disfluencies, particularly atypical disfluencies compared to healthy controls. One proposed theory, known as the dualistic model of dopamine levels and stuttering, posits that abnormally high or low levels of dopamine may cause an increase in disfluencies. The aim of the current study is to examine how levodopa medication and deep-brain stimulation affect fluency in people with PD. Twenty-seven participants with PD underwent testing before (on and off medicine) and six months after deep-brain stimulator implant surgery (optimally medicated, on and off stimulation). Participants read a passage aloud and provided a 2-minute monologue. Speech samples were transcribed. The number of typical and atypical disfluencies were identified auditorily and using a wide-band spectrogram. After surgery, most participants reduced their levodopa equivalency dose from pre-implant levels. Results demonstrated no significant differences in frequency of disfluencies across time (pre-surgery, post-surgery) or condition (on/off medication/stimulation). Overall, participants produced more typical than atypical disfluencies and more disfluencies in the monologue task than the reading task. Results do not support the dualistic model of dopamine, but instead support a more nuanced and individualized role for dopamine in speech fluency. For example, patterns within individual subjects suggest changes in dopamine may play a role in speech fluency for individual patients with PD. Data support the effect of cognition and language formulation in the production of disfluencies, particularly typical disfluencies.</p>

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