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.

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.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a resting tremor combined with varying degrees of rigidity and bradykinesia. Introduced in the 1950s, thalamotomy is used as a surgical procedure to improve brain function in patients and serves as an effective treatment method for the PD tremor where connections within the thalamus are cut. In 1987, deep brain stimulation (DBS), chronic electrical stimulation of deep neural structures using electrodes, was introduced as a clinical treatment for medically refractory tremor in patients with PD. Though thalamotomy has historically been the primary treatment method for PD, an increasing number of patients have chosen to undergo DBS as it has become increasingly touted as an alternative to ablative therapies. The proposed study examines the advantages and disadvantages of both treatment methods to improve cardinal features in highly-skilled, career-oriented PD patients who actively use motor functions in their work. As an alternative to a simple finger-tapping test used for normal PD patients, a more complex strength-dexterity (S-D) test would be performed on 50 skilled patients to evaluate and compare the effectiveness of tremor suppression between both surgeries. The goal of this experiment is to determine which treatment produces the most short-term benefits for the patient to continue with his or her career with minimal future management required. The results of this study will help determine the preferred treatment method when taking into consideration other external factors such as cost, continual management, and preference for short-term vs. long-term results.

Background: The birth of stereotactic functional neurosurgery in 1947 was to a great extent dependent on the development of ventriculography. The last decades have witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders. Initially, these procedures were largely based on the same imaging technique that had been used since the birth of this technique, and that is still used in some centers. The introduction of new imaging modalities such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) provided new potentials, but also new challenges for accurate identification and visualisation of the targets in the basal ganglia and the thalamus with an urge to thoroughly evaluate and optimize the stereotactic targeting technique, as well as evaluate accurately in stereotactic space the location and extent of stereotactic Radiofrequency (RF) lesions and the position of deep brain stimulation (DBS) electrodes. Aims: To study the differences between CT and MRI regarding indirect atlas coordinates in thalamic and pallidal procedures and to evaluate and validate visualisation of the pallidum and the subthalamic nucleus in view of direct targeting irrespective of atlas-derived coordinates. Furthermore, to evaluate the contribution of RF parameters on the size of stereotactic lesions, as well as the impact of size and location on clinical outcome. Method: The coordinates in relation to the landmarks of the 3rd ventricle of the targets in the pallidum and ventrolateral thalamus were compared between CT and MRI in 34 patients. In another 48 patients direct visualization  of the pallidum was evaluated and compared to indirect atlas based targeting. The possibility and versatility of visualizing the Subthalamic Nucleus (STN) on short acquisition MRI were evaluated in a multicentre study, and the use of alternative landmarks in identification of the STN was demonstrated in another study. In 46 patients CT and MRI were compared regarding the volume of the visible RF lesions. The volume was analysed with regard to coagulation parameters, and the location and size of the lesions were further evaluated concerning the clinical outcome. Results:Minor deviations were seen between MRI and  CT coordinates of brain targets. The rostro-caudal direction of these deviations were such that they would be easily accounted for during surgery, why MRI can obviate the need for CT in these procedures. MRI using a proton density sequence provided detailed images of the pallidal structures, which demonstrated considerable inter-individual variations in relation to the landmarks of the 3rd ventricle. By using a direct visualization of the target, each patient will act as his or her own atlas, avoiding the uncertainties of atlas-based targeting. The STN could be visualized on various brands of MRI machines in 8 centers in 6 countries with good discrimination and with a short acquisition time, allowing direct visual targeting. The same scanning technique could be used for postoperative localization of the implanted electrodes. In cases where the lateral and inferior borders of the STN cannot be easily distinguished on MRI the Sukeroku sign and the dent internal-capsule-sign signs might be useful. The volume of a stereotactic RF lesion could be as accurately assessed by CT as by MRI. The lesion´s size was most strongly influenced by the temperature used for coagulation. The lesions´ volumes were however rather scattered and difficult to predict in the individual patient based solely on the coagulation parameters. For thalamotomy, the results on tremor was not related to the lesion´s volume. For pallidotomy, larger and more posterior-ventral lesions had better effect on akinesia while effects on tremor and dyskinesias were not related to size or location of the lesions. Conclusions: The minor deviations of MRI from CT coordinates can be accounted for during surgery, why MRI can obviate the need of CT in these procedures. Direct visualized targeting on MRI of the pallidum is superior to atlas based targeting. The targets in the pallidum and the STN, as well as the location of the electrodes, can be well visualized with short acquisition MRI. When borders of the STN are poorly defined on MRI the Sukeroku sign and the dent internal-capsule-sign signs proved to be useful. The volumes of RF lesions can be accurately assessed by both stereotactic thin slice CT and MRI. The size of these lesions is most strongly influenced by the temperature of coagulation, but difficult to predict in the individual patient based on the coagulation parameters. Within certain limits, there were no clear relationships between lesions´ volume and location and clinical effects of thalamotomies and pallidotomies.

The Deep Brain Stimulation (DBS) is an invasive therapy that alleviates the symptoms of several neurological disorders by electrically stimulating specific regions of the brain, generally within the basal ganglia. Until now Medtronic DBS system is the only approved by the Food and Drug Administration, nevertheless European and Australian countries  have recently approved St. Jude DBS systems to treat Parkinson’s disease and related movement disorders.      Traditionally, voltage-controlled stimulation (the type of systems provided by Medtronic) has been used and clinicians are familiar with its settings; however the knowledge about systems based in current-controlled stimulation (St. Jude systems) is rather scarce. One of the key factors for a successful therapy is the optimal selection of the electrical parameters for stimulation. Due to the critical zone where the surgery is performed, modeling and simulations of DBS systems have been extensively used to observe how the electric field is distributed in the brain tissue and ultimately to help the clinicians to select the best parameters.      In this thesis two finite element models of the DBS systems mentioned above have been developed; five examinations were designed, based on the physical and electrical differences between the systems, to observe and quantitatively compare the electric field distribution.     The aim of this thesis was to investigate the differences between two representative models of each company but moreover to contribute with information regarding current-controlled stimulation. The results obtained are expected to be useful for further investigations where the magnitude and distribution of the electric field generated by this type of electrodes are needed.

The in-vivo observation of the neural activities generated by a large number of closely located neurons is believed to be crucial for understanding the nervous system. Moreover, the functional electrical stimulation of the central nervous system is an effective method to restore physiological functions such as limb control, sound sensation, and light perception. The Deep Brain Stimulation (DBS) is being successfully used in the treatment of tremor and rigidity associated with advanced Parkinson's disease. Cochlear implants have also been employed as an effective treatment for sensorineural deafness by means of delivering the electrical stimulation directly to the auditory nerve. The most significant contribution of this PhD study is the development of next-generation microprobes for the simultaneous stimulation and recording of the cortex and deep brain structures. For intracortical applications, millimetre length multisite microprobes that are rigid enough to penetrate into the cortex while integrated with flexible interconnection cables are demanded. In chronic applications, the flexibility of the cable minimizes the tissue damage caused by the relative micro-motion between the brain and the microprobe. Although hybrid approaches have been reported to construct such neural microprobes, these devices are brittle and may impose severe complications if they break inside the tissue. In this project, MEMS fabrication processes were employed to produce non-breakable intracortical microprobes with an improved structural design. These 32 channel devices are integrated with flexible interconnection cables and provide enough mechanical strength for penetration into the tissue. Polyimide-based flexible implants were successfully fabricated and locally reinforced at the tip with embedded 15 µm-thick gold micro-needles. In DBS applications, centimetre long microprobes capable of stimulating and recording the neural activity are required. The currently available DBS probes, manufactured by Medtronic, provide only four cylindrical shaped electrode sites, each 1.5 mm in height and 1.27 mm in diameter. Although suitable for the stimulation of a large brain volume, to measure the activity of a single neuron but to avoid measuring the average response of adjacent cells, recording sites with dimensions in the range of 10 - 20 µm are required. In this work, novel Three Dimensional (3D) multi channel microprobes were fabricated offering 32 independent stimulation and recording electrodes around the shaft of the implant. These microprobes can control the spatial distribution of the charge injected into the tissue to enhance the efficacy and minimize the adverse effects of the DBS treatment. Furthermore, the device volume has been reduced to one third the volume of a conventional Medtronic DBS lead to significantly decrease the tissue damage induced by implantation of the microprobe. For both DBS and intracortical microprobes, the impedance characteristics of the electrodes were studied in acidic and saline solutions. To reduce the channel impedance and enhance the signal to noise ratio, iridium (Ir) was electroplated on gold electrode sites. Stable electrical characteristics were demonstrated for the Ir and gold electrodes over the course of a prolonged pulse stress test for 100 million cycles. The functionality and application potential of the fabricated microprobes were confirmed by the in-vitro measurements of the neural activity in the mouse hippocampus. In order to reduce the number of channels and simplify the signal processing circuitry, multiport electrostatic-actuated switch matrices were successfully developed, fabricated, and characterized for possible integration with neural microprobes to construct a site selection matrix. Magnetic-actuated switches have been also investigated to improve the operation reliability of the MEMS switching devices.

Background In advanced Parkinson’s disease (PD) the motor symptoms can be treated with deep brain stimulation (DBS). Subthalamic nucleus (STN) has been the most common target and caudal zona incerta (cZi) is a more recent target for stimulation. Stimulation in both of these targets has proved to be positive for the motor symptoms but there is no consensus about how DBS affects the speech and the articulation. Aim The aim of this study was to investigate how fricatives are realized within patients suffering from PD treated with DBS in STN or cZi. Method 9 patients stimulated in STN and 10 patients stimulated in cZi were recorded reading a shorter text.  The recordings were made preoperatively (Pre) and 12 months after surgery with the stimulation switched off (sOff) and on (sOn). From the recordings the fricatives were extracted and assessed in a blinded and randomized procedure. Results For the patients stimulated in cZi the target fricative /s/ had significant lower correct realizations in the sOn condition compared to the other two conditions. The other target fricatives in cZi showed the same pattern as well. For the STN group no unequivocal pattern could be seen. Conclusions The results suggest that stimulation in cZi may affect the patients’ articulation of fricatives and thereby their extended articulatory movements more negative than stimulation in STN.

Abstract Objective Patients with Parkinson’s disease often have symptoms of dysphagia. These swallowingproblems have consequences for quality of life as well for the physical wellbeing of thepatients. AimThe aim of this study was to describe and correlate Swallowing Quality of Life (SWAL-QOL)scores, self-assessment of swallowing function using a visual analogue scale and the resultsfrom a fiber endoscopic evaluation of swallowing function in patients who had been selectedfor Deep Brain Stimulation in caudal zona incerta. A secondary aim was to correlate diseaseduration with results from SWAL-QOL and the fiber endoscopic evaluation of swallowingfunction. Method Ten male Parkinson’s patients (age 45-69 yrs, median 61.5 yrs) who were selected for DeepBrain Stimulation completing the Swallowing Quality of life form, as well as rating theirswallowing function using a visual analogue scale and undergoing a fiber endoscopicevaluation of their swallowing function.     Results The median total SWAL-QOL score was 94% while the mean was 91%. The median scorefrom the self-assessment was 85% while the mean was 93%. The total SWAL-QOL scorecorrelated with disease duration measured as years since diagnosis (r=-.72, p<.05). Diseaseduration measured as years with symptoms correlated with pre-swallow spillage (r>.63,p<.05).    Conclusions The results showed high levels of swallowing related quality of life for the studied group. Theself-assessment on the visual analogue scale and the fiber endoscopic evaluations alsorevealed that swallowing function was good in this sample. There were significantcorrelations between disease duration and some SWAL-QOL parameters as well as some ofthe outcomes from the fiber endoscopic evaluation.

Hippocampal neurogenesis continues throughout life in mammals. These adult-generated dentate granule cells (DGCs) are generally believed to contribute to hippocampal memory processing and are generated at varying rates in response to neuronal network activity. Deep brain stimulation (DBS) allows clinicians to influence brain activity for therapeutic purposes and raises the possibility of targeted modulation of adult hippocampal neurogenesis. It has recently been shown that DBS may ameliorate cognitive decline associated with Alzheimer’s disease (AD), and while underlying mechanisms are unknown, one possibility is activity-dependent regulation of hippocampal neurogenesis. To this end, whether or not adult-generated DGCs can assume functional roles of developmentally-generated neurons, and stimulation-induced enhanced neurogenesis can benefit memory function in the normal and diseased brain, warrant study. First, we examined separate cohorts of developmentally- and adult-generated DGCs in intact mice and demonstrated similar rates of activation during hippocampus-dependent spatial memory processing, suggesting functional equivalence. Second, we examined the neurogenic and cognitive effects of targeted entorhinal cortex (EC) stimulation in mice using parameters analogous to clinical high frequency DBS. Stimulation increased the generation of DGCs. Moreover, stimulation-induced neurons were functionally recruited by hippocampal spatial memory processing in a cell age-dependent fashion that is consistent with DGC maturation. Importantly, stimulation facilitated spatial memory in the same maturation-dependent manner, and not when stimulation-induced promotion of adult neurogenesis was blocked, suggesting a causal relationship. Finally, we are in the process of testing whether similar stimulation facilitates spatial memory in a transgenic (Tg) disease model of AD that exhibits amyloid neuropathology and cognitive impairment. Preliminary results suggest stimulation promotes neurogenesis and rescues impaired spatial memory in Tg animals. When considered in the context of promising clinical results, this body of work suggests stimulation-induced neurogenesis could provide a novel therapeutic modality in settings where functional hippocampal regenerative therapy is desirable.

Hippocampal neurogenesis continues throughout life in mammals. These adult-generated dentate granule cells (DGCs) are generally believed to contribute to hippocampal memory processing and are generated at varying rates in response to neuronal network activity. Deep brain stimulation (DBS) allows clinicians to influence brain activity for therapeutic purposes and raises the possibility of targeted modulation of adult hippocampal neurogenesis. It has recently been shown that DBS may ameliorate cognitive decline associated with Alzheimer’s disease (AD), and while underlying mechanisms are unknown, one possibility is activity-dependent regulation of hippocampal neurogenesis. To this end, whether or not adult-generated DGCs can assume functional roles of developmentally-generated neurons, and stimulation-induced enhanced neurogenesis can benefit memory function in the normal and diseased brain, warrant study. First, we examined separate cohorts of developmentally- and adult-generated DGCs in intact mice and demonstrated similar rates of activation during hippocampus-dependent spatial memory processing, suggesting functional equivalence. Second, we examined the neurogenic and cognitive effects of targeted entorhinal cortex (EC) stimulation in mice using parameters analogous to clinical high frequency DBS. Stimulation increased the generation of DGCs. Moreover, stimulation-induced neurons were functionally recruited by hippocampal spatial memory processing in a cell age-dependent fashion that is consistent with DGC maturation. Importantly, stimulation facilitated spatial memory in the same maturation-dependent manner, and not when stimulation-induced promotion of adult neurogenesis was blocked, suggesting a causal relationship. Finally, we are in the process of testing whether similar stimulation facilitates spatial memory in a transgenic (Tg) disease model of AD that exhibits amyloid neuropathology and cognitive impairment. Preliminary results suggest stimulation promotes neurogenesis and rescues impaired spatial memory in Tg animals. When considered in the context of promising clinical results, this body of work suggests stimulation-induced neurogenesis could provide a novel therapeutic modality in settings where functional hippocampal regenerative therapy is desirable.